Immuno-oncology

For previously untreated patients with BRAF wild-type advanced melanoma, the antiprogrammed death-ligand 1 agent nivolumab dramatically improved overall survival (OS), compared with standard first-line chemotherapy, according to new data from the CheckMate 066 trial.

At the 3-year follow-up, more than twice as many nivolumab-treated patients were alive, compared with those who received dacarbazine, reported lead author Paolo A. Ascierto, MD, director of the unit of melanoma, cancer immunotherapy, and innovative therapy at the Istituto Nazionale Tumori Fondazione Pascale in Naples, Italy, and his colleagues. Longer median progression-free survival (PFS) and higher complete response rates were also reported.

“The results of this 3-year follow-up analysis provided evidence for a durable survival benefit with nivolumab monotherapy in patients with previously untreated BRAF wild-type advanced melanoma,” the investigators wrote in JAMA Oncology.

The double-blind, phase 3 trial involved 418 patients with unresectable, previously untreated stage III or IV melanoma not exhibiting a BRAF mutation. Patients were randomized to receive either nivolumab (n = 210; 3 mg/kg every 2 weeks plus placebo every 3 weeks) or dacarbazine (n = 208; 1,000 mg/m2 every 3 weeks plus placebo every 2 weeks). Treatment continued until unacceptable toxicity or disease progression occurred.

The results showed dramatic benefits, measured by OS and PFS, when patients were treated with nivolumab. The 3-year OS rate was 51.2% in the nivolumab group, compared with 21.6% in the dacarbazine group, an approximate 130% difference. Median OS and median PFS were also multiplied by the checkpoint inhibitor, showing 230% and 130% improvements, respectively (OS, 37.5 months vs. 11.2 months; PFS, 5.1 months vs. 2.2 months; P less than .001). Grade 3 or higher treatment-related adverse events (AEs) were comparable between treatment arms (nivolumab, 15.0% vs. dacarbazine, 17.6%).

“Responses to nivolumab were long lasting in many patients who discontinued treatment, with most patients who stopped treatment still alive and without disease progression at the time of the last assessment,” the investigators wrote.

“Collectively, our results showed durable responses and long-term survival with nivolumab monotherapy, with no new AEs developing at late time points,” they concluded.

The study was funded by Bristol-Myers Squibb. The authors reported financial relationships with Bristol-Myers Squibb, Roche/Genentech, Novartis, Amgen, and others.

SOURCE: Ascierto PA et al. JAMA Oncol. 2018 Oct 25. doi: 10.1001/jamaoncol.2018.4514.

For previously untreated patients with BRAF wild-type advanced melanoma, the antiprogrammed death-ligand 1 agent nivolumab dramatically improved overall survival (OS), compared with standard first-line chemotherapy, according to new data from the CheckMate 066 trial.

At the 3-year follow-up, more than twice as many nivolumab-treated patients were alive, compared with those who received dacarbazine, reported lead author Paolo A. Ascierto, MD, director of the unit of melanoma, cancer immunotherapy, and innovative therapy at the Istituto Nazionale Tumori Fondazione Pascale in Naples, Italy, and his colleagues. Longer median progression-free survival (PFS) and higher complete response rates were also reported.

“The results of this 3-year follow-up analysis provided evidence for a durable survival benefit with nivolumab monotherapy in patients with previously untreated BRAF wild-type advanced melanoma,” the investigators wrote in JAMA Oncology.

The double-blind, phase 3 trial involved 418 patients with unresectable, previously untreated stage III or IV melanoma not exhibiting a BRAF mutation. Patients were randomized to receive either nivolumab (n = 210; 3 mg/kg every 2 weeks plus placebo every 3 weeks) or dacarbazine (n = 208; 1,000 mg/m2 every 3 weeks plus placebo every 2 weeks). Treatment continued until unacceptable toxicity or disease progression occurred.

The results showed dramatic benefits, measured by OS and PFS, when patients were treated with nivolumab. The 3-year OS rate was 51.2% in the nivolumab group, compared with 21.6% in the dacarbazine group, an approximate 130% difference. Median OS and median PFS were also multiplied by the checkpoint inhibitor, showing 230% and 130% improvements, respectively (OS, 37.5 months vs. 11.2 months; PFS, 5.1 months vs. 2.2 months; P less than .001). Grade 3 or higher treatment-related adverse events (AEs) were comparable between treatment arms (nivolumab, 15.0% vs. dacarbazine, 17.6%).

