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Osimertinib bests PFS achieved with standard care for EGFR-mutated NSCLC
MADRID – The EGFR inhibitor osimertinib (Tagrisso) is being hailed as a new standard of care for first-line therapy of advanced, treatment naïve non-small cell lung cancer (NSCLC) with mutations in the epidermal growth factor receptor (EGFR).
Osimertinib cut the risk of disease progression in these patients by 54% compared gefitinib (Iressa) or erlotinib (Tarceva).
Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osemirtinib, the median progression-free survival (PFS) was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translates into a hazard ratio (HR) of 0.46 (P less than .0001).
“We wanted to see if by shutting down a major escape pathway by giving osemirtinib upfront, whether we would be able to improve patient outcomes,” he said at a briefing at the European Society of Medical Oncology (ESMO) Congress.
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) selective for EGFR mutations, including the T790M resistance mutation. It is currently approved in the US for the treatment of patients with EGFR T790M mutation-positive NSCLC whose disease has progressed on or after EGFR TKI therapy.
In the FLAURA trial (NCT02296125) investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).
Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.
The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.
Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.
PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR 0.47, P = .0009 for patients with CNS metastases, HR 0.46, P less than .0001 for patients with no CNS metastases).
For this interim analysis, with OS data at only 25% maturity, median OS had not been reached in either trial arm. The HR for OS with osimertinib was 0.63, with a P value of .0068, but this was not statistically significant, as the statistical method used required a P of less than .0015 for significance, Dr. Ramalingam explained.
The safety profile of osimertinib was comparable to that of the standard of care, with lower rates of grade 3 or greater adverse events, and a lower discontinuation rate, than with either gefitinib or erlotinib.
Enriqueta Felip, MD, the invited commentator at the briefing, said that “based on these results, osimertinib should be considered a new first-line treatment option for patients with EGFR mutations.”
Tony Mok, MD, from the Chinese University of Hong Kong, the invited discussant at the presidential symposium where Dr. Ramalingam presented the study, commented that “there is little doubt that FLAURA is a positive study demonstrating superiority in PFS with first-line osimertinib.”
He questioned, however whether all patients with EGFR mutation-positve NSCLC should receive osimertinib up front.
“I have confidence that patients with CNS metastases at presentation would benefit the most considering osimertinib’s higher CNS penetration, but the optimal sequence for overall survival benefit is controversial,” he said.
Dr. Mok said that he was reserving judgment about elevating osimertinib to standard-of-care status until there were more answers about the final number of patients who are able to crossover to osimertinib, and about the “mechanism and management of osimertinib resistance upon disease progression.”
The study was funded by AstraZeneca, the maker of osimertinib. Dr Ramalingam is on the advisory boards of AstraZeneca and other companies. Dr Mok disclosed honoraria, fees, and research funding from Astra-Zeneca. Dr. Felip disclosed financial relationships with multiple companies not including AstraZeneca.
MADRID – The EGFR inhibitor osimertinib (Tagrisso) is being hailed as a new standard of care for first-line therapy of advanced, treatment naïve non-small cell lung cancer (NSCLC) with mutations in the epidermal growth factor receptor (EGFR).
Osimertinib cut the risk of disease progression in these patients by 54% compared gefitinib (Iressa) or erlotinib (Tarceva).
Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osemirtinib, the median progression-free survival (PFS) was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translates into a hazard ratio (HR) of 0.46 (P less than .0001).
“We wanted to see if by shutting down a major escape pathway by giving osemirtinib upfront, whether we would be able to improve patient outcomes,” he said at a briefing at the European Society of Medical Oncology (ESMO) Congress.
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) selective for EGFR mutations, including the T790M resistance mutation. It is currently approved in the US for the treatment of patients with EGFR T790M mutation-positive NSCLC whose disease has progressed on or after EGFR TKI therapy.
In the FLAURA trial (NCT02296125) investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).
Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.
The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.
Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.
PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR 0.47, P = .0009 for patients with CNS metastases, HR 0.46, P less than .0001 for patients with no CNS metastases).
For this interim analysis, with OS data at only 25% maturity, median OS had not been reached in either trial arm. The HR for OS with osimertinib was 0.63, with a P value of .0068, but this was not statistically significant, as the statistical method used required a P of less than .0015 for significance, Dr. Ramalingam explained.
The safety profile of osimertinib was comparable to that of the standard of care, with lower rates of grade 3 or greater adverse events, and a lower discontinuation rate, than with either gefitinib or erlotinib.
Enriqueta Felip, MD, the invited commentator at the briefing, said that “based on these results, osimertinib should be considered a new first-line treatment option for patients with EGFR mutations.”
Tony Mok, MD, from the Chinese University of Hong Kong, the invited discussant at the presidential symposium where Dr. Ramalingam presented the study, commented that “there is little doubt that FLAURA is a positive study demonstrating superiority in PFS with first-line osimertinib.”
He questioned, however whether all patients with EGFR mutation-positve NSCLC should receive osimertinib up front.
“I have confidence that patients with CNS metastases at presentation would benefit the most considering osimertinib’s higher CNS penetration, but the optimal sequence for overall survival benefit is controversial,” he said.
Dr. Mok said that he was reserving judgment about elevating osimertinib to standard-of-care status until there were more answers about the final number of patients who are able to crossover to osimertinib, and about the “mechanism and management of osimertinib resistance upon disease progression.”
The study was funded by AstraZeneca, the maker of osimertinib. Dr Ramalingam is on the advisory boards of AstraZeneca and other companies. Dr Mok disclosed honoraria, fees, and research funding from Astra-Zeneca. Dr. Felip disclosed financial relationships with multiple companies not including AstraZeneca.
MADRID – The EGFR inhibitor osimertinib (Tagrisso) is being hailed as a new standard of care for first-line therapy of advanced, treatment naïve non-small cell lung cancer (NSCLC) with mutations in the epidermal growth factor receptor (EGFR).
Osimertinib cut the risk of disease progression in these patients by 54% compared gefitinib (Iressa) or erlotinib (Tarceva).
Among 279 patients with EGFR-mutated locally advanced or metastatic NSCLC treated with osemirtinib, the median progression-free survival (PFS) was 18.9 months, compared with 10.2 months for 277 patients treated with the standard of care, which translates into a hazard ratio (HR) of 0.46 (P less than .0001).
“We wanted to see if by shutting down a major escape pathway by giving osemirtinib upfront, whether we would be able to improve patient outcomes,” he said at a briefing at the European Society of Medical Oncology (ESMO) Congress.
Osimertinib is a third-generation EGFR tyrosine kinase inhibitor (TKI) selective for EGFR mutations, including the T790M resistance mutation. It is currently approved in the US for the treatment of patients with EGFR T790M mutation-positive NSCLC whose disease has progressed on or after EGFR TKI therapy.
In the FLAURA trial (NCT02296125) investigators stratified patients with previously untreated NSCLC positive for EGFR resistance mutations according to mutation status (exon 19 deletion or the L858R amino acid substitution in exon 21) and race (Asian or non-Asian).
Patients were randomly assigned to treatment with either oral osimertinib 80 mg daily or an EGFR TKI, either oral gefitinib 250 mg or erlotinib 150 mg daily.
The patients were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 6 weeks until objective disease progression.
Patients assigned to the standard-of-care arm who had central confirmation of progression and T790M positivity were allowed to cross over to open-label osimertinib.
PFS, the primary endpoint, was also significantly better with osimertinib than with either of the comparator TKIs in patients with and without central nervous system metastases at study entry (HR 0.47, P = .0009 for patients with CNS metastases, HR 0.46, P less than .0001 for patients with no CNS metastases).
For this interim analysis, with OS data at only 25% maturity, median OS had not been reached in either trial arm. The HR for OS with osimertinib was 0.63, with a P value of .0068, but this was not statistically significant, as the statistical method used required a P of less than .0015 for significance, Dr. Ramalingam explained.
The safety profile of osimertinib was comparable to that of the standard of care, with lower rates of grade 3 or greater adverse events, and a lower discontinuation rate, than with either gefitinib or erlotinib.
Enriqueta Felip, MD, the invited commentator at the briefing, said that “based on these results, osimertinib should be considered a new first-line treatment option for patients with EGFR mutations.”
Tony Mok, MD, from the Chinese University of Hong Kong, the invited discussant at the presidential symposium where Dr. Ramalingam presented the study, commented that “there is little doubt that FLAURA is a positive study demonstrating superiority in PFS with first-line osimertinib.”
He questioned, however whether all patients with EGFR mutation-positve NSCLC should receive osimertinib up front.
“I have confidence that patients with CNS metastases at presentation would benefit the most considering osimertinib’s higher CNS penetration, but the optimal sequence for overall survival benefit is controversial,” he said.
Dr. Mok said that he was reserving judgment about elevating osimertinib to standard-of-care status until there were more answers about the final number of patients who are able to crossover to osimertinib, and about the “mechanism and management of osimertinib resistance upon disease progression.”
The study was funded by AstraZeneca, the maker of osimertinib. Dr Ramalingam is on the advisory boards of AstraZeneca and other companies. Dr Mok disclosed honoraria, fees, and research funding from Astra-Zeneca. Dr. Felip disclosed financial relationships with multiple companies not including AstraZeneca.
AT ESMO 2017
Key clinical point:
Major finding: The median PFS with osimertinib was 18.9 months, compared with 10.2 months for the standard of care (gefitinib or erlotinib).
Data source: Randomized double-blind study of 556 patients with EGFR-mutated NSCLC.
Disclosures: The study was funded by AstraZeneca. Dr Ramalingam is on the advisory boards of AstraZeneca and other companies. Dr Mok disclosed honoraria, fees, and research funding from Astra-Zeneca. Dr. Felip disclosed financial relationships with multiple companies not including AstraZeneca.
PACIFIC: Durvalumab extends PFS in stage 3 NSCLC
MADRID – For patients with locally advanced, unresectable non-small cell lung cancer, consolidation therapy with the anti-programmed death ligand 1 (PD-L1) inhibitor durvalumab after chemoradiation was associated with significantly better progression-free survival (PFS) than placebo, results of an interim analysis of the phase 3 PACIFIC trial showed.
Among 713 patients with stage III NSCLC treated with definitive chemoradiotherapy, the median PFS from randomization was 16.8 months for patients assigned to durvalumab compared with 5.6 months for patients assigned to placebo, reported Luis Paz-Ares, MD, from the University of Madrid, Spain.
“Overall, we think durvalumab is a promising option for patients with stage III non-small cell lung cancer treated with chemoradiation,” he said at a briefing at the European Society of Medical Oncology (ESMO) Congress.
Approximately 25% to 30% of patients with NSCLC have locally advanced disease at the time of presentation. Patients with unresectable disease and good performance status are treated with chemoradiotheraoy consisting of a platinum doublet with concurrent radiation, but median PFS in these patients is generally short, on the order of 8 months. The 5-year overall survival (OS) rate is 15%, he said.
Given the lack of major advances in the care of patients with stage 3 disease, investigators have been looking to newer therapies such as immune checkpoint inhibitors to see whether they could improve outcomes.
PACIFIC is a phase 3 trial in which patients with stage III NSCLC who did not have disease progression after a minimum of two cycles of platinum-based chemotherapy were assigned on a 2:1 basis to receive intravenous durvalumab 10 mg/kg or placebo every 2 weeks for up to 12 months. Patients were stratified by age, sex, and smoking history.
Dr. Paz-Ares presented PFS results from the interim analysis, planned when about 367 events had occurred. Data on the co-primary endpoint of OS were not mature at the time of the data cutoff.
Median PFS from randomization according to blinded independent central review for 476 patients treated with durvalumab was 16.8 months, compared with 5.6 months for 237 patients who received the placebo. This translated into a stratified hazard ratio (HR) of 0.52 (P less than .0001).
The respective PFS rates for durvalumab and placebo, were 59.9% vs. 35.3% at 12 months, and 44.2% vs. 27% at 18 months.
Among 443 patients on durvalumab and 213 on placebo who were evaluable for objective responses (OR), the respective OR rates were 28.4% vs. 16.
There were 6 complete responses (CR), 120 partial responses (PR), and 233 cases of stable disease in the durvalumab arm, compared with one CR, 33 PR, and 119 cases of stable disease in the placebo arm. In the durvalumab arm, 73 patients (16.5%) had progressive disease, compared with 59 patients (27.7%) in the placebo arm.
The median duration of response was not reached in the durvalumab arm, compared with 13.8 months in the placebo arm.
The PD-L1 inhibitor was also associated with a lower incidence of any new lesion among the intention-to-treat population (20.4% vs. 32.1%).
Grade 3 or 4 toxicities from any cause were slightly higher with durvalumab, at 29.9% vs. 26.1%. Events leading to discontinuation were also higher with the active drug, at 15.4% vs. 9.8% for placebo.
There were 21 deaths (4.4%) of patients treated with durvalumab, and 13 deaths (5.6%) of patients treated with placebo.
“In my opinion, this is a very well-designed study, and the results are very promising,” commented Enriqueta Felip, MD, who was not involved in the PACIFIC trial.
“We need to wait for the overall survival results, but in my opinion this is a very valuable trial in a group of patients [for whom] we need new strategies,” she said.
Dr. Felip was invited to the briefing as an independent commentator.
Results of the interim analysis of the PACIFIC trial were also published online in the New England Journal of Medicine.
The PACIFIC trial was funded by AstraZeneca. Dr. Paz-Ares has received consultancy fees from the company. Dr. Felip disclosed financial relationships with multiple companies not including AstraZeneca.
MADRID – For patients with locally advanced, unresectable non-small cell lung cancer, consolidation therapy with the anti-programmed death ligand 1 (PD-L1) inhibitor durvalumab after chemoradiation was associated with significantly better progression-free survival (PFS) than placebo, results of an interim analysis of the phase 3 PACIFIC trial showed.