“Responses to nivolumab were long lasting in many patients who discontinued treatment, with most patients who stopped treatment still alive and without disease progression at the time of the last assessment,” the investigators wrote.

“Collectively, our results showed durable responses and long-term survival with nivolumab monotherapy, with no new AEs developing at late time points,” they concluded.

The study was funded by Bristol-Myers Squibb. The authors reported financial relationships with Bristol-Myers Squibb, Roche/Genentech, Novartis, Amgen, and others.

SOURCE: Ascierto PA et al. JAMA Oncol. 2018 Oct 25. doi: 10.1001/jamaoncol.2018.4514.

For previously untreated patients with BRAF wild-type advanced melanoma, the antiprogrammed death-ligand 1 agent nivolumab dramatically improved overall survival (OS), compared with standard first-line chemotherapy, according to new data from the CheckMate 066 trial.

At the 3-year follow-up, more than twice as many nivolumab-treated patients were alive, compared with those who received dacarbazine, reported lead author Paolo A. Ascierto, MD, director of the unit of melanoma, cancer immunotherapy, and innovative therapy at the Istituto Nazionale Tumori Fondazione Pascale in Naples, Italy, and his colleagues. Longer median progression-free survival (PFS) and higher complete response rates were also reported.

“The results of this 3-year follow-up analysis provided evidence for a durable survival benefit with nivolumab monotherapy in patients with previously untreated BRAF wild-type advanced melanoma,” the investigators wrote in JAMA Oncology.

The double-blind, phase 3 trial involved 418 patients with unresectable, previously untreated stage III or IV melanoma not exhibiting a BRAF mutation. Patients were randomized to receive either nivolumab (n = 210; 3 mg/kg every 2 weeks plus placebo every 3 weeks) or dacarbazine (n = 208; 1,000 mg/m2 every 3 weeks plus placebo every 2 weeks). Treatment continued until unacceptable toxicity or disease progression occurred.

The results showed dramatic benefits, measured by OS and PFS, when patients were treated with nivolumab. The 3-year OS rate was 51.2% in the nivolumab group, compared with 21.6% in the dacarbazine group, an approximate 130% difference. Median OS and median PFS were also multiplied by the checkpoint inhibitor, showing 230% and 130% improvements, respectively (OS, 37.5 months vs. 11.2 months; PFS, 5.1 months vs. 2.2 months; P less than .001). Grade 3 or higher treatment-related adverse events (AEs) were comparable between treatment arms (nivolumab, 15.0% vs. dacarbazine, 17.6%).

“Responses to nivolumab were long lasting in many patients who discontinued treatment, with most patients who stopped treatment still alive and without disease progression at the time of the last assessment,” the investigators wrote.

“Collectively, our results showed durable responses and long-term survival with nivolumab monotherapy, with no new AEs developing at late time points,” they concluded.

The study was funded by Bristol-Myers Squibb. The authors reported financial relationships with Bristol-Myers Squibb, Roche/Genentech, Novartis, Amgen, and others.

SOURCE: Ascierto PA et al. JAMA Oncol. 2018 Oct 25. doi: 10.1001/jamaoncol.2018.4514.

Alveolar soft part sarcoma (ASPS) has often proven to be resistant to conventional doxorubicin-based chemotherapy, but tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) may provide new treatment strategies for this rare type of sarcoma, according to a literature review.

A rare, translocation-driven sarcoma of the soft tissues, ASPS often affects young adults and is characterized by indolent behavior and early metastasis. Despite its resistance to chemotherapy, studies indicate that survival is often prolonged in patients with metastatic disease. The literature has shown 5-year survival rates at about 60%, and this percentage has remained fairly consistent for the past 3 decades.

Luca Paoluzzi, MD, of New York University, and Robert G. Maki, MD, PhD, of Hofstra University, Hempstead, N.Y., reviewed the literature from 1952 to March 2018, in order to gain a better understanding of ASPS and the opportunities “for the translation of such knowledge into clinical practice,” they wrote in JAMA.