Among 713 patients with stage III NSCLC treated with definitive chemoradiotherapy, the median PFS from randomization was 16.8 months for patients assigned to durvalumab compared with 5.6 months for patients assigned to placebo, reported Luis Paz-Ares, MD, from the University of Madrid, Spain.
“Overall, we think durvalumab is a promising option for patients with stage III non-small cell lung cancer treated with chemoradiation,” he said at a briefing at the European Society of Medical Oncology (ESMO) Congress.
Approximately 25% to 30% of patients with NSCLC have locally advanced disease at the time of presentation. Patients with unresectable disease and good performance status are treated with chemoradiotheraoy consisting of a platinum doublet with concurrent radiation, but median PFS in these patients is generally short, on the order of 8 months. The 5-year overall survival (OS) rate is 15%, he said.
Given the lack of major advances in the care of patients with stage 3 disease, investigators have been looking to newer therapies such as immune checkpoint inhibitors to see whether they could improve outcomes.
PACIFIC is a phase 3 trial in which patients with stage III NSCLC who did not have disease progression after a minimum of two cycles of platinum-based chemotherapy were assigned on a 2:1 basis to receive intravenous durvalumab 10 mg/kg or placebo every 2 weeks for up to 12 months. Patients were stratified by age, sex, and smoking history.
Dr. Paz-Ares presented PFS results from the interim analysis, planned when about 367 events had occurred. Data on the co-primary endpoint of OS were not mature at the time of the data cutoff.
Median PFS from randomization according to blinded independent central review for 476 patients treated with durvalumab was 16.8 months, compared with 5.6 months for 237 patients who received the placebo. This translated into a stratified hazard ratio (HR) of 0.52 (P less than .0001).
The respective PFS rates for durvalumab and placebo, were 59.9% vs. 35.3% at 12 months, and 44.2% vs. 27% at 18 months.
Among 443 patients on durvalumab and 213 on placebo who were evaluable for objective responses (OR), the respective OR rates were 28.4% vs. 16.
There were 6 complete responses (CR), 120 partial responses (PR), and 233 cases of stable disease in the durvalumab arm, compared with one CR, 33 PR, and 119 cases of stable disease in the placebo arm. In the durvalumab arm, 73 patients (16.5%) had progressive disease, compared with 59 patients (27.7%) in the placebo arm.
The median duration of response was not reached in the durvalumab arm, compared with 13.8 months in the placebo arm.
The PD-L1 inhibitor was also associated with a lower incidence of any new lesion among the intention-to-treat population (20.4% vs. 32.1%).
Grade 3 or 4 toxicities from any cause were slightly higher with durvalumab, at 29.9% vs. 26.1%. Events leading to discontinuation were also higher with the active drug, at 15.4% vs. 9.8% for placebo.
There were 21 deaths (4.4%) of patients treated with durvalumab, and 13 deaths (5.6%) of patients treated with placebo.
“In my opinion, this is a very well-designed study, and the results are very promising,” commented Enriqueta Felip, MD, who was not involved in the PACIFIC trial.
“We need to wait for the overall survival results, but in my opinion this is a very valuable trial in a group of patients [for whom] we need new strategies,” she said.
Dr. Felip was invited to the briefing as an independent commentator.
Results of the interim analysis of the PACIFIC trial were also published online in the New England Journal of Medicine.
The PACIFIC trial was funded by AstraZeneca. Dr. Paz-Ares has received consultancy fees from the company. Dr. Felip disclosed financial relationships with multiple companies not including AstraZeneca.
MADRID – For patients with locally advanced, unresectable non-small cell lung cancer, consolidation therapy with the anti-programmed death ligand 1 (PD-L1) inhibitor durvalumab after chemoradiation was associated with significantly better progression-free survival (PFS) than placebo, results of an interim analysis of the phase 3 PACIFIC trial showed.
Among 713 patients with stage III NSCLC treated with definitive chemoradiotherapy, the median PFS from randomization was 16.8 months for patients assigned to durvalumab compared with 5.6 months for patients assigned to placebo, reported Luis Paz-Ares, MD, from the University of Madrid, Spain.
“Overall, we think durvalumab is a promising option for patients with stage III non-small cell lung cancer treated with chemoradiation,” he said at a briefing at the European Society of Medical Oncology (ESMO) Congress.
Approximately 25% to 30% of patients with NSCLC have locally advanced disease at the time of presentation. Patients with unresectable disease and good performance status are treated with chemoradiotheraoy consisting of a platinum doublet with concurrent radiation, but median PFS in these patients is generally short, on the order of 8 months. The 5-year overall survival (OS) rate is 15%, he said.
Given the lack of major advances in the care of patients with stage 3 disease, investigators have been looking to newer therapies such as immune checkpoint inhibitors to see whether they could improve outcomes.
PACIFIC is a phase 3 trial in which patients with stage III NSCLC who did not have disease progression after a minimum of two cycles of platinum-based chemotherapy were assigned on a 2:1 basis to receive intravenous durvalumab 10 mg/kg or placebo every 2 weeks for up to 12 months. Patients were stratified by age, sex, and smoking history.
Dr. Paz-Ares presented PFS results from the interim analysis, planned when about 367 events had occurred. Data on the co-primary endpoint of OS were not mature at the time of the data cutoff.
Median PFS from randomization according to blinded independent central review for 476 patients treated with durvalumab was 16.8 months, compared with 5.6 months for 237 patients who received the placebo. This translated into a stratified hazard ratio (HR) of 0.52 (P less than .0001).
The respective PFS rates for durvalumab and placebo, were 59.9% vs. 35.3% at 12 months, and 44.2% vs. 27% at 18 months.
Among 443 patients on durvalumab and 213 on placebo who were evaluable for objective responses (OR), the respective OR rates were 28.4% vs. 16.
There were 6 complete responses (CR), 120 partial responses (PR), and 233 cases of stable disease in the durvalumab arm, compared with one CR, 33 PR, and 119 cases of stable disease in the placebo arm. In the durvalumab arm, 73 patients (16.5%) had progressive disease, compared with 59 patients (27.7%) in the placebo arm.
The median duration of response was not reached in the durvalumab arm, compared with 13.8 months in the placebo arm.
The PD-L1 inhibitor was also associated with a lower incidence of any new lesion among the intention-to-treat population (20.4% vs. 32.1%).
Grade 3 or 4 toxicities from any cause were slightly higher with durvalumab, at 29.9% vs. 26.1%. Events leading to discontinuation were also higher with the active drug, at 15.4% vs. 9.8% for placebo.
There were 21 deaths (4.4%) of patients treated with durvalumab, and 13 deaths (5.6%) of patients treated with placebo.
“In my opinion, this is a very well-designed study, and the results are very promising,” commented Enriqueta Felip, MD, who was not involved in the PACIFIC trial.
“We need to wait for the overall survival results, but in my opinion this is a very valuable trial in a group of patients [for whom] we need new strategies,” she said.
Dr. Felip was invited to the briefing as an independent commentator.
Results of the interim analysis of the PACIFIC trial were also published online in the New England Journal of Medicine.
The PACIFIC trial was funded by AstraZeneca. Dr. Paz-Ares has received consultancy fees from the company. Dr. Felip disclosed financial relationships with multiple companies not including AstraZeneca.
AT ESMO 2017
Off-the-shelf T cells used to treat viral infections after HSCT
One-size-fits-all T cells designed to recognize and mount an immune response against five common viral pathogens may help to reduce the incidence of severe viral infections and treatment-related deaths in patients who have undergone hematopoietic stem cell transplants (HSCT), investigators reported.
Among 37 evaluable patients who had undergone an allogeneic HSCT, a single infusion of banked virus-specific T cells (VSTs) directed against adenovirus, BK virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6) was associated with a 92% cumulative complete or partial response rate, reported Ifigeneia Tzannou, MD, and her colleagues from Baylor College of Medicine in Houston.
“Although a randomized trial will be required to definitively assess the value of banked VSTs, this study strongly suggests that off-the-shelf, multiple-virus–directed VSTs are a safe and effective broad-spectrum approach to treat severe viral infections after HSCT. These VSTs can be rapidly and cost effectively produced in scalable quantities with excellent long-term stability, which facilitates the broad implementation of this therapy,” they wrote in the Journal of Clinical Oncology (2017 Aug 7. doi: 10.1200/JCO.2017.73.0655).
Although adoptive transfer of VSTs derived from donor stem cells has been shown to protect patients against viral pathogens, the technique is hampered by costs, complexity, the time-consuming manufacturing process, and the need for seropositive donors, Dr. Tzannou and her colleagues pointed out.
“One way to overcome these limitations and to supply antiviral protection to recipients of allogeneic HSCT would be to prepare and cryopreserve banks of VST lines from healthy seropositive donors, which would be available for immediate use as an off-the-shelf product,” they wrote.
They tested this concept in a phase 2 clinical trial in 38 patients with a total of 45 infections.
A single infusion was associated with cumulative complete and partial responses rates of 71% in 7 patients with adenoviral infections, 100% in 16 patients with BK virus infections, 94% in 17 patients with CMV infections, 100% for 2 patients with EBV infections, and 67% for 3 patients with HHV-6 infections.
Seven of the 38 patients received VSTs for two viral infections, and all patients had viral control after a single infusion. All cases of CMV, adenovirus, and EBV infections were cleared from serum. One patient with HHV-6 encephalitis had complete resolution of encephalitis after one infusion and resolution of hemorrhagic cystitis after a second infusion; 14 patients with BK virus–associated hemorrhagic cystitis had clinical improvement or resolution of disease.
The infusions were delivered safely. After infusion, one patient developed recurrent grade 3 gastrointestinal graft versus host disease (GVHD) after a rapid corticosteroid taper, three patients had recurrent grade 1 or 2 skin GVHD, and two patients had de novo skin GVHD. Of the five cases of skin GVHD, four resolved with the administration of topical treatments and one with the reinstitution of corticosteroids after a taper.
“More widespread and earlier use of this modality could minimize both drug-related and virus-associated complications and thereby decrease treatment-related mortality in recipients of allogeneic HSCT,” the investigators wrote.
The study was supported by the National Heart, Lung, and Blood Institute; Conquer Cancer Foundation; and Dan L. Duncan Comprehensive Cancer Center. Dr. Tzannou disclosed having a consulting or advisory role with ViraCyte, and several coauthors reported financial ties with various companies.
One-size-fits-all T cells designed to recognize and mount an immune response against five common viral pathogens may help to reduce the incidence of severe viral infections and treatment-related deaths in patients who have undergone hematopoietic stem cell transplants (HSCT), investigators reported.
Among 37 evaluable patients who had undergone an allogeneic HSCT, a single infusion of banked virus-specific T cells (VSTs) directed against adenovirus, BK virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6) was associated with a 92% cumulative complete or partial response rate, reported Ifigeneia Tzannou, MD, and her colleagues from Baylor College of Medicine in Houston.
“Although a randomized trial will be required to definitively assess the value of banked VSTs, this study strongly suggests that off-the-shelf, multiple-virus–directed VSTs are a safe and effective broad-spectrum approach to treat severe viral infections after HSCT. These VSTs can be rapidly and cost effectively produced in scalable quantities with excellent long-term stability, which facilitates the broad implementation of this therapy,” they wrote in the Journal of Clinical Oncology (2017 Aug 7. doi: 10.1200/JCO.2017.73.0655).
Although adoptive transfer of VSTs derived from donor stem cells has been shown to protect patients against viral pathogens, the technique is hampered by costs, complexity, the time-consuming manufacturing process, and the need for seropositive donors, Dr. Tzannou and her colleagues pointed out.
“One way to overcome these limitations and to supply antiviral protection to recipients of allogeneic HSCT would be to prepare and cryopreserve banks of VST lines from healthy seropositive donors, which would be available for immediate use as an off-the-shelf product,” they wrote.
They tested this concept in a phase 2 clinical trial in 38 patients with a total of 45 infections.
A single infusion was associated with cumulative complete and partial responses rates of 71% in 7 patients with adenoviral infections, 100% in 16 patients with BK virus infections, 94% in 17 patients with CMV infections, 100% for 2 patients with EBV infections, and 67% for 3 patients with HHV-6 infections.
Seven of the 38 patients received VSTs for two viral infections, and all patients had viral control after a single infusion. All cases of CMV, adenovirus, and EBV infections were cleared from serum. One patient with HHV-6 encephalitis had complete resolution of encephalitis after one infusion and resolution of hemorrhagic cystitis after a second infusion; 14 patients with BK virus–associated hemorrhagic cystitis had clinical improvement or resolution of disease.
The infusions were delivered safely. After infusion, one patient developed recurrent grade 3 gastrointestinal graft versus host disease (GVHD) after a rapid corticosteroid taper, three patients had recurrent grade 1 or 2 skin GVHD, and two patients had de novo skin GVHD. Of the five cases of skin GVHD, four resolved with the administration of topical treatments and one with the reinstitution of corticosteroids after a taper.
“More widespread and earlier use of this modality could minimize both drug-related and virus-associated complications and thereby decrease treatment-related mortality in recipients of allogeneic HSCT,” the investigators wrote.
The study was supported by the National Heart, Lung, and Blood Institute; Conquer Cancer Foundation; and Dan L. Duncan Comprehensive Cancer Center. Dr. Tzannou disclosed having a consulting or advisory role with ViraCyte, and several coauthors reported financial ties with various companies.
One-size-fits-all T cells designed to recognize and mount an immune response against five common viral pathogens may help to reduce the incidence of severe viral infections and treatment-related deaths in patients who have undergone hematopoietic stem cell transplants (HSCT), investigators reported.