From a therapeutic standpoint, ASPS is characterized by sensitivity to vascular endothelial growth factor receptor–predominant TKIs, compared with other soft tissue sarcomas (STS), and recent data have emphasized that it is responsive to new immunotherapy regimens including ICIs. Pazopanib is currently the only agent that has received regulatory approval for use in STS refractory to other treatments and it appears to have consistent activity in metastatic ASPS. Management of ASPS generally also involves surgical resection and/or systemic treatment for metastatic disease. Conventional agents such as anthracycline-based chemotherapy have demonstrated a poor response rate lower than 10%, and while a complete resection may be curative, metastases are common and can occur years after resection of the primary tumor.

Conversely, ICIs “represent a promising area of drug development in ASPS; the data to date are limited but encouraging,” wrote Dr. Paoluzzi and Dr. Maki.

They pointed to one study that included 50 patients with sarcoma with 14 different subtypes of STS who were enrolled in immunotherapy trials conducted at the University of Texas MD Anderson Cancer Center, Houston. There were two pretreated patients with ASPS (two to four prior lines) in the cohort who received antiprogrammed death-ligand 1–based therapy, and achieved a partial response bordering on a complete response that lasted 8 and 12 months. An additional two patients achieved stable disease.

Another paper, presented at the 2017 Connective Tissue Oncology Society annual meeting, presented preliminary data from a phase 2 study that showed four of nine evaluable patients with ASPS treated with the TKI axitinib, combined with pembrolizumab, achieved a partial response. Three others had stable disease.

“Pathway-driven basket trials facilitate the enrollment of patients with such uncommon cancers and should provide valuable information regarding a second type of immune responsiveness to ICIs, one that is not a function of high tumor mutational burden,” the authors concluded.

No outside funding sources were reported. Dr. Maki reported receiving consultant fees from numerous sources and research support to New York University from Immune Design, Immunocore, Eli Lilly, Presage Biosciences, TRACON Pharmaceuticals, SARC, Regeneron, and Genentech. No other conflicts were reported.

SOURCE: Paoluzzi L et al. JAMA Oncol. 2018 Oct 18. doi: 10.1001/jamaoncol.2018.4490.

Alveolar soft part sarcoma (ASPS) has often proven to be resistant to conventional doxorubicin-based chemotherapy, but tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) may provide new treatment strategies for this rare type of sarcoma, according to a literature review.

A rare, translocation-driven sarcoma of the soft tissues, ASPS often affects young adults and is characterized by indolent behavior and early metastasis. Despite its resistance to chemotherapy, studies indicate that survival is often prolonged in patients with metastatic disease. The literature has shown 5-year survival rates at about 60%, and this percentage has remained fairly consistent for the past 3 decades.

Luca Paoluzzi, MD, of New York University, and Robert G. Maki, MD, PhD, of Hofstra University, Hempstead, N.Y., reviewed the literature from 1952 to March 2018, in order to gain a better understanding of ASPS and the opportunities “for the translation of such knowledge into clinical practice,” they wrote in JAMA.

From a therapeutic standpoint, ASPS is characterized by sensitivity to vascular endothelial growth factor receptor–predominant TKIs, compared with other soft tissue sarcomas (STS), and recent data have emphasized that it is responsive to new immunotherapy regimens including ICIs. Pazopanib is currently the only agent that has received regulatory approval for use in STS refractory to other treatments and it appears to have consistent activity in metastatic ASPS. Management of ASPS generally also involves surgical resection and/or systemic treatment for metastatic disease. Conventional agents such as anthracycline-based chemotherapy have demonstrated a poor response rate lower than 10%, and while a complete resection may be curative, metastases are common and can occur years after resection of the primary tumor.

Conversely, ICIs “represent a promising area of drug development in ASPS; the data to date are limited but encouraging,” wrote Dr. Paoluzzi and Dr. Maki.

They pointed to one study that included 50 patients with sarcoma with 14 different subtypes of STS who were enrolled in immunotherapy trials conducted at the University of Texas MD Anderson Cancer Center, Houston. There were two pretreated patients with ASPS (two to four prior lines) in the cohort who received antiprogrammed death-ligand 1–based therapy, and achieved a partial response bordering on a complete response that lasted 8 and 12 months. An additional two patients achieved stable disease.

Another paper, presented at the 2017 Connective Tissue Oncology Society annual meeting, presented preliminary data from a phase 2 study that showed four of nine evaluable patients with ASPS treated with the TKI axitinib, combined with pembrolizumab, achieved a partial response. Three others had stable disease.

“Pathway-driven basket trials facilitate the enrollment of patients with such uncommon cancers and should provide valuable information regarding a second type of immune responsiveness to ICIs, one that is not a function of high tumor mutational burden,” the authors concluded.

No outside funding sources were reported. Dr. Maki reported receiving consultant fees from numerous sources and research support to New York University from Immune Design, Immunocore, Eli Lilly, Presage Biosciences, TRACON Pharmaceuticals, SARC, Regeneron, and Genentech. No other conflicts were reported.

SOURCE: Paoluzzi L et al. JAMA Oncol. 2018 Oct 18. doi: 10.1001/jamaoncol.2018.4490.

Alveolar soft part sarcoma (ASPS) has often proven to be resistant to conventional doxorubicin-based chemotherapy, but tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) may provide new treatment strategies for this rare type of sarcoma, according to a literature review.

A rare, translocation-driven sarcoma of the soft tissues, ASPS often affects young adults and is characterized by indolent behavior and early metastasis. Despite its resistance to chemotherapy, studies indicate that survival is often prolonged in patients with metastatic disease. The literature has shown 5-year survival rates at about 60%, and this percentage has remained fairly consistent for the past 3 decades.

Luca Paoluzzi, MD, of New York University, and Robert G. Maki, MD, PhD, of Hofstra University, Hempstead, N.Y., reviewed the literature from 1952 to March 2018, in order to gain a better understanding of ASPS and the opportunities “for the translation of such knowledge into clinical practice,” they wrote in JAMA.

From a therapeutic standpoint, ASPS is characterized by sensitivity to vascular endothelial growth factor receptor–predominant TKIs, compared with other soft tissue sarcomas (STS), and recent data have emphasized that it is responsive to new immunotherapy regimens including ICIs. Pazopanib is currently the only agent that has received regulatory approval for use in STS refractory to other treatments and it appears to have consistent activity in metastatic ASPS. Management of ASPS generally also involves surgical resection and/or systemic treatment for metastatic disease. Conventional agents such as anthracycline-based chemotherapy have demonstrated a poor response rate lower than 10%, and while a complete resection may be curative, metastases are common and can occur years after resection of the primary tumor.

Conversely, ICIs “represent a promising area of drug development in ASPS; the data to date are limited but encouraging,” wrote Dr. Paoluzzi and Dr. Maki.

They pointed to one study that included 50 patients with sarcoma with 14 different subtypes of STS who were enrolled in immunotherapy trials conducted at the University of Texas MD Anderson Cancer Center, Houston. There were two pretreated patients with ASPS (two to four prior lines) in the cohort who received antiprogrammed death-ligand 1–based therapy, and achieved a partial response bordering on a complete response that lasted 8 and 12 months. An additional two patients achieved stable disease.

Another paper, presented at the 2017 Connective Tissue Oncology Society annual meeting, presented preliminary data from a phase 2 study that showed four of nine evaluable patients with ASPS treated with the TKI axitinib, combined with pembrolizumab, achieved a partial response. Three others had stable disease.

“Pathway-driven basket trials facilitate the enrollment of patients with such uncommon cancers and should provide valuable information regarding a second type of immune responsiveness to ICIs, one that is not a function of high tumor mutational burden,” the authors concluded.

No outside funding sources were reported. Dr. Maki reported receiving consultant fees from numerous sources and research support to New York University from Immune Design, Immunocore, Eli Lilly, Presage Biosciences, TRACON Pharmaceuticals, SARC, Regeneron, and Genentech. No other conflicts were reported.

SOURCE: Paoluzzi L et al. JAMA Oncol. 2018 Oct 18. doi: 10.1001/jamaoncol.2018.4490.

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.

MUNICH – Patients with HIV who are treated with nivolumab, a programmed death-1 (PD-1) inhibitor, appear to have similar safety and efficacy outcomes compared with HIV-negative patients treated with the same agent, investigators found.

The retrospective study also showed that viral load and CD4 status were largely unchanged by immunotherapy, lead author Aurélien Gobert, MD, of Groupe Hospitalier Pitié Salpêtrière, Paris, reported at the European Society for Medical Oncology Congress.

HIV increases risks of certain cancer types, Dr. Gobert said in a press release. “These patients are at higher risk for a number of cancers: AIDS-defining forms, the diagnosis of which results in the categorization of a person as suffering from AIDS, but also various other types that they are two to three times more likely to develop than in the general population, such as anal, skin, head and neck, and lung cancer,” he said.