Among 37 evaluable patients who had undergone an allogeneic HSCT, a single infusion of banked virus-specific T cells (VSTs) directed against adenovirus, BK virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and human herpesvirus 6 (HHV-6) was associated with a 92% cumulative complete or partial response rate, reported Ifigeneia Tzannou, MD, and her colleagues from Baylor College of Medicine in Houston.
“Although a randomized trial will be required to definitively assess the value of banked VSTs, this study strongly suggests that off-the-shelf, multiple-virus–directed VSTs are a safe and effective broad-spectrum approach to treat severe viral infections after HSCT. These VSTs can be rapidly and cost effectively produced in scalable quantities with excellent long-term stability, which facilitates the broad implementation of this therapy,” they wrote in the Journal of Clinical Oncology (2017 Aug 7. doi: 10.1200/JCO.2017.73.0655).
Although adoptive transfer of VSTs derived from donor stem cells has been shown to protect patients against viral pathogens, the technique is hampered by costs, complexity, the time-consuming manufacturing process, and the need for seropositive donors, Dr. Tzannou and her colleagues pointed out.
“One way to overcome these limitations and to supply antiviral protection to recipients of allogeneic HSCT would be to prepare and cryopreserve banks of VST lines from healthy seropositive donors, which would be available for immediate use as an off-the-shelf product,” they wrote.
They tested this concept in a phase 2 clinical trial in 38 patients with a total of 45 infections.
A single infusion was associated with cumulative complete and partial responses rates of 71% in 7 patients with adenoviral infections, 100% in 16 patients with BK virus infections, 94% in 17 patients with CMV infections, 100% for 2 patients with EBV infections, and 67% for 3 patients with HHV-6 infections.
Seven of the 38 patients received VSTs for two viral infections, and all patients had viral control after a single infusion. All cases of CMV, adenovirus, and EBV infections were cleared from serum. One patient with HHV-6 encephalitis had complete resolution of encephalitis after one infusion and resolution of hemorrhagic cystitis after a second infusion; 14 patients with BK virus–associated hemorrhagic cystitis had clinical improvement or resolution of disease.
The infusions were delivered safely. After infusion, one patient developed recurrent grade 3 gastrointestinal graft versus host disease (GVHD) after a rapid corticosteroid taper, three patients had recurrent grade 1 or 2 skin GVHD, and two patients had de novo skin GVHD. Of the five cases of skin GVHD, four resolved with the administration of topical treatments and one with the reinstitution of corticosteroids after a taper.
“More widespread and earlier use of this modality could minimize both drug-related and virus-associated complications and thereby decrease treatment-related mortality in recipients of allogeneic HSCT,” the investigators wrote.
The study was supported by the National Heart, Lung, and Blood Institute; Conquer Cancer Foundation; and Dan L. Duncan Comprehensive Cancer Center. Dr. Tzannou disclosed having a consulting or advisory role with ViraCyte, and several coauthors reported financial ties with various companies.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: Off-the-shelf virus-specific T-cell preparations can effectively treat infections following HSCT.
Major finding: Banked T cells directed against five common viruses were associated with a 92% cumulative partial or complete response rate.
Data source: Phase 2 clinical trial in 38 patients with viral infections following HSCT.
Disclosures: The study was supported by the National Heart, Lung, and Blood Institute; Conquer Cancer Foundation; and Dan L. Duncan Comprehensive Cancer Center. Dr. Tzannou disclosed having a consulting or advisory role with ViraCyte, and several coauthors reported financial ties with various companies.
Vitamin D level linked to post-alloSCT relapse risk in myeloma
Patients with myeloid malignancies who have vitamin D deficiency prior to an allogeneic stem cell transplant (alloSCT) are significantly more likely to experience a relapse and have worse overall survival after transplant than patients with adequate vitamin D levels at baseline, investigators have found.
Among 492 patients with lymphoid or myeloid malignancies who had an alloSCT at a single center, those with vitamin D deficiency had a risk of post-transplant relapse that was nearly double the risk of patients with sufficient vitamin D levels. Also, this relapse risk contributed to significantly worse overall survival for the vitamin D–deficient patients, reported Thomas Luft, MD, PhD, and his colleagues from the University of Heidelberg, Germany.
In multivariate analysis, the risk for relapse was limited to patients with myeloid rather than lymphatic disease, they reported in the Journal of Clinical Oncology.
“[O]ur study suggests that VitD deficiency might affect disease control after alloSCT, in particular, in patients allografted for myeloid malignancies. However, the question of whether improving VitD status before alloSCT has an impact on outcome can only be answered by clinical trial,” they wrote.
To see whether pre-transplant vitamin D deficiency – serum levels of 25-hydroxyvitamin D3 less than 20 ng/mL – might have prognostic significance, the investigators looked at a training cohort of 492 patients who underwent alloSCT at their center from 2002 through 2013, and a validation cohort consisting of 398 additional patients with myeloid malignancies treated at the University of Essen, Germany.
Overall survival for the 396 patients (80%) in the training cohort with vitamin D deficiency was significantly worse than for patients with adequate levels (hazard ratio, 1.78; P = .007) in a multivariate analysis adjusted for type of malignancy, disease stage, conditioning intensity, patient age, donor type, and recipient/donor sex match.
Analysis also showed that the excess hazard was accounted for by higher risk of relapse than nonrelapse mortality (HR, 1.96; P = .006).
When the investigators looked at relapse risk by disease type, they found a significantly higher risk among vitamin D–deficient patients with myeloid malignancies (HR, 2.55; P = .014) but not with lymphoid malignancies.
The risk for relapse among patients with myeloid malignancies in the validation cohort was similarly high (HR, 2.60; P = .017).
“The growth inhibitory, pro-differentiation, and pro-apoptotic effects of VitD in vitro are well recognized, and low VitD levels have been shown to enhance clonal proliferation of leukemic cells. Therefore, with regard to treatment before alloSCT but also to conditioning, one might speculate that VitD deficiency facilitates resistance to chemotherapy,” the researchers wrote.
Low vitamin D levels have been associated in other studies with shorter relapse-free and overall survival in patients with acute myeloid leukemia apart from alloSCT.
The researchers recommend clinical trials to explore the possibility that vitamin D supplementation pre-transplant could improve post-transplant outcomes.
The study was supported by a grant from the BLUT Foundation and the European Union’s Seventh Framework Program. Dr. Luft disclosed consulting with Alexion and Jazz Pharmaceuticals, and institutional research funding and travel support from Medac, Neovii, and Jazz.
Patients with myeloid malignancies who have vitamin D deficiency prior to an allogeneic stem cell transplant (alloSCT) are significantly more likely to experience a relapse and have worse overall survival after transplant than patients with adequate vitamin D levels at baseline, investigators have found.
Among 492 patients with lymphoid or myeloid malignancies who had an alloSCT at a single center, those with vitamin D deficiency had a risk of post-transplant relapse that was nearly double the risk of patients with sufficient vitamin D levels. Also, this relapse risk contributed to significantly worse overall survival for the vitamin D–deficient patients, reported Thomas Luft, MD, PhD, and his colleagues from the University of Heidelberg, Germany.
In multivariate analysis, the risk for relapse was limited to patients with myeloid rather than lymphatic disease, they reported in the Journal of Clinical Oncology.
“[O]ur study suggests that VitD deficiency might affect disease control after alloSCT, in particular, in patients allografted for myeloid malignancies. However, the question of whether improving VitD status before alloSCT has an impact on outcome can only be answered by clinical trial,” they wrote.
To see whether pre-transplant vitamin D deficiency – serum levels of 25-hydroxyvitamin D3 less than 20 ng/mL – might have prognostic significance, the investigators looked at a training cohort of 492 patients who underwent alloSCT at their center from 2002 through 2013, and a validation cohort consisting of 398 additional patients with myeloid malignancies treated at the University of Essen, Germany.
Overall survival for the 396 patients (80%) in the training cohort with vitamin D deficiency was significantly worse than for patients with adequate levels (hazard ratio, 1.78; P = .007) in a multivariate analysis adjusted for type of malignancy, disease stage, conditioning intensity, patient age, donor type, and recipient/donor sex match.
Analysis also showed that the excess hazard was accounted for by higher risk of relapse than nonrelapse mortality (HR, 1.96; P = .006).
When the investigators looked at relapse risk by disease type, they found a significantly higher risk among vitamin D–deficient patients with myeloid malignancies (HR, 2.55; P = .014) but not with lymphoid malignancies.
The risk for relapse among patients with myeloid malignancies in the validation cohort was similarly high (HR, 2.60; P = .017).
“The growth inhibitory, pro-differentiation, and pro-apoptotic effects of VitD in vitro are well recognized, and low VitD levels have been shown to enhance clonal proliferation of leukemic cells. Therefore, with regard to treatment before alloSCT but also to conditioning, one might speculate that VitD deficiency facilitates resistance to chemotherapy,” the researchers wrote.
Low vitamin D levels have been associated in other studies with shorter relapse-free and overall survival in patients with acute myeloid leukemia apart from alloSCT.
The researchers recommend clinical trials to explore the possibility that vitamin D supplementation pre-transplant could improve post-transplant outcomes.
The study was supported by a grant from the BLUT Foundation and the European Union’s Seventh Framework Program. Dr. Luft disclosed consulting with Alexion and Jazz Pharmaceuticals, and institutional research funding and travel support from Medac, Neovii, and Jazz.
Patients with myeloid malignancies who have vitamin D deficiency prior to an allogeneic stem cell transplant (alloSCT) are significantly more likely to experience a relapse and have worse overall survival after transplant than patients with adequate vitamin D levels at baseline, investigators have found.
Among 492 patients with lymphoid or myeloid malignancies who had an alloSCT at a single center, those with vitamin D deficiency had a risk of post-transplant relapse that was nearly double the risk of patients with sufficient vitamin D levels. Also, this relapse risk contributed to significantly worse overall survival for the vitamin D–deficient patients, reported Thomas Luft, MD, PhD, and his colleagues from the University of Heidelberg, Germany.
In multivariate analysis, the risk for relapse was limited to patients with myeloid rather than lymphatic disease, they reported in the Journal of Clinical Oncology.
“[O]ur study suggests that VitD deficiency might affect disease control after alloSCT, in particular, in patients allografted for myeloid malignancies. However, the question of whether improving VitD status before alloSCT has an impact on outcome can only be answered by clinical trial,” they wrote.
To see whether pre-transplant vitamin D deficiency – serum levels of 25-hydroxyvitamin D3 less than 20 ng/mL – might have prognostic significance, the investigators looked at a training cohort of 492 patients who underwent alloSCT at their center from 2002 through 2013, and a validation cohort consisting of 398 additional patients with myeloid malignancies treated at the University of Essen, Germany.
Overall survival for the 396 patients (80%) in the training cohort with vitamin D deficiency was significantly worse than for patients with adequate levels (hazard ratio, 1.78; P = .007) in a multivariate analysis adjusted for type of malignancy, disease stage, conditioning intensity, patient age, donor type, and recipient/donor sex match.
Analysis also showed that the excess hazard was accounted for by higher risk of relapse than nonrelapse mortality (HR, 1.96; P = .006).
When the investigators looked at relapse risk by disease type, they found a significantly higher risk among vitamin D–deficient patients with myeloid malignancies (HR, 2.55; P = .014) but not with lymphoid malignancies.
The risk for relapse among patients with myeloid malignancies in the validation cohort was similarly high (HR, 2.60; P = .017).
“The growth inhibitory, pro-differentiation, and pro-apoptotic effects of VitD in vitro are well recognized, and low VitD levels have been shown to enhance clonal proliferation of leukemic cells. Therefore, with regard to treatment before alloSCT but also to conditioning, one might speculate that VitD deficiency facilitates resistance to chemotherapy,” the researchers wrote.
Low vitamin D levels have been associated in other studies with shorter relapse-free and overall survival in patients with acute myeloid leukemia apart from alloSCT.
The researchers recommend clinical trials to explore the possibility that vitamin D supplementation pre-transplant could improve post-transplant outcomes.
The study was supported by a grant from the BLUT Foundation and the European Union’s Seventh Framework Program. Dr. Luft disclosed consulting with Alexion and Jazz Pharmaceuticals, and institutional research funding and travel support from Medac, Neovii, and Jazz.
FROM JCO
Key clinical point: Vitamin D deficiency pre–allogenic stem cell transplant was associated with greater risk of relapse and lower survival for patients with myeloid malignancies.
Major finding: The hazard for relapse among patients with myeloid malignancies and low pre-transplant vitamin D was 2.55 (P = .014), compared with patients with adequate vitamin D.
Data source: Retrospective cohort study of 492 patients with myeloid or lymphoid malignancies, and a validation cohort of 398 patients.
Disclosures: The study was supported by a grant from the BLUT Foundation and the European Union’s Seventh Framework Program. Dr. Luft disclosed consulting with Alexion and Jazz Pharmaceuticals, and institutional research funding and travel support from Medac, Neovii, and Jazz.
Lenalidomide maintenance boosts survival in de novo myeloma after ASCT
Patients with newly diagnosed multiple myeloma who received lenalidomide as maintenance therapy following an autologous stem cell transplant (ASCT) had significantly better progression-free and overall survival, compared with patients who received placebo or observation after transplant, results of a meta-analysis showed.
Among 1,208 patients in an intention-to-treat analysis, the median progression-free survival (PFS) for patients who received lenalidomide maintenance was nearly double that of patients treated with placebo or observation alone after ASCT, and the median overall survival for patients on maintenance had not been reached after a median follow-up of 79.5 months, reported Phillip J McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, N.Y., and his colleagues.
“This study demonstrates a statistically significant and clinically meaningful improvement in OS with lenalidomide maintenance. With new, highly active, triplet induction regimens enhancing depth and duration of response, as well as ongoing studies evaluating the optimal timing of ASCT, the use of lenalidomide maintenance for transplantation-eligible patients can be considered a standard of care,” they wrote in the Journal of Clinical Oncology.
The authors drew on data from three randomized controlled trials in which patients with newly diagnosed multiple myeloma underwent ASCT followed by lenalidomide maintenance, placebo, or observation. The trials were the Cancer and Leukemia Group B (CALGB) 100104, Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) RV-MM-PI-209, and Intergroupe Francophone du Myelome (IFM) 2005-02.
Because all three studies had PFS as the primary endpoint and were not powered to detect an overall survival (OS) benefit, the investigators conducted a meta-analysis to get a better sense of the effect of maintenance on both PFS and OS.
The meta-analysis included 605 patients randomized to lenalidomide maintenance and 603 to placebo or observation.
The median PFS was 52.8 months with lenalidomide, vs. 23.5 months for placebo or observation (hazard ratio [HR] 0.48; 95% confidence interval, 0.41-0.55).
After a median follow-up of 79.5 months for all survivors, the median OS for patients on lenalidomide was not reached, compared with 86.0 months for placebo/observation (HR, 0.75, P = .001).
An analysis of safety data from the CALGB and IFM studies (GIMEMA data were not available) showed that second primary malignancies occurring before disease progression were more frequent in the lenalidomide maintenance group, at 5.3%, compared with 0.8%. In contrast, the cumulative incidence rates of progression, death, or myeloma-specific death were all higher with placebo or observation versus lenalidomide maintenance, the investigators found.
Although lenalidomide maintenance adds to the cost of care, the “costs of maintenance therapy should be weighed against the costs of shorter survival, earlier progression, and earlier use of subsequent lines of therapies for patients without maintenance,” the researchers wrote.
The study was supported by Celgene. Dr. McCarthy and multiple coauthors reported consulting/advisory roles, honoraria, travel support, and/or research support from the company.
Patients with newly diagnosed multiple myeloma who received lenalidomide as maintenance therapy following an autologous stem cell transplant (ASCT) had significantly better progression-free and overall survival, compared with patients who received placebo or observation after transplant, results of a meta-analysis showed.
Among 1,208 patients in an intention-to-treat analysis, the median progression-free survival (PFS) for patients who received lenalidomide maintenance was nearly double that of patients treated with placebo or observation alone after ASCT, and the median overall survival for patients on maintenance had not been reached after a median follow-up of 79.5 months, reported Phillip J McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, N.Y., and his colleagues.
“This study demonstrates a statistically significant and clinically meaningful improvement in OS with lenalidomide maintenance. With new, highly active, triplet induction regimens enhancing depth and duration of response, as well as ongoing studies evaluating the optimal timing of ASCT, the use of lenalidomide maintenance for transplantation-eligible patients can be considered a standard of care,” they wrote in the Journal of Clinical Oncology.
The authors drew on data from three randomized controlled trials in which patients with newly diagnosed multiple myeloma underwent ASCT followed by lenalidomide maintenance, placebo, or observation. The trials were the Cancer and Leukemia Group B (CALGB) 100104, Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) RV-MM-PI-209, and Intergroupe Francophone du Myelome (IFM) 2005-02.
Because all three studies had PFS as the primary endpoint and were not powered to detect an overall survival (OS) benefit, the investigators conducted a meta-analysis to get a better sense of the effect of maintenance on both PFS and OS.
The meta-analysis included 605 patients randomized to lenalidomide maintenance and 603 to placebo or observation.
The median PFS was 52.8 months with lenalidomide, vs. 23.5 months for placebo or observation (hazard ratio [HR] 0.48; 95% confidence interval, 0.41-0.55).
After a median follow-up of 79.5 months for all survivors, the median OS for patients on lenalidomide was not reached, compared with 86.0 months for placebo/observation (HR, 0.75, P = .001).
An analysis of safety data from the CALGB and IFM studies (GIMEMA data were not available) showed that second primary malignancies occurring before disease progression were more frequent in the lenalidomide maintenance group, at 5.3%, compared with 0.8%. In contrast, the cumulative incidence rates of progression, death, or myeloma-specific death were all higher with placebo or observation versus lenalidomide maintenance, the investigators found.
Although lenalidomide maintenance adds to the cost of care, the “costs of maintenance therapy should be weighed against the costs of shorter survival, earlier progression, and earlier use of subsequent lines of therapies for patients without maintenance,” the researchers wrote.
The study was supported by Celgene. Dr. McCarthy and multiple coauthors reported consulting/advisory roles, honoraria, travel support, and/or research support from the company.
Patients with newly diagnosed multiple myeloma who received lenalidomide as maintenance therapy following an autologous stem cell transplant (ASCT) had significantly better progression-free and overall survival, compared with patients who received placebo or observation after transplant, results of a meta-analysis showed.
Among 1,208 patients in an intention-to-treat analysis, the median progression-free survival (PFS) for patients who received lenalidomide maintenance was nearly double that of patients treated with placebo or observation alone after ASCT, and the median overall survival for patients on maintenance had not been reached after a median follow-up of 79.5 months, reported Phillip J McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, N.Y., and his colleagues.
“This study demonstrates a statistically significant and clinically meaningful improvement in OS with lenalidomide maintenance. With new, highly active, triplet induction regimens enhancing depth and duration of response, as well as ongoing studies evaluating the optimal timing of ASCT, the use of lenalidomide maintenance for transplantation-eligible patients can be considered a standard of care,” they wrote in the Journal of Clinical Oncology.
The authors drew on data from three randomized controlled trials in which patients with newly diagnosed multiple myeloma underwent ASCT followed by lenalidomide maintenance, placebo, or observation. The trials were the Cancer and Leukemia Group B (CALGB) 100104, Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) RV-MM-PI-209, and Intergroupe Francophone du Myelome (IFM) 2005-02.
Because all three studies had PFS as the primary endpoint and were not powered to detect an overall survival (OS) benefit, the investigators conducted a meta-analysis to get a better sense of the effect of maintenance on both PFS and OS.
The meta-analysis included 605 patients randomized to lenalidomide maintenance and 603 to placebo or observation.
The median PFS was 52.8 months with lenalidomide, vs. 23.5 months for placebo or observation (hazard ratio [HR] 0.48; 95% confidence interval, 0.41-0.55).
After a median follow-up of 79.5 months for all survivors, the median OS for patients on lenalidomide was not reached, compared with 86.0 months for placebo/observation (HR, 0.75, P = .001).
An analysis of safety data from the CALGB and IFM studies (GIMEMA data were not available) showed that second primary malignancies occurring before disease progression were more frequent in the lenalidomide maintenance group, at 5.3%, compared with 0.8%. In contrast, the cumulative incidence rates of progression, death, or myeloma-specific death were all higher with placebo or observation versus lenalidomide maintenance, the investigators found.
Although lenalidomide maintenance adds to the cost of care, the “costs of maintenance therapy should be weighed against the costs of shorter survival, earlier progression, and earlier use of subsequent lines of therapies for patients without maintenance,” the researchers wrote.
The study was supported by Celgene. Dr. McCarthy and multiple coauthors reported consulting/advisory roles, honoraria, travel support, and/or research support from the company.
FROM JCO
Key clinical point: Lenalidomide maintenance after stem cell transplant in patients with newly diagnosed multiple myeloma is associated with better progression-free and overall survival.
Major finding: Median overall survival was not reached with lenalidomide after a median 79.5 months’ follow-up, vs. 86 months for placebo/observation.
Data source: A meta-analysis of data from three randomized controlled trials, with a total of 1,208 patients with newly diagnosed multiple myeloma.
Disclosures: The study was supported by Celgene. Dr. McCarthy and multiple coauthors reported consulting/advisory roles, honoraria, travel support, and/or research support from the company.
Hospice care underused in older patients with de novo AML
Although adults older than 65 newly diagnosed with acute myeloid leukemia (AML) have a generally poor prognosis and short life expectancy, fewer than half were enrolled in hospice, and of those patients who were enrolled, two-thirds entered hospice within the last week of life, results of a retrospective cohort study show.
The findings suggest that there is substantial room for improvement in the care of older patients with AML in their last days of life, said investigators led by Rong Wang, PhD, and colleagues from Yale University in New Haven, Connecticut.
“[We] found that the current end-of-life care for older patients with AML is suboptimal, as reflected by low hospice enrollment and high use of potentially aggressive treatment. Transfer in and out of hospice was associated with the receipt of transfusions. Changes to current hospice services, such as enabling the provision of transfusion support, and improvements in physician-patient communications, may help facilitate better end-of-life care in this patient population,” they wrote (J Clin Oncol. 2017 Aug 7. doi: 10.1200/JCO.2017.72.7149)
Patients aged 65 and over with AML have a median overall survival (OS) of only about 2 months, and the older the patient, the worse the survival, with patients 85 and older having a median OS of just 1 month, the investigators noted.
“Hence, end-of-life care is particularly relevant for this patient population,” they wrote.
To get a better idea of how clinicians prescribe hospice and palliative care for older patients with AML, Dr. Wang and colleagues conducted a population-based, retrospective cohort study of patients with AML who were 66 or older at diagnosis, received a diagnosis from 1999 through 2011, and died before the end of 2012.
They reviewed Medicare claims data on 13,156 patients to see whether patients were receiving aggressive care such as chemotherapy and whether and when they were enrolled in hospice.
The investigators found that the proportion of patients who were enrolled in hospice after an AML diagnosis increased from 31.3% in 1999 to 56.4% in 2012 (P for trend less than .01).
They also discovered, however, that most of the increase was attributable to patients who were enrolled within the last week of life.
When they compared patients who died within 30 days of diagnosis to those who lived longer than 30 days after diagnosis, they found that the longer-lived patients were significantly more likely to have been enrolled in hospice (48.1% vs. 30.7%, P less than .01). Additionally, of those patients who were enrolled in hospice, 51.2% of those who died within 30 days of entering hospice had been enrolled in the last 3 days of life, compared with 24.9% of those who survived for more than a month after entering hospice (P value not shown).
Over the course of the study 1,528 patients (11.6%) had chemotherapy within their last two weeks of life. The proportion of patients undergoing chemotherapy within their last 14 days increased from 7.7% in 1999 to 18.8% in 2012 (P for trend less than .01).
Patients who had end-of-life chemotherapy were significantly more likely to have had an ICU stay in the last month of life (43.0% vs. 28.4%; P less than .01) and were significantly more likely to be enrolled in hospice (22.1% vs. 47.4%, P less than .01) than patients who did not get chemotherapy with the last 14 days of life.
Predictors for end-of-life chemotherapy were male sex, being married, and dying in more recent years. Patients who were older, had state Medicaid buy-in (an optional program for workers with disabilities), or who lived outside the Northeast or major metropolitan areas were less likely to be subjected to chemotherapy in their final days.
Overall, 3,956 patients (30.1%) were admitted to the ICU within 30 days of their deaths. The percentage of ICU admissions just before death increased from 25.2% in 1999 to 31.3% in 2012 (P for trend .01).
Predictors for late-life ICU admission were similar to those for chemotherapy, except that patients with state Medicaid buy-in had 19% greater odds of being admitted to an ICU within 30 days of death (P less than .01).
The study was funded by the National Cancer Institute. Dr. Wang reported no relevant conflicts of interests. Multiple coauthors reported financial relationships with various companies.
Although adults older than 65 newly diagnosed with acute myeloid leukemia (AML) have a generally poor prognosis and short life expectancy, fewer than half were enrolled in hospice, and of those patients who were enrolled, two-thirds entered hospice within the last week of life, results of a retrospective cohort study show.
The findings suggest that there is substantial room for improvement in the care of older patients with AML in their last days of life, said investigators led by Rong Wang, PhD, and colleagues from Yale University in New Haven, Connecticut.
“[We] found that the current end-of-life care for older patients with AML is suboptimal, as reflected by low hospice enrollment and high use of potentially aggressive treatment. Transfer in and out of hospice was associated with the receipt of transfusions. Changes to current hospice services, such as enabling the provision of transfusion support, and improvements in physician-patient communications, may help facilitate better end-of-life care in this patient population,” they wrote (J Clin Oncol. 2017 Aug 7. doi: 10.1200/JCO.2017.72.7149)
Patients aged 65 and over with AML have a median overall survival (OS) of only about 2 months, and the older the patient, the worse the survival, with patients 85 and older having a median OS of just 1 month, the investigators noted.
“Hence, end-of-life care is particularly relevant for this patient population,” they wrote.
To get a better idea of how clinicians prescribe hospice and palliative care for older patients with AML, Dr. Wang and colleagues conducted a population-based, retrospective cohort study of patients with AML who were 66 or older at diagnosis, received a diagnosis from 1999 through 2011, and died before the end of 2012.
They reviewed Medicare claims data on 13,156 patients to see whether patients were receiving aggressive care such as chemotherapy and whether and when they were enrolled in hospice.
The investigators found that the proportion of patients who were enrolled in hospice after an AML diagnosis increased from 31.3% in 1999 to 56.4% in 2012 (P for trend less than .01).
They also discovered, however, that most of the increase was attributable to patients who were enrolled within the last week of life.
When they compared patients who died within 30 days of diagnosis to those who lived longer than 30 days after diagnosis, they found that the longer-lived patients were significantly more likely to have been enrolled in hospice (48.1% vs. 30.7%, P less than .01). Additionally, of those patients who were enrolled in hospice, 51.2% of those who died within 30 days of entering hospice had been enrolled in the last 3 days of life, compared with 24.9% of those who survived for more than a month after entering hospice (P value not shown).
Over the course of the study 1,528 patients (11.6%) had chemotherapy within their last two weeks of life. The proportion of patients undergoing chemotherapy within their last 14 days increased from 7.7% in 1999 to 18.8% in 2012 (P for trend less than .01).
Patients who had end-of-life chemotherapy were significantly more likely to have had an ICU stay in the last month of life (43.0% vs. 28.4%; P less than .01) and were significantly more likely to be enrolled in hospice (22.1% vs. 47.4%, P less than .01) than patients who did not get chemotherapy with the last 14 days of life.