Despite the increased risks, few studies have evaluated cancer treatments for patients with HIV due to exclusions from most clinical trials. As HIV is an immune-based disease, concerns have arisen surrounding the safety and efficacy of using anti-neoplastic immunotherapies for HIV-positive patients. Considering that millions of people worldwide are HIV positive, research in this area can have real-world consequences.

Dr. Gobert and his colleagues analyzed data from CANCERVIH, a French national database of patients with cancer and HIV. Since May 2014, nivolumab has been administered to 20 patients. Nineteen had metastatic non–small-cell lung cancer and 1 had metastatic melanoma. At diagnosis, the median CD4 count was 338.5 per cubic millimeter. Seventeen patients had undetectable viral load, two had fewer than 40 copies per millimeter, and one patient’s viral load was unknown. Dr. Gobert described the population as “demographically homogenous,” with “most patients being males around 60 years old.”

Analysis showed that nivolumab had little impact on CD4 count or viral load. One patient had a decreased CD4 count and an increased viral load, but this occurred during an interruption to antiretroviral therapy, which clouds potential associations with nivolumab. No immune-related adverse events or deaths due to drug toxicity occurred. Efficacy was assessed in 17 patients: Four (24%) showed a partial response, 2 (12%) had stable disease, and 11 (64%) had disease progression.

“Based on these preliminary data, treatment with anti-PD-1 ... seems to be feasible in people with HIV,” Dr. Gobert reported. He added that “antiretroviral therapy should not be interrupted.”

In a comment for ESMO, John Haanen, PhD, of the Netherlands Cancer Institute, Amsterdam, said that the results “confirm those of other, smaller cohorts in showing that while on antiretroviral therapy, cancer patients living with HIV can safely receive anti-PD-1 treatment. The efficacy data also suggests that the overall response rate of HIV-positive patients seems to be similar to that of other cancer patients. These promising results need to be confirmed in larger studies – ideally, in a prospective clinical trial.”

Principal investigator Jean-Philippe Spano, MD, PhD, disclosed relationships with Gilead, Roche, BMS, and others.

SOURCE: Gobert et al. ESMO 2018, Abstract 1213P_PR.

MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.

Neil Osterweil/MDedge News

The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.

“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.

Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.

Neil Osterweil/MDedge News

MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.

Neil Osterweil/MDedge News

The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.

“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.

Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.

Neil Osterweil/MDedge News

MUNICH – The combination of the immune checkpoint inhibitor avelumab (Bavencio) and the tyrosine kinase inhibitor axitinib (Inlyta) was associated with longer progression-free survival and higher objective response rates than was sunitinib as frontline therapy for patients with advanced renal cell carcinoma, investigators found.

Neil Osterweil/MDedge News

The progression-free survival (PFS) benefit of the combination was seen both in the subset of patients with tumors expressing programmed death-1 ligand 1 (PD-L1) on at least 1% of their cells as well as in the overall study population, reported Robert J. Motzer, MD, of Memorial Sloan Kettering Cancer Center, New York, on behalf of colleagues in the JAVELIN Renal 101 trial.

“This was very early on, at an interim analysis, showing a profound effect,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.

“The results support this being a new first-line standard of care, and possibly a first-line option for advanced RCC based on these data,” he added.

Briefing discussant John Haanen, PhD, of the Netherlands Cancer Institute in Amsterdam, said that “based on preclinical data, it makes sense to combine angiogenesis inhibitors and immunotherapy, because we know angiogenesis, VEGF [vascular endothelial growth factor] especially impacts on the way the immune system can respond to the kidney cancer, and by taking away some of these negative effects of the VEGF by using an anti-VEGF drug, the immunotherapy may work better,” he said.

Neil Osterweil/MDedge News

MUNICH – For the first time, a combination of an immune checkpoint inhibitor and a taxane has shown significant clinical benefit in patients with metastatic triple-negative breast cancer in a phase 3 trial, but the benefit was seen only in patients positive for programmed death-ligand 1 (PD-L1), investigators reported.

Neil Osterweil/MDedge News

Among 902 patients with untreated metastatic triple-negative breast cancer (mTNBC) randomly assigned to receive the PD-L1 inhibitor atezolizumab (Tecentriq) plus nanoparticle albumin-bound (nab)-paclitaxel or placebo plus nab-paclitaxel, atezolizumab was associated with a 38% improvement in median overall survival among patients with PD-L1–positive disease in an interim analysis of the IMpassion 130 trial.