Predictors for end-of-life chemotherapy were male sex, being married, and dying in more recent years. Patients who were older, had state Medicaid buy-in (an optional program for workers with disabilities), or who lived outside the Northeast or major metropolitan areas were less likely to be subjected to chemotherapy in their final days.
Overall, 3,956 patients (30.1%) were admitted to the ICU within 30 days of their deaths. The percentage of ICU admissions just before death increased from 25.2% in 1999 to 31.3% in 2012 (P for trend .01).
Predictors for late-life ICU admission were similar to those for chemotherapy, except that patients with state Medicaid buy-in had 19% greater odds of being admitted to an ICU within 30 days of death (P less than .01).
The study was funded by the National Cancer Institute. Dr. Wang reported no relevant conflicts of interests. Multiple coauthors reported financial relationships with various companies.
Although adults older than 65 newly diagnosed with acute myeloid leukemia (AML) have a generally poor prognosis and short life expectancy, fewer than half were enrolled in hospice, and of those patients who were enrolled, two-thirds entered hospice within the last week of life, results of a retrospective cohort study show.
The findings suggest that there is substantial room for improvement in the care of older patients with AML in their last days of life, said investigators led by Rong Wang, PhD, and colleagues from Yale University in New Haven, Connecticut.
“[We] found that the current end-of-life care for older patients with AML is suboptimal, as reflected by low hospice enrollment and high use of potentially aggressive treatment. Transfer in and out of hospice was associated with the receipt of transfusions. Changes to current hospice services, such as enabling the provision of transfusion support, and improvements in physician-patient communications, may help facilitate better end-of-life care in this patient population,” they wrote (J Clin Oncol. 2017 Aug 7. doi: 10.1200/JCO.2017.72.7149)
Patients aged 65 and over with AML have a median overall survival (OS) of only about 2 months, and the older the patient, the worse the survival, with patients 85 and older having a median OS of just 1 month, the investigators noted.
“Hence, end-of-life care is particularly relevant for this patient population,” they wrote.
To get a better idea of how clinicians prescribe hospice and palliative care for older patients with AML, Dr. Wang and colleagues conducted a population-based, retrospective cohort study of patients with AML who were 66 or older at diagnosis, received a diagnosis from 1999 through 2011, and died before the end of 2012.
They reviewed Medicare claims data on 13,156 patients to see whether patients were receiving aggressive care such as chemotherapy and whether and when they were enrolled in hospice.
The investigators found that the proportion of patients who were enrolled in hospice after an AML diagnosis increased from 31.3% in 1999 to 56.4% in 2012 (P for trend less than .01).
They also discovered, however, that most of the increase was attributable to patients who were enrolled within the last week of life.
When they compared patients who died within 30 days of diagnosis to those who lived longer than 30 days after diagnosis, they found that the longer-lived patients were significantly more likely to have been enrolled in hospice (48.1% vs. 30.7%, P less than .01). Additionally, of those patients who were enrolled in hospice, 51.2% of those who died within 30 days of entering hospice had been enrolled in the last 3 days of life, compared with 24.9% of those who survived for more than a month after entering hospice (P value not shown).
Over the course of the study 1,528 patients (11.6%) had chemotherapy within their last two weeks of life. The proportion of patients undergoing chemotherapy within their last 14 days increased from 7.7% in 1999 to 18.8% in 2012 (P for trend less than .01).
Patients who had end-of-life chemotherapy were significantly more likely to have had an ICU stay in the last month of life (43.0% vs. 28.4%; P less than .01) and were significantly more likely to be enrolled in hospice (22.1% vs. 47.4%, P less than .01) than patients who did not get chemotherapy with the last 14 days of life.
Predictors for end-of-life chemotherapy were male sex, being married, and dying in more recent years. Patients who were older, had state Medicaid buy-in (an optional program for workers with disabilities), or who lived outside the Northeast or major metropolitan areas were less likely to be subjected to chemotherapy in their final days.
Overall, 3,956 patients (30.1%) were admitted to the ICU within 30 days of their deaths. The percentage of ICU admissions just before death increased from 25.2% in 1999 to 31.3% in 2012 (P for trend .01).
Predictors for late-life ICU admission were similar to those for chemotherapy, except that patients with state Medicaid buy-in had 19% greater odds of being admitted to an ICU within 30 days of death (P less than .01).
The study was funded by the National Cancer Institute. Dr. Wang reported no relevant conflicts of interests. Multiple coauthors reported financial relationships with various companies.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: End-of-life care for patients 65 and older with acute myeloid leukemia is suboptimal.
Major finding: Patients who lived more than 30 days after an AML diagnosis were significantly more likely to have been enrolled in hospice than those who died within 30 days of diagnosis.
Data source: Retrospective cohort study of 13,156 patients diagnosed with AML at age 66 or older from 1999 through 2012.
Disclosures: The study was funded by the National Cancer Institute. Dr. Wang reported no relevant conflicts of interests. Multiple coauthors reported financial relationships with various companies.
Abiraterone plus ADT boosts prostate cancer survival
In findings that are being hailed as practice changing, men with metastatic prostate cancer had a near 40% lower risk of death when they were treated with a combination of abiraterone acetate (Zytiga), androgen deprivation therapy, and prednisone or prednisolone, compared with ADT alone.
After a median follow-up of 30.4 months, median overall survival for men with newly diagnosed metastatic, castration-sensitive prostate cancer treated with ADT plus dual placebos was 34.7 months, vs. not reached for men treated with ADT, abiraterone, and prednisone in the LATITUDE trial. Similarly, in the STAMPEDE trial, men with newly diagnosed locally advanced or metastatic disease who were randomized to ADT with abiraterone and prednisolone had a 37% reduction in their risk for death and a 79% reduction in their risk for treatment failure, compared with men randomized to ADT alone.
The majority of men with metastatic castration-sensitive prostate cancer who are started on androgen deprivation therapy with a luteinizing hormone–releasing hormone (LHRH) analog with or without a first-generation androgen receptor inhibitor will have responses to therapy, but within a median of 1-year most will progress to castration-resistant disease, noted Karim Fizazi, MD, from the Gustave Roussy Cancer Institute at the University of Paris Sud, Villejuif, France, and coinvestigators of the LATITUDE trial.
“Resistance to androgen-deprivation therapy is largely driven by the reactivation of androgen receptor signaling through persistent adrenal androgen production, upregulation of intratumoral testosterone production, modification of the biologic characteristics of androgen receptors, and steroidogenic parallel pathways,” they wrote.
Although ADT and docetaxel is the standard of care for men with metastatic castration-sensitive disease who are eligible for chemotherapy, data from real-world practice suggest that patients with this presentation are older than those enrolled in clinical trials, and may not be able to tolerate the toxicities that occur when docetaxel is added to ADT, they noted.
Abiraterone, in combination with prednisone, has been shown to increase overall survival (OS) in men with metastatic castration-resistant prostate cancer who have not undergone chemotherapy, and among patients who had previously been treated with docetaxel.
The drug is thought to exert its antitumor effects through a combination of androgen receptor antagonism and blockade of steroidogenic enzymes, the investigators wrote.
The LATITUDE trial
LATITUDE investigators from 235 sites in 34 countries in Europe, Asia/Pacific, Latin America and Canada enrolled 1,199 patients with newly diagnosed metastatic castration-sensitive prostate cancer and randomly assigned them to receive either abiraterone and prednisone plus ADT (597 patients), or ADT plus dual placebos (602).
At a planned interim analysis at a median follow-up of 30.4 months, after 406 patients had died, median OS, a co-primary end point, had not been reached among patients in the abiraterone group, compared with 34.7 months for patients assigned to ADT/placebo. This difference translates into a hazard ratio for death of 0.62 (P less than .001).
The median duration of radiographic progression-free survival (PFS), the other primary end point, was 33.0 months among patients treated with abiraterone vs. 14.8 months for those treated with placebo (HR for disease progression or death, 0.47; P less than .001)
Abiraterone was also associated with significantly better outcomes in all secondary endpoints, including time until pain progression, subsequent therapy, initiation of chemotherapy, and prostate-specific antigen (PSA) progression (P less than .001 for each comparison).
The frequency of adverse events leading to treatment discontinuation was 12% for patients in the abiraterone group vs. 10% for those in the placebo group. Rates of grade 3 or 4 hypertension and hypokalemia were higher among patients who received abiraterone.
Based on the trial results, the independent data and safety monitoring committee unanimously recommended unblinding of the trial and allowing patients in the placebo group to receive abiraterone.
The STAMPEDE trial
The STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial was designed to test whether adding other therapies to ADT can improve OS in the first-line setting for men with locally advanced or metastatic prostate cancer.
The investigators enrolled 1,917 patients with either newly diagnosed node-positive or metastatic prostate cancer, high-risk locally advanced disease, or relapsed, high-risk disease following radical surgery or radiotherapy.
In all, 95% of patients had newly diagnosed disease; 52% had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative nonmetastatic disease.
After a median follow-up of 40 months, there had been 184 deaths among the 960 patients assigned to received ADT plus abiraterone and prednisolone, compared with 262 deaths among 957 patients assigned to ADT alone. The respective 3-year survival rates were 83% vs. 76%, translating into a HR of 0.63 (P less than .001) favoring abiraterone. The respective hazard ratios for abiraterone in patients with metastatic and nonmetastatic disease were 0.75 and 0.61, respectively.
Failure-free survival (no radiologic, clinical, or prostate-specific antigen progression or prostate cancer death) also favored abiraterone, with a HR of 0.29, compared with ADT alone (P less than .001). The respective hazard ratios for patients with nonmetastatic disease and metastatic disease were 0.21 and 0.31, respectively.
Grade 3 or greater adverse events occurred in 47% of patients on abiraterone, and in 33% of patients treated with ADT alone. There nine deaths on treatment in the abiraterone group, including two cases of pneumonia (one with sepsis), two strokes, and one case each of dyspnea, lower respiratory tract infection, liver failure, pulmonary hemorrhage, and chest infections.
There were three deaths in the ADT alone group, two from myocardial infarctions and one from bronchopneumonia.
LATITUDE was supported by Janssen Research and Development. Dr. Fizazi reported having no relevant conflicts of interest. Multiple coauthors reported personal fees or other support from Janssen and other companies. STAMPEDE was supported by Cancer Research UK, Medical Research Council, Astellas Pharma, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis. Lead author Nicholas D. James, PhD, reports receiving support, fees, grants and/or other considerations from Astellas Pharma, Novartis, Pfizer, Clovis Oncology, and Sanofi-Aventis. Multiple coauthors reported similar relationships with various entities.
The LATITUDE and STAMPEDE research teams report encouraging improvements in the initial treatment of men with advanced prostate cancer. Metastatic, castration-sensitive prostate cancer is diagnosed in a small proportion of men with prostate cancer at initial presentation and is disproportionately represented in lethal prostate cancer. The findings of these two trials suggest that therapeutically relevant biologic features of this form of cancer are shared with castration-resistant prostate cancer and raise the broader question of whether earlier application of approved life-prolonging therapies will further improve outcomes.
The reports support the hypothesis that more complete suppression of androgen signaling with abiraterone acetate plus prednisone added to a luteinizing hormone–releasing hormone (LHRH) agonist lengthens survival of men with metastatic, castration-sensitive prostate cancer. The findings are in line with the efficacy of abiraterone plus LHRH agonist therapy as a preoperative treatment. Confidence in the conclusion stems from the observation that treatment with abiraterone plus an LHRH agonist was superior to an LHRH agonist alone in these two large studies among patients with distant metastases, including those with nonosseous visceral metastases. The reported toxic effects of the combination therapy relative to those observed with the LHRH agonist alone did not adversely affect outcomes. The findings may extend to second-generation androgen-receptor inhibitors or combinations with abiraterone currently under study. This practice-changing evidence supports the conclusion that men with metastatic, castration-sensitive prostate cancer, particularly those with more than three bone metastases on conventional imaging, should be treated with abiraterone plus an LHRH agonist.
Christopher J. Logothetis, MD, University of Texas MD Anderson Cancer Center, Houston. This comment is excerpted from an editorial accompanying the studies (N Engl J Med. 2017 Jul 27. doi: 10.1056/NEJMe1704992).
The LATITUDE and STAMPEDE research teams report encouraging improvements in the initial treatment of men with advanced prostate cancer. Metastatic, castration-sensitive prostate cancer is diagnosed in a small proportion of men with prostate cancer at initial presentation and is disproportionately represented in lethal prostate cancer. The findings of these two trials suggest that therapeutically relevant biologic features of this form of cancer are shared with castration-resistant prostate cancer and raise the broader question of whether earlier application of approved life-prolonging therapies will further improve outcomes.
The reports support the hypothesis that more complete suppression of androgen signaling with abiraterone acetate plus prednisone added to a luteinizing hormone–releasing hormone (LHRH) agonist lengthens survival of men with metastatic, castration-sensitive prostate cancer. The findings are in line with the efficacy of abiraterone plus LHRH agonist therapy as a preoperative treatment. Confidence in the conclusion stems from the observation that treatment with abiraterone plus an LHRH agonist was superior to an LHRH agonist alone in these two large studies among patients with distant metastases, including those with nonosseous visceral metastases. The reported toxic effects of the combination therapy relative to those observed with the LHRH agonist alone did not adversely affect outcomes. The findings may extend to second-generation androgen-receptor inhibitors or combinations with abiraterone currently under study. This practice-changing evidence supports the conclusion that men with metastatic, castration-sensitive prostate cancer, particularly those with more than three bone metastases on conventional imaging, should be treated with abiraterone plus an LHRH agonist.