However, although there was a significant progression-free survival (PFS) benefit with atezolizumab in an intention-to-treat (ITT) analysis that included patients with PD-L1 negative tumors, there was no significant difference in median overall survival (OS) when all patients were considered together, said Peter Schmid, MD, PhD, Barts Cancer Institute, Queen Mary University of London.

“For patients with PD-L1–positive tumors, these data establish atezolizumab and nab-paclitaxel as a new standard of care,” he said at the European Society for Medical Oncology Congress.

The results were published online in the New England Journal of Medicine to coincide with the presentation of the data.

Neil Osterweil/MDedge News

At a briefing prior to presentation of the data in a symposium, discussant Nadia Harbeck, MD, of the University of Munich Medical Center, a breast cancer specialist, confessed to being of envious of her colleagues in other oncology specialties in which immunotherapy has made great inroads.

“We have a lot of patients out there right now in clinical trials with immune therapy, but so far in breast cancer, we have not seen the tremendous effects we have seen in melanoma or lung cancer, so this is the first time we have a phase 3 trial proving that immune therapy in triple-negative breast cancer improves survival, and I think this is something that will change the way we practice in triple-negative breast cancer,” she said.

The rationale for using a PD-L1 inhibitor comes from the discovery that PD-L1 expression occurs primarily on tumor-infiltrating cells in TNBC rather than on tumor cells, which can inhibit immune responses directed against tumors.

The investigators enrolled 902 patients with previously untreated mTNBC and randomly assigned them to receive nab-paclitaxel 100 mg/m² intravenously on days 1, 8, and 15 of each 28-day cycle, plus either atezolizumab 804 mg intravenously or placebo on days 1 and 15 of each cycle.

Patients were stratified according to whether they received neoadjuvant or adjuvant taxane therapy, the presence of liver metastases at baseline, and PD-L1 expression at baseline.

Treatment was continued until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS in both the ITT and PD-L1–positive population.

In the ITT analysis, 1-year PFS rate was significantly improved in the atezolizumab arm, at 24% vs. 18% in the placebo arm. This translated into a stratified hazard ratio of 0.80 (P = .0025).

In the analysis restricted to the PD-L1-positive population (369 patients), the 1-year PFS rates were 29% for atezolizumab vs. 16% for placebo, translating into to an HR of 0.62 (P less than .0001).

As noted before, the interim OS analysis in the PD-L1 population showed a clinical benefit with atezolizumab, with a 2-year OS rate of 54% vs. 37%, respectively. The median OS in this analysis was 25 months with atezolizumab, vs. 15.5 months with placebo. The stratified HR favoring the PD-L1 inhibitor was 0.62, but because of the hierarchical statistical analysis design of the trial, formal testing of OS was not performed for the interim analysis.

Adverse events of any kind occurred in 99.3% of patients assigned to atezolizumab/nab-paclitaxel and 97.9% of those assigned to placebo/nab-paclitaxel.

Grade 1 or 2 immune-related hypothyroidism occurred more frequently with atezolizumab (17.3% vs. 4.3%), but none led to discontinuation of the drug regimen.

Six patients assigned to atezolizumab and three assigned to placebo died. Four of the deaths were deemed by investigators to be related to the trial regimen, include three deaths in the atezolizumab arm (from autoimmune hepatitis, mucosal inflammation, and septic shock), and one death in the placebo arm (from hepatic failure).

“A benefit with atezolizumab/nab-paclitaxel in patients with PD-L1–positive tumors that was shown in our trial provides evidence of the efficacy of immunotherapy in at least a subset of patients. It is important for patients’ PD-L1 expression status on tumor-infiltrating immune cells to be taken into consideration to inform treatment choices for patients with metastatic triple-negative breast cancer,” Dr. Schmid and his colleagues wrote in the study’s conclusion.

“I really do think that these results are going to make a very big difference,” said coinvestigator Hope S. Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

“We believed from the phase 1 data and the less-than-exciting phase 2 data that there was clearly some role for immunotherapy in breast cancer but were really struggling as to what that role was. We knew for example that if they had a response, patients lived longer and really dramatically longer,” she said in an interview.

But unlike the clinical revolution brought about by the introduction of trastuzumab, in which clinicians had a biomarker and a large number of patients benefited, “here we have no biomarker and a small number of patients benefited, but the benefit is huge,” she said.

Neil Osterweil/MDedge News

Giuseppe Curigliano, MD, PhD, from the University of Milan and European Cancer Institute, Italy, the invited discussant at the symposium, agreed that the study “brings breast cancer into the immunotherapy era.”

Dr. Curigliano added, however, that the study was missing an arm – atezolizumab alone, which might be a good option for a subset of patients.

He also questioned whether nab-paclitaxel was the best partner for atezolizumab, vs. other drugs with known immunogenic effects, such as doxorubicin, cyclophosphamide, other taxanes, gemcitabine, or platinum salts.

The study was supported by F. Hoffmann–La Roche/Genentech. Dr. Schmid reported grant and nonfinancial support from Roche. Multiple coauthors reported financial relationships with Roche/Genentech and others. Dr. Harbeck has disclosed honoraria from and serving as a consultant for Roche and others. Dr. Rugo disclosed grants and nonfinancial support from F. Hoffmann–La Roche. Dr. Curigliano disclosed consulting/advising, speakers bureau participation, and travel/accommodations from Roche/Genentech.

SOURCE: Schmid P et al. N Engl J Med. 2018 Oct 20. doi: 10.1056/NEJMoa1809615.

MUNICH – For the first time, a combination of an immune checkpoint inhibitor and a taxane has shown significant clinical benefit in patients with metastatic triple-negative breast cancer in a phase 3 trial, but the benefit was seen only in patients positive for programmed death-ligand 1 (PD-L1), investigators reported.

Neil Osterweil/MDedge News

Among 902 patients with untreated metastatic triple-negative breast cancer (mTNBC) randomly assigned to receive the PD-L1 inhibitor atezolizumab (Tecentriq) plus nanoparticle albumin-bound (nab)-paclitaxel or placebo plus nab-paclitaxel, atezolizumab was associated with a 38% improvement in median overall survival among patients with PD-L1–positive disease in an interim analysis of the IMpassion 130 trial.

However, although there was a significant progression-free survival (PFS) benefit with atezolizumab in an intention-to-treat (ITT) analysis that included patients with PD-L1 negative tumors, there was no significant difference in median overall survival (OS) when all patients were considered together, said Peter Schmid, MD, PhD, Barts Cancer Institute, Queen Mary University of London.

“For patients with PD-L1–positive tumors, these data establish atezolizumab and nab-paclitaxel as a new standard of care,” he said at the European Society for Medical Oncology Congress.

The results were published online in the New England Journal of Medicine to coincide with the presentation of the data.

Neil Osterweil/MDedge News

At a briefing prior to presentation of the data in a symposium, discussant Nadia Harbeck, MD, of the University of Munich Medical Center, a breast cancer specialist, confessed to being of envious of her colleagues in other oncology specialties in which immunotherapy has made great inroads.

“We have a lot of patients out there right now in clinical trials with immune therapy, but so far in breast cancer, we have not seen the tremendous effects we have seen in melanoma or lung cancer, so this is the first time we have a phase 3 trial proving that immune therapy in triple-negative breast cancer improves survival, and I think this is something that will change the way we practice in triple-negative breast cancer,” she said.

The rationale for using a PD-L1 inhibitor comes from the discovery that PD-L1 expression occurs primarily on tumor-infiltrating cells in TNBC rather than on tumor cells, which can inhibit immune responses directed against tumors.

The investigators enrolled 902 patients with previously untreated mTNBC and randomly assigned them to receive nab-paclitaxel 100 mg/m² intravenously on days 1, 8, and 15 of each 28-day cycle, plus either atezolizumab 804 mg intravenously or placebo on days 1 and 15 of each cycle.

Patients were stratified according to whether they received neoadjuvant or adjuvant taxane therapy, the presence of liver metastases at baseline, and PD-L1 expression at baseline.

Treatment was continued until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS in both the ITT and PD-L1–positive population.

In the ITT analysis, 1-year PFS rate was significantly improved in the atezolizumab arm, at 24% vs. 18% in the placebo arm. This translated into a stratified hazard ratio of 0.80 (P = .0025).

In the analysis restricted to the PD-L1-positive population (369 patients), the 1-year PFS rates were 29% for atezolizumab vs. 16% for placebo, translating into to an HR of 0.62 (P less than .0001).