Christopher J. Logothetis, MD, University of Texas MD Anderson Cancer Center, Houston. This comment is excerpted from an editorial accompanying the studies (N Engl J Med. 2017 Jul 27. doi: 10.1056/NEJMe1704992).
The LATITUDE and STAMPEDE research teams report encouraging improvements in the initial treatment of men with advanced prostate cancer. Metastatic, castration-sensitive prostate cancer is diagnosed in a small proportion of men with prostate cancer at initial presentation and is disproportionately represented in lethal prostate cancer. The findings of these two trials suggest that therapeutically relevant biologic features of this form of cancer are shared with castration-resistant prostate cancer and raise the broader question of whether earlier application of approved life-prolonging therapies will further improve outcomes.
The reports support the hypothesis that more complete suppression of androgen signaling with abiraterone acetate plus prednisone added to a luteinizing hormone–releasing hormone (LHRH) agonist lengthens survival of men with metastatic, castration-sensitive prostate cancer. The findings are in line with the efficacy of abiraterone plus LHRH agonist therapy as a preoperative treatment. Confidence in the conclusion stems from the observation that treatment with abiraterone plus an LHRH agonist was superior to an LHRH agonist alone in these two large studies among patients with distant metastases, including those with nonosseous visceral metastases. The reported toxic effects of the combination therapy relative to those observed with the LHRH agonist alone did not adversely affect outcomes. The findings may extend to second-generation androgen-receptor inhibitors or combinations with abiraterone currently under study. This practice-changing evidence supports the conclusion that men with metastatic, castration-sensitive prostate cancer, particularly those with more than three bone metastases on conventional imaging, should be treated with abiraterone plus an LHRH agonist.
Christopher J. Logothetis, MD, University of Texas MD Anderson Cancer Center, Houston. This comment is excerpted from an editorial accompanying the studies (N Engl J Med. 2017 Jul 27. doi: 10.1056/NEJMe1704992).
In findings that are being hailed as practice changing, men with metastatic prostate cancer had a near 40% lower risk of death when they were treated with a combination of abiraterone acetate (Zytiga), androgen deprivation therapy, and prednisone or prednisolone, compared with ADT alone.
After a median follow-up of 30.4 months, median overall survival for men with newly diagnosed metastatic, castration-sensitive prostate cancer treated with ADT plus dual placebos was 34.7 months, vs. not reached for men treated with ADT, abiraterone, and prednisone in the LATITUDE trial. Similarly, in the STAMPEDE trial, men with newly diagnosed locally advanced or metastatic disease who were randomized to ADT with abiraterone and prednisolone had a 37% reduction in their risk for death and a 79% reduction in their risk for treatment failure, compared with men randomized to ADT alone.
The majority of men with metastatic castration-sensitive prostate cancer who are started on androgen deprivation therapy with a luteinizing hormone–releasing hormone (LHRH) analog with or without a first-generation androgen receptor inhibitor will have responses to therapy, but within a median of 1-year most will progress to castration-resistant disease, noted Karim Fizazi, MD, from the Gustave Roussy Cancer Institute at the University of Paris Sud, Villejuif, France, and coinvestigators of the LATITUDE trial.
“Resistance to androgen-deprivation therapy is largely driven by the reactivation of androgen receptor signaling through persistent adrenal androgen production, upregulation of intratumoral testosterone production, modification of the biologic characteristics of androgen receptors, and steroidogenic parallel pathways,” they wrote.
Although ADT and docetaxel is the standard of care for men with metastatic castration-sensitive disease who are eligible for chemotherapy, data from real-world practice suggest that patients with this presentation are older than those enrolled in clinical trials, and may not be able to tolerate the toxicities that occur when docetaxel is added to ADT, they noted.
Abiraterone, in combination with prednisone, has been shown to increase overall survival (OS) in men with metastatic castration-resistant prostate cancer who have not undergone chemotherapy, and among patients who had previously been treated with docetaxel.
The drug is thought to exert its antitumor effects through a combination of androgen receptor antagonism and blockade of steroidogenic enzymes, the investigators wrote.
The LATITUDE trial
LATITUDE investigators from 235 sites in 34 countries in Europe, Asia/Pacific, Latin America and Canada enrolled 1,199 patients with newly diagnosed metastatic castration-sensitive prostate cancer and randomly assigned them to receive either abiraterone and prednisone plus ADT (597 patients), or ADT plus dual placebos (602).
At a planned interim analysis at a median follow-up of 30.4 months, after 406 patients had died, median OS, a co-primary end point, had not been reached among patients in the abiraterone group, compared with 34.7 months for patients assigned to ADT/placebo. This difference translates into a hazard ratio for death of 0.62 (P less than .001).
The median duration of radiographic progression-free survival (PFS), the other primary end point, was 33.0 months among patients treated with abiraterone vs. 14.8 months for those treated with placebo (HR for disease progression or death, 0.47; P less than .001)
Abiraterone was also associated with significantly better outcomes in all secondary endpoints, including time until pain progression, subsequent therapy, initiation of chemotherapy, and prostate-specific antigen (PSA) progression (P less than .001 for each comparison).
The frequency of adverse events leading to treatment discontinuation was 12% for patients in the abiraterone group vs. 10% for those in the placebo group. Rates of grade 3 or 4 hypertension and hypokalemia were higher among patients who received abiraterone.
Based on the trial results, the independent data and safety monitoring committee unanimously recommended unblinding of the trial and allowing patients in the placebo group to receive abiraterone.
The STAMPEDE trial
The STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial was designed to test whether adding other therapies to ADT can improve OS in the first-line setting for men with locally advanced or metastatic prostate cancer.
The investigators enrolled 1,917 patients with either newly diagnosed node-positive or metastatic prostate cancer, high-risk locally advanced disease, or relapsed, high-risk disease following radical surgery or radiotherapy.
In all, 95% of patients had newly diagnosed disease; 52% had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative nonmetastatic disease.
After a median follow-up of 40 months, there had been 184 deaths among the 960 patients assigned to received ADT plus abiraterone and prednisolone, compared with 262 deaths among 957 patients assigned to ADT alone. The respective 3-year survival rates were 83% vs. 76%, translating into a HR of 0.63 (P less than .001) favoring abiraterone. The respective hazard ratios for abiraterone in patients with metastatic and nonmetastatic disease were 0.75 and 0.61, respectively.
Failure-free survival (no radiologic, clinical, or prostate-specific antigen progression or prostate cancer death) also favored abiraterone, with a HR of 0.29, compared with ADT alone (P less than .001). The respective hazard ratios for patients with nonmetastatic disease and metastatic disease were 0.21 and 0.31, respectively.
Grade 3 or greater adverse events occurred in 47% of patients on abiraterone, and in 33% of patients treated with ADT alone. There nine deaths on treatment in the abiraterone group, including two cases of pneumonia (one with sepsis), two strokes, and one case each of dyspnea, lower respiratory tract infection, liver failure, pulmonary hemorrhage, and chest infections.
There were three deaths in the ADT alone group, two from myocardial infarctions and one from bronchopneumonia.
LATITUDE was supported by Janssen Research and Development. Dr. Fizazi reported having no relevant conflicts of interest. Multiple coauthors reported personal fees or other support from Janssen and other companies. STAMPEDE was supported by Cancer Research UK, Medical Research Council, Astellas Pharma, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis. Lead author Nicholas D. James, PhD, reports receiving support, fees, grants and/or other considerations from Astellas Pharma, Novartis, Pfizer, Clovis Oncology, and Sanofi-Aventis. Multiple coauthors reported similar relationships with various entities.
In findings that are being hailed as practice changing, men with metastatic prostate cancer had a near 40% lower risk of death when they were treated with a combination of abiraterone acetate (Zytiga), androgen deprivation therapy, and prednisone or prednisolone, compared with ADT alone.
After a median follow-up of 30.4 months, median overall survival for men with newly diagnosed metastatic, castration-sensitive prostate cancer treated with ADT plus dual placebos was 34.7 months, vs. not reached for men treated with ADT, abiraterone, and prednisone in the LATITUDE trial. Similarly, in the STAMPEDE trial, men with newly diagnosed locally advanced or metastatic disease who were randomized to ADT with abiraterone and prednisolone had a 37% reduction in their risk for death and a 79% reduction in their risk for treatment failure, compared with men randomized to ADT alone.
The majority of men with metastatic castration-sensitive prostate cancer who are started on androgen deprivation therapy with a luteinizing hormone–releasing hormone (LHRH) analog with or without a first-generation androgen receptor inhibitor will have responses to therapy, but within a median of 1-year most will progress to castration-resistant disease, noted Karim Fizazi, MD, from the Gustave Roussy Cancer Institute at the University of Paris Sud, Villejuif, France, and coinvestigators of the LATITUDE trial.
“Resistance to androgen-deprivation therapy is largely driven by the reactivation of androgen receptor signaling through persistent adrenal androgen production, upregulation of intratumoral testosterone production, modification of the biologic characteristics of androgen receptors, and steroidogenic parallel pathways,” they wrote.
Although ADT and docetaxel is the standard of care for men with metastatic castration-sensitive disease who are eligible for chemotherapy, data from real-world practice suggest that patients with this presentation are older than those enrolled in clinical trials, and may not be able to tolerate the toxicities that occur when docetaxel is added to ADT, they noted.
Abiraterone, in combination with prednisone, has been shown to increase overall survival (OS) in men with metastatic castration-resistant prostate cancer who have not undergone chemotherapy, and among patients who had previously been treated with docetaxel.
The drug is thought to exert its antitumor effects through a combination of androgen receptor antagonism and blockade of steroidogenic enzymes, the investigators wrote.
The LATITUDE trial
LATITUDE investigators from 235 sites in 34 countries in Europe, Asia/Pacific, Latin America and Canada enrolled 1,199 patients with newly diagnosed metastatic castration-sensitive prostate cancer and randomly assigned them to receive either abiraterone and prednisone plus ADT (597 patients), or ADT plus dual placebos (602).
At a planned interim analysis at a median follow-up of 30.4 months, after 406 patients had died, median OS, a co-primary end point, had not been reached among patients in the abiraterone group, compared with 34.7 months for patients assigned to ADT/placebo. This difference translates into a hazard ratio for death of 0.62 (P less than .001).
The median duration of radiographic progression-free survival (PFS), the other primary end point, was 33.0 months among patients treated with abiraterone vs. 14.8 months for those treated with placebo (HR for disease progression or death, 0.47; P less than .001)
Abiraterone was also associated with significantly better outcomes in all secondary endpoints, including time until pain progression, subsequent therapy, initiation of chemotherapy, and prostate-specific antigen (PSA) progression (P less than .001 for each comparison).
The frequency of adverse events leading to treatment discontinuation was 12% for patients in the abiraterone group vs. 10% for those in the placebo group. Rates of grade 3 or 4 hypertension and hypokalemia were higher among patients who received abiraterone.
Based on the trial results, the independent data and safety monitoring committee unanimously recommended unblinding of the trial and allowing patients in the placebo group to receive abiraterone.
The STAMPEDE trial
The STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial was designed to test whether adding other therapies to ADT can improve OS in the first-line setting for men with locally advanced or metastatic prostate cancer.
The investigators enrolled 1,917 patients with either newly diagnosed node-positive or metastatic prostate cancer, high-risk locally advanced disease, or relapsed, high-risk disease following radical surgery or radiotherapy.
In all, 95% of patients had newly diagnosed disease; 52% had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative nonmetastatic disease.
After a median follow-up of 40 months, there had been 184 deaths among the 960 patients assigned to received ADT plus abiraterone and prednisolone, compared with 262 deaths among 957 patients assigned to ADT alone. The respective 3-year survival rates were 83% vs. 76%, translating into a HR of 0.63 (P less than .001) favoring abiraterone. The respective hazard ratios for abiraterone in patients with metastatic and nonmetastatic disease were 0.75 and 0.61, respectively.
Failure-free survival (no radiologic, clinical, or prostate-specific antigen progression or prostate cancer death) also favored abiraterone, with a HR of 0.29, compared with ADT alone (P less than .001). The respective hazard ratios for patients with nonmetastatic disease and metastatic disease were 0.21 and 0.31, respectively.
Grade 3 or greater adverse events occurred in 47% of patients on abiraterone, and in 33% of patients treated with ADT alone. There nine deaths on treatment in the abiraterone group, including two cases of pneumonia (one with sepsis), two strokes, and one case each of dyspnea, lower respiratory tract infection, liver failure, pulmonary hemorrhage, and chest infections.
There were three deaths in the ADT alone group, two from myocardial infarctions and one from bronchopneumonia.
LATITUDE was supported by Janssen Research and Development. Dr. Fizazi reported having no relevant conflicts of interest. Multiple coauthors reported personal fees or other support from Janssen and other companies. STAMPEDE was supported by Cancer Research UK, Medical Research Council, Astellas Pharma, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis. Lead author Nicholas D. James, PhD, reports receiving support, fees, grants and/or other considerations from Astellas Pharma, Novartis, Pfizer, Clovis Oncology, and Sanofi-Aventis. Multiple coauthors reported similar relationships with various entities.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Key clinical point: Adding abiraterone acetate to androgen deprivation therapy (ADT) significantly improved overall survival in men with metastatic prostate cancer.
Major finding: The hazard ratio for death with abiraterone/ADT vs. ADT alone in LATITUDE was 0.62, and in STAMPEDE was 0.63.
Data source: Randomized LATITUDE study in 1,199 men with metastatic castration-sensitive prostate cancer. Randomized STAMPEDE trial in 1,917 patients with newly diagnosed node-positive or metastatic prostate cancer, high-risk locally advanced disease, or relapsed, high-risk disease.
Disclosures: LATITUDE was supported by Janssen Research and Development. Dr. Fizazi reported having no relevant conflicts of interest. Multiple coauthors reported personal fees or other support from Janssen and other companies. STAMPEDE was supported by Cancer Research UK, Medical Research Council, Astellas Pharma, Clovis Oncology, Janssen, Novartis, Pfizer, and Sanofi-Aventis. Lead author Nicholas D. James, PhD, reports receiving support, fees, grants and/or other considerations from Astellas Pharma, Novartis, Pfizer, Clovis Oncology, and Sanofi-Aventis. Multiple coauthors reported similar relationships with various entities.
Four drugs better than three for myeloma induction
MADRID – A four-drug induction regimen induced quicker and deeper remissions than sequential triplet regimens in patients with newly diagnosed multiple myeloma.
In addition, fast, deep remissions may lead to improved progression-free survival (PFS) following autologous stem cell transplantation (ASCT), said investigators from a U.K. Medical Research Council study.
In the phase 3 randomized, parallel group Myeloma XI study, very good partial responses (VGPR) or better were seen following induction in 79.5% of patients assigned to the quadruplet (KCRD) of carfilzomib (Kyprolis), cyclophosphamide, lenalidomide (Revlimid), and dexamethasone, compared with 60.8% for those assigned to cyclophosphamide, lenalidomide, and dexamethasone (CRD) and 52.8% for those assigned to cyclophosphamide, thalidomide, and dexamethasone (CTD), said Charlotte Pawlyn, MD, PhD, at the annual congress of the European Hematology Association.
“In our study, we see a very much deeper response after initial induction with the quadruplet regimen, compared with triplet regimens,” Dr. Pawlyn of the Institute of Cancer Research, London, said in an interview.
Medical Research Council investigators showed in the Myeloma IX study that among patients who had a less than VGPR to an immunomodulator-based triplet regimen such as CRD, a triplet regimen including the proteasome inhibitor bortezomib (Velcade) could improve both pre- and post-transplant response rates, and that the improved responses translated into improved PFS.
For the Myeloma XI study, the investigators employed the same response-adapted approach to compare outcomes following induction with the proteasome inhibitor–containing KCRD regimen and the lenalidomide- or thalidomide-based regimens.
They chose carfilzomib as the proteasome-inhibitor backbone of the quadruplet because of its selective, irreversible target binding, lower incidence of peripheral neuropathy (compared with bortezomib), and efficacy in both the frontline and relapsed/refractory setting, she said.
Asked why the comparator regimens did not contain a proteasome inhibitor, Dr. Pawlyn said that while the current standard for induction therapy in the United Kingdom is bortezomib, thalidomide, and dexamethasone, CTD was the standard of care at the time of study planning and initial enrollment.
The trial was open to all patients in the United Kingdom of all ages with newly diagnosed symptomatic multiple myeloma, with pathways for both transplant-eligible and transplant-ineligible patients. The only main exclusion criteria were for patients with dialysis-dependent renal failure and for those who had a prior or concurrent malignancy.
A total of 1,021 patients were assigned to each of the CTD and CRD cohorts, and 526 patients were assigned to the KCRD cohort. The cohorts were well balanced by sex, age, World Health Organization performance score, and other parameters.
Patients randomized to either CTD or CRD were assessed for response after a minimum of four induction cycles, with treatment continued until best response. Those with a VGPR or better went on to ASCT, while those with a partial response were randomized to either a second induction with cyclophosphamide, bortezomib, and dexamethasone (CVD) or no CVD, and then proceeded to transplant. Patients with stable disease or disease progression in either of these arms went on to CVD prior to ASCT.
In the KCRD arm, all patients went from induction to transplant. Following ASCT, patients were randomized to either observation or lenalidomide maintenance.
A higher proportion of patients assigned to KCRD completed the minimum of four induction cycles, and few patients in any trial arm had to stop induction therapy because of adverse events. Dose modifications were required in 63.9% of patients on KCRD, 56.3% of patients on CRD, and 82.2% of patients on CTD.
There was no significant cardiac signal seen in the study, and no difference in the incidence of venous thromboembolic events among the treatment arms.
As noted before, rates of VGPR or better after initial induction were highest in the KCRD arm, at 79.5%, compared with 60% for CRD, and 52.8% for CTD.
“The KCRD quadruplet achieved the highest speed and depth of response,” Dr. Pawlyn said.
The pattern of responses was similar across all cytogenetic risk groups, she added.
A higher proportion of patients treated with KCRD went on to ASCT, and the pattern of deeper responses among patients who underwent induction with KCRD persisted, with 92.1% of patients having a post-transplant VGPR or better, compared with 81.8% for CRD and 77.0% for CTD (statistical significance not shown).
Again, the pattern of responses post-transplant was similar across cytogenetic risk groups.
The investigators anticipate receiving PFS results from the Myeloma XI study in the third or fourth quarter of 2017.
The study was sponsored by the University of Leeds (England), with support from the U.K. National Cancer Research Institute, Cancer Research UK, and Myeloma UK, and collaboration with Celgene, Merck Sharp & Dohme, and Amgen. Dr. Pawlyn disclosed travel support from Celgene and Janssen, and honoraria from Celgene and Takeda.
MADRID – A four-drug induction regimen induced quicker and deeper remissions than sequential triplet regimens in patients with newly diagnosed multiple myeloma.
In addition, fast, deep remissions may lead to improved progression-free survival (PFS) following autologous stem cell transplantation (ASCT), said investigators from a U.K. Medical Research Council study.
In the phase 3 randomized, parallel group Myeloma XI study, very good partial responses (VGPR) or better were seen following induction in 79.5% of patients assigned to the quadruplet (KCRD) of carfilzomib (Kyprolis), cyclophosphamide, lenalidomide (Revlimid), and dexamethasone, compared with 60.8% for those assigned to cyclophosphamide, lenalidomide, and dexamethasone (CRD) and 52.8% for those assigned to cyclophosphamide, thalidomide, and dexamethasone (CTD), said Charlotte Pawlyn, MD, PhD, at the annual congress of the European Hematology Association.
“In our study, we see a very much deeper response after initial induction with the quadruplet regimen, compared with triplet regimens,” Dr. Pawlyn of the Institute of Cancer Research, London, said in an interview.
Medical Research Council investigators showed in the Myeloma IX study that among patients who had a less than VGPR to an immunomodulator-based triplet regimen such as CRD, a triplet regimen including the proteasome inhibitor bortezomib (Velcade) could improve both pre- and post-transplant response rates, and that the improved responses translated into improved PFS.
For the Myeloma XI study, the investigators employed the same response-adapted approach to compare outcomes following induction with the proteasome inhibitor–containing KCRD regimen and the lenalidomide- or thalidomide-based regimens.
They chose carfilzomib as the proteasome-inhibitor backbone of the quadruplet because of its selective, irreversible target binding, lower incidence of peripheral neuropathy (compared with bortezomib), and efficacy in both the frontline and relapsed/refractory setting, she said.
Asked why the comparator regimens did not contain a proteasome inhibitor, Dr. Pawlyn said that while the current standard for induction therapy in the United Kingdom is bortezomib, thalidomide, and dexamethasone, CTD was the standard of care at the time of study planning and initial enrollment.
The trial was open to all patients in the United Kingdom of all ages with newly diagnosed symptomatic multiple myeloma, with pathways for both transplant-eligible and transplant-ineligible patients. The only main exclusion criteria were for patients with dialysis-dependent renal failure and for those who had a prior or concurrent malignancy.
A total of 1,021 patients were assigned to each of the CTD and CRD cohorts, and 526 patients were assigned to the KCRD cohort. The cohorts were well balanced by sex, age, World Health Organization performance score, and other parameters.
Patients randomized to either CTD or CRD were assessed for response after a minimum of four induction cycles, with treatment continued until best response. Those with a VGPR or better went on to ASCT, while those with a partial response were randomized to either a second induction with cyclophosphamide, bortezomib, and dexamethasone (CVD) or no CVD, and then proceeded to transplant. Patients with stable disease or disease progression in either of these arms went on to CVD prior to ASCT.
In the KCRD arm, all patients went from induction to transplant. Following ASCT, patients were randomized to either observation or lenalidomide maintenance.
A higher proportion of patients assigned to KCRD completed the minimum of four induction cycles, and few patients in any trial arm had to stop induction therapy because of adverse events. Dose modifications were required in 63.9% of patients on KCRD, 56.3% of patients on CRD, and 82.2% of patients on CTD.
There was no significant cardiac signal seen in the study, and no difference in the incidence of venous thromboembolic events among the treatment arms.
As noted before, rates of VGPR or better after initial induction were highest in the KCRD arm, at 79.5%, compared with 60% for CRD, and 52.8% for CTD.
“The KCRD quadruplet achieved the highest speed and depth of response,” Dr. Pawlyn said.
The pattern of responses was similar across all cytogenetic risk groups, she added.
A higher proportion of patients treated with KCRD went on to ASCT, and the pattern of deeper responses among patients who underwent induction with KCRD persisted, with 92.1% of patients having a post-transplant VGPR or better, compared with 81.8% for CRD and 77.0% for CTD (statistical significance not shown).
Again, the pattern of responses post-transplant was similar across cytogenetic risk groups.
The investigators anticipate receiving PFS results from the Myeloma XI study in the third or fourth quarter of 2017.
The study was sponsored by the University of Leeds (England), with support from the U.K. National Cancer Research Institute, Cancer Research UK, and Myeloma UK, and collaboration with Celgene, Merck Sharp & Dohme, and Amgen. Dr. Pawlyn disclosed travel support from Celgene and Janssen, and honoraria from Celgene and Takeda.
MADRID – A four-drug induction regimen induced quicker and deeper remissions than sequential triplet regimens in patients with newly diagnosed multiple myeloma.
In addition, fast, deep remissions may lead to improved progression-free survival (PFS) following autologous stem cell transplantation (ASCT), said investigators from a U.K. Medical Research Council study.
In the phase 3 randomized, parallel group Myeloma XI study, very good partial responses (VGPR) or better were seen following induction in 79.5% of patients assigned to the quadruplet (KCRD) of carfilzomib (Kyprolis), cyclophosphamide, lenalidomide (Revlimid), and dexamethasone, compared with 60.8% for those assigned to cyclophosphamide, lenalidomide, and dexamethasone (CRD) and 52.8% for those assigned to cyclophosphamide, thalidomide, and dexamethasone (CTD), said Charlotte Pawlyn, MD, PhD, at the annual congress of the European Hematology Association.
“In our study, we see a very much deeper response after initial induction with the quadruplet regimen, compared with triplet regimens,” Dr. Pawlyn of the Institute of Cancer Research, London, said in an interview.
Medical Research Council investigators showed in the Myeloma IX study that among patients who had a less than VGPR to an immunomodulator-based triplet regimen such as CRD, a triplet regimen including the proteasome inhibitor bortezomib (Velcade) could improve both pre- and post-transplant response rates, and that the improved responses translated into improved PFS.
For the Myeloma XI study, the investigators employed the same response-adapted approach to compare outcomes following induction with the proteasome inhibitor–containing KCRD regimen and the lenalidomide- or thalidomide-based regimens.
They chose carfilzomib as the proteasome-inhibitor backbone of the quadruplet because of its selective, irreversible target binding, lower incidence of peripheral neuropathy (compared with bortezomib), and efficacy in both the frontline and relapsed/refractory setting, she said.
Asked why the comparator regimens did not contain a proteasome inhibitor, Dr. Pawlyn said that while the current standard for induction therapy in the United Kingdom is bortezomib, thalidomide, and dexamethasone, CTD was the standard of care at the time of study planning and initial enrollment.
The trial was open to all patients in the United Kingdom of all ages with newly diagnosed symptomatic multiple myeloma, with pathways for both transplant-eligible and transplant-ineligible patients. The only main exclusion criteria were for patients with dialysis-dependent renal failure and for those who had a prior or concurrent malignancy.
A total of 1,021 patients were assigned to each of the CTD and CRD cohorts, and 526 patients were assigned to the KCRD cohort. The cohorts were well balanced by sex, age, World Health Organization performance score, and other parameters.
Patients randomized to either CTD or CRD were assessed for response after a minimum of four induction cycles, with treatment continued until best response. Those with a VGPR or better went on to ASCT, while those with a partial response were randomized to either a second induction with cyclophosphamide, bortezomib, and dexamethasone (CVD) or no CVD, and then proceeded to transplant. Patients with stable disease or disease progression in either of these arms went on to CVD prior to ASCT.
In the KCRD arm, all patients went from induction to transplant. Following ASCT, patients were randomized to either observation or lenalidomide maintenance.
A higher proportion of patients assigned to KCRD completed the minimum of four induction cycles, and few patients in any trial arm had to stop induction therapy because of adverse events. Dose modifications were required in 63.9% of patients on KCRD, 56.3% of patients on CRD, and 82.2% of patients on CTD.
There was no significant cardiac signal seen in the study, and no difference in the incidence of venous thromboembolic events among the treatment arms.
As noted before, rates of VGPR or better after initial induction were highest in the KCRD arm, at 79.5%, compared with 60% for CRD, and 52.8% for CTD.
“The KCRD quadruplet achieved the highest speed and depth of response,” Dr. Pawlyn said.
The pattern of responses was similar across all cytogenetic risk groups, she added.
A higher proportion of patients treated with KCRD went on to ASCT, and the pattern of deeper responses among patients who underwent induction with KCRD persisted, with 92.1% of patients having a post-transplant VGPR or better, compared with 81.8% for CRD and 77.0% for CTD (statistical significance not shown).
Again, the pattern of responses post-transplant was similar across cytogenetic risk groups.
The investigators anticipate receiving PFS results from the Myeloma XI study in the third or fourth quarter of 2017.
The study was sponsored by the University of Leeds (England), with support from the U.K. National Cancer Research Institute, Cancer Research UK, and Myeloma UK, and collaboration with Celgene, Merck Sharp & Dohme, and Amgen. Dr. Pawlyn disclosed travel support from Celgene and Janssen, and honoraria from Celgene and Takeda.
AT THE EHA CONGRESS
Key clinical point:
Major finding: An induction quadruplet containing carfilzomib induced a higher rate of very good partial responses or better vs. regimens without a proteasome inhibitor.
Data source: A randomized, open-label, parallel group study of 2,568 patients with newly diagnosed multiple myeloma.
Disclosures: The study was sponsored by the University of Leeds (England), with support from the U.K. National Cancer Research Institute, Cancer Research UK, and Myeloma UK, and collaboration with Celgene, Merck Sharp & Dohme, and Amgen. Dr. Pawlyn disclosed travel support from Celgene and Janssen, and honoraria from Celgene and Takeda.
Pembrolizumab takes on r/r PMBCL
LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.
Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.
“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.
Although standard cytotoxic chemotherapy regimens are curative in approximately 80% of patients with PMBCL, those with relapsed/refractory disease have a poor prognosis and limited treatment options. In the United States, about 200 patients are diagnosed with relapsed/refractory PMBCL each year, Dr. Zinzani noted.
The rationale for using a programmed death-1 (PD-1) inhibitor such as pembrolizumab is that PMBCL tumors frequently harbor amplifications and/or translocations in the 9p24.1 locus that lead to overexpression of PD ligand 1 (PD-L1) or PD-L2. Pembrolizumab blocks interactions between PD-1 and its ligands.
In the Keynote-013 PMBCL cohort, the objective response rate (ORR) was 48%, including 24% CR.
Keynote 170 investigators are enrolling adults with relapsed/refractory PMBCL who are either ineligible for ASCT following at least two prior lines of therapy, or who had a relapse following a transplant.
Patients receive pembrolizumab 200 mg every 3 weeks. Those who achieve a complete response are allowed to discontinue after a minimum of 24 weeks on study, those with partial response or stable disease are treated for 35 cycles or until disease progression or intolerable toxicities, and those with disease progression are discontinued, but are allowed to remain on study until progression is confirmed.
Responses are assessed by PET and CT scans according to 2007 International Working Group criteria.
Among the 29 patients assessable for efficacy at the time of Dr. Zinzani’s presentations, the best response by blinded central review was 41% (12 patients: 4 CR and 8 PR). Three patients had stable disease, and eight had disease progression. Six patients died or discontinued participation prior to the first assessment.
In all, 16 of 22 patients had reductions in target lesions, and all but one of these patients had reductions greater than 50%.
After a median follow-up of 6.6 months, 10 patients had ongoing responses. The median time to response was 2.9 months. The median duration of response has not been reached.
Of the 10 patients for whom ASCT had failed, three had a CR, and three had a PR. Among 19 ASCT-ineligible patients, one had a CR and five had a PR.
The interim safety analysis included 49 patients. Of this group, only one discontinued treatment because of adverse events. There were 26 treatment-related adverse events, but no treatment-related deaths.
The most frequent adverse events were neutropenia, asthenia, hypothyroidism, and pyrexia.
The study is supported by Merck. Dr Zinzani disclosed serving on advisory boards for several companies.
LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.
Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.
“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.
Although standard cytotoxic chemotherapy regimens are curative in approximately 80% of patients with PMBCL, those with relapsed/refractory disease have a poor prognosis and limited treatment options. In the United States, about 200 patients are diagnosed with relapsed/refractory PMBCL each year, Dr. Zinzani noted.
The rationale for using a programmed death-1 (PD-1) inhibitor such as pembrolizumab is that PMBCL tumors frequently harbor amplifications and/or translocations in the 9p24.1 locus that lead to overexpression of PD ligand 1 (PD-L1) or PD-L2. Pembrolizumab blocks interactions between PD-1 and its ligands.
In the Keynote-013 PMBCL cohort, the objective response rate (ORR) was 48%, including 24% CR.
Keynote 170 investigators are enrolling adults with relapsed/refractory PMBCL who are either ineligible for ASCT following at least two prior lines of therapy, or who had a relapse following a transplant.
Patients receive pembrolizumab 200 mg every 3 weeks. Those who achieve a complete response are allowed to discontinue after a minimum of 24 weeks on study, those with partial response or stable disease are treated for 35 cycles or until disease progression or intolerable toxicities, and those with disease progression are discontinued, but are allowed to remain on study until progression is confirmed.
Responses are assessed by PET and CT scans according to 2007 International Working Group criteria.
Among the 29 patients assessable for efficacy at the time of Dr. Zinzani’s presentations, the best response by blinded central review was 41% (12 patients: 4 CR and 8 PR). Three patients had stable disease, and eight had disease progression. Six patients died or discontinued participation prior to the first assessment.
In all, 16 of 22 patients had reductions in target lesions, and all but one of these patients had reductions greater than 50%.
After a median follow-up of 6.6 months, 10 patients had ongoing responses. The median time to response was 2.9 months. The median duration of response has not been reached.
Of the 10 patients for whom ASCT had failed, three had a CR, and three had a PR. Among 19 ASCT-ineligible patients, one had a CR and five had a PR.
The interim safety analysis included 49 patients. Of this group, only one discontinued treatment because of adverse events. There were 26 treatment-related adverse events, but no treatment-related deaths.
The most frequent adverse events were neutropenia, asthenia, hypothyroidism, and pyrexia.
The study is supported by Merck. Dr Zinzani disclosed serving on advisory boards for several companies.
LUGANO, SWITZERLAND – Patients with relapsed/refractory primary mediastinal large B-cell lymphoma (PMBCL) have few good therapeutic options, but pembrolizumab (Keytruda) may be one of them, an interim analysis from a phase 2 trial suggests.
Six of 10 patients with relapsed/refractory PMBCL for whom autologous stem cell transplantation (ASCT) had failed had responses to salvage therapy with pembrolizumab, including three complete responses (CR) and three partial responses (PR), reported Pier Luigi Zinzani, MD, PhD, of the University of Bologna, Italy.
“In relapsed/refractory primary mediastinal large B-cell lymphoma including heavily pretreated patients in our series, pembrolizumab showed promising antitumor activity in these preliminary data from a phase 2 study, and a manageable safety profile,” Dr. Zinzani said at the International Conference on Malignant Lymphoma.
Although standard cytotoxic chemotherapy regimens are curative in approximately 80% of patients with PMBCL, those with relapsed/refractory disease have a poor prognosis and limited treatment options. In the United States, about 200 patients are diagnosed with relapsed/refractory PMBCL each year, Dr. Zinzani noted.
The rationale for using a programmed death-1 (PD-1) inhibitor such as pembrolizumab is that PMBCL tumors frequently harbor amplifications and/or translocations in the 9p24.1 locus that lead to overexpression of PD ligand 1 (PD-L1) or PD-L2. Pembrolizumab blocks interactions between PD-1 and its ligands.
In the Keynote-013 PMBCL cohort, the objective response rate (ORR) was 48%, including 24% CR.
Keynote 170 investigators are enrolling adults with relapsed/refractory PMBCL who are either ineligible for ASCT following at least two prior lines of therapy, or who had a relapse following a transplant.
Patients receive pembrolizumab 200 mg every 3 weeks. Those who achieve a complete response are allowed to discontinue after a minimum of 24 weeks on study, those with partial response or stable disease are treated for 35 cycles or until disease progression or intolerable toxicities, and those with disease progression are discontinued, but are allowed to remain on study until progression is confirmed.
Responses are assessed by PET and CT scans according to 2007 International Working Group criteria.
Among the 29 patients assessable for efficacy at the time of Dr. Zinzani’s presentations, the best response by blinded central review was 41% (12 patients: 4 CR and 8 PR). Three patients had stable disease, and eight had disease progression. Six patients died or discontinued participation prior to the first assessment.
In all, 16 of 22 patients had reductions in target lesions, and all but one of these patients had reductions greater than 50%.
After a median follow-up of 6.6 months, 10 patients had ongoing responses. The median time to response was 2.9 months. The median duration of response has not been reached.
Of the 10 patients for whom ASCT had failed, three had a CR, and three had a PR. Among 19 ASCT-ineligible patients, one had a CR and five had a PR.
The interim safety analysis included 49 patients. Of this group, only one discontinued treatment because of adverse events. There were 26 treatment-related adverse events, but no treatment-related deaths.
The most frequent adverse events were neutropenia, asthenia, hypothyroidism, and pyrexia.
The study is supported by Merck. Dr Zinzani disclosed serving on advisory boards for several companies.
AT 14-ICML
Key clinical point: Poor-prognosis relapsed/refractory primary mediastinal large B-cell lymphoma may respond to PD-1 inhibition.
Major finding: The best response by blinded central review was 41% (12 patients: 4 complete and 8 partial responses).
Data source: Interim analysis from a phase 2 study with 29 patients evaluable for efficacy, 49 for safety.
Disclosures: Merck supports the study. Dr Zinzani disclosed serving on advisory boards for several companies.
Avelumab induces response in Hodgkin lymphoma after failed allo-SCT
LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.
Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.
“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.
Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.
Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.
“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.
Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.
In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).
A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).
The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.
The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.
The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.
In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.
In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.
In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.
Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.
“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.
The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.
Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.
“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.
Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.
Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.
“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.
Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.
In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).
A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).
The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.
The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.
The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.
In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.
In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.
In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.
Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.
“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.
The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
LUGANO, SWITZERLAND – The immune checkpoint inhibitor avelumab showed efficacy against classical Hodgkin lymphoma among patients with disease progression following allogeneic stem cell transplants (allo-SCT), based on results of a phase 1 trial.
Two of eight patients with disease progression following an allogeneic transplant (allo-SCT) had complete responses (CR) to the programmed death ligand-1 (PD-L1) inhibitor avelumab (Bavencio), three had partial responses (PRs), and two had stable disease, reported Robert Chen, MD, of City of Hope Medical Center in Duarte, California.
“The overall response rate observed in the postallo population of 62.5% suggests that the PD-L1 blockade inhibitor may potentiate a graft-vs.-lymphoma response,” he said at the 14th International Conference on Malignant Lymphoma.
Amplification of the chromosome 9p24.1 locus is frequent in classical Hodgkin lymphoma, and the amplicon contains the genes encoding for PD-L1 and PD-L2, resulting in the over expression of both ligands, Dr. Chen said.
Both nivolumab (Opdivo) and pembrolizumab (Keytruda) are indicated for the treatment of relapsed/refractory classical Hodgkin lymphoma. Both agents block the interactions between PD-1 and both PD-L1 and PD-L2.
“However, it has not been established whether blockade of the PD-1/PD-L1 interaction is necessary and/or sufficient for the therapeutic effect observed in classical Hodgkin lymphoma,” he said.
Avelumab is an anti–PD-L1, immunoglobulin G1 monoclonal antibody that inhibits PD-1/PD-L1 interactions but leaves PD-1/PD-L2 interactions intact. This agent, which recently received FDA approval for the treatment of Merkel cell carcinoma and locally advanced or metastatic urothelial carcinoma, targets tumor cells rather than the T cells targeted by nivolumab and pembrolizumab.
In the phase 1b JAVELIN Hodgkin study, patients with histologically confirmed relapsed/refractory classical Hodgkin lymphoma who were ineligible for transplant or for whom allogeneic or autologous stem cell transplants had failed were enrolled and were assigned to one of five cohorts to receive avelumab in doses ranging from 70 mg intravenously to 10 mg/kg IV every 2 weeks (or every 3 weeks for the 500 mg dose cohort).
A total of 31 patients were randomized in the dose-finding phase of the study. The median patient age was 38 years, 24 patients were younger than 65, and 7 were 65 or older. Only 1 of the 31 patients had received a single prior line of therapy. Of those, 3 had received two prior therapies, 7 had been treated with three prior lines, and 20 had four or more prior lines of therapy. All patients had received brentuximab vedotin (Adcetris).
The median follow-up was 43.3 weeks. In all, nine patients were continuing on avelumab at the time of the data analysis. Because of disease progression, 10 patients discontinued therapy. Additionally, four discontinued because of adverse events, two chose to withdraw, one was removed from the study by the treating physicians, one did not receive treatment, and four others discontinued because of unspecified reasons.
The median treatment duration was 16.9 weeks. The mean number of cycles was 8.6.
The objective response rate was 42%, including five CRs and eight PRs. Three of the CRs were in patients treated at the 70 mg every 2 week dose, and two were in patients treated at the 500 mg every 3 week level.
In all, 23 patients experienced some degree of tumor shrinkage, and 13 had shrinkage greater than 50%.
In an analysis of best overall response among patients whose disease progressed following SCT, the investigators found that two of eight patients (25%) who had disease progression following allo-SCT had a complete response. Three of these patients had a PR, two had stable disease, and one was not eligible for response evaluation.
In contrast, there was only one objective response, a PR, among five patients who had relapses following autologous SCT.
Grade 3 or 4 treatment-related adverse events occurred in 37% of patients. There were no treatment-related deaths. The incidence of treatment-related adverse events was similar across the five dosing cohorts.
“Based on the observed efficacy and safety profiles and unmet need, this study has recently been amended to focus the expansion of patients who progressed post allo-SCT,” Dr. Chen said.
The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.
AT 14-ICML
Key clinical point: Avelumab showed efficacy in patients with classical Hodgkin lymphoma that relapsed following allogeneic stem cell transplant.
Major finding: The objective response rate among all patients in the study was 41.9%.
Data source: A phase 1 dose-finding and expansion study in 31 patients with relapsed/refractory classical Hodgkin lymphoma who were ineligible for SCT or experienced relapses following SCT.
Disclosures: The study was sponsored by Pfizer in collaboration with Merck KGaA, Germany. Dr. Chen has consulted and served in a speakers’ bureau for Seattle Genetics, Millennium, and Genentech. He has also received research funding from Pharmacyclics, Seattle Genetics, Millennium, and Merck.