As noted before, the interim OS analysis in the PD-L1 population showed a clinical benefit with atezolizumab, with a 2-year OS rate of 54% vs. 37%, respectively. The median OS in this analysis was 25 months with atezolizumab, vs. 15.5 months with placebo. The stratified HR favoring the PD-L1 inhibitor was 0.62, but because of the hierarchical statistical analysis design of the trial, formal testing of OS was not performed for the interim analysis.

Adverse events of any kind occurred in 99.3% of patients assigned to atezolizumab/nab-paclitaxel and 97.9% of those assigned to placebo/nab-paclitaxel.

Grade 1 or 2 immune-related hypothyroidism occurred more frequently with atezolizumab (17.3% vs. 4.3%), but none led to discontinuation of the drug regimen.

Six patients assigned to atezolizumab and three assigned to placebo died. Four of the deaths were deemed by investigators to be related to the trial regimen, include three deaths in the atezolizumab arm (from autoimmune hepatitis, mucosal inflammation, and septic shock), and one death in the placebo arm (from hepatic failure).

“A benefit with atezolizumab/nab-paclitaxel in patients with PD-L1–positive tumors that was shown in our trial provides evidence of the efficacy of immunotherapy in at least a subset of patients. It is important for patients’ PD-L1 expression status on tumor-infiltrating immune cells to be taken into consideration to inform treatment choices for patients with metastatic triple-negative breast cancer,” Dr. Schmid and his colleagues wrote in the study’s conclusion.

“I really do think that these results are going to make a very big difference,” said coinvestigator Hope S. Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

“We believed from the phase 1 data and the less-than-exciting phase 2 data that there was clearly some role for immunotherapy in breast cancer but were really struggling as to what that role was. We knew for example that if they had a response, patients lived longer and really dramatically longer,” she said in an interview.

But unlike the clinical revolution brought about by the introduction of trastuzumab, in which clinicians had a biomarker and a large number of patients benefited, “here we have no biomarker and a small number of patients benefited, but the benefit is huge,” she said.

Neil Osterweil/MDedge News

Giuseppe Curigliano, MD, PhD, from the University of Milan and European Cancer Institute, Italy, the invited discussant at the symposium, agreed that the study “brings breast cancer into the immunotherapy era.”

Dr. Curigliano added, however, that the study was missing an arm – atezolizumab alone, which might be a good option for a subset of patients.

He also questioned whether nab-paclitaxel was the best partner for atezolizumab, vs. other drugs with known immunogenic effects, such as doxorubicin, cyclophosphamide, other taxanes, gemcitabine, or platinum salts.

The study was supported by F. Hoffmann–La Roche/Genentech. Dr. Schmid reported grant and nonfinancial support from Roche. Multiple coauthors reported financial relationships with Roche/Genentech and others. Dr. Harbeck has disclosed honoraria from and serving as a consultant for Roche and others. Dr. Rugo disclosed grants and nonfinancial support from F. Hoffmann–La Roche. Dr. Curigliano disclosed consulting/advising, speakers bureau participation, and travel/accommodations from Roche/Genentech.

SOURCE: Schmid P et al. N Engl J Med. 2018 Oct 20. doi: 10.1056/NEJMoa1809615.

MUNICH – For the first time, a combination of an immune checkpoint inhibitor and a taxane has shown significant clinical benefit in patients with metastatic triple-negative breast cancer in a phase 3 trial, but the benefit was seen only in patients positive for programmed death-ligand 1 (PD-L1), investigators reported.

Neil Osterweil/MDedge News

Among 902 patients with untreated metastatic triple-negative breast cancer (mTNBC) randomly assigned to receive the PD-L1 inhibitor atezolizumab (Tecentriq) plus nanoparticle albumin-bound (nab)-paclitaxel or placebo plus nab-paclitaxel, atezolizumab was associated with a 38% improvement in median overall survival among patients with PD-L1–positive disease in an interim analysis of the IMpassion 130 trial.

However, although there was a significant progression-free survival (PFS) benefit with atezolizumab in an intention-to-treat (ITT) analysis that included patients with PD-L1 negative tumors, there was no significant difference in median overall survival (OS) when all patients were considered together, said Peter Schmid, MD, PhD, Barts Cancer Institute, Queen Mary University of London.

“For patients with PD-L1–positive tumors, these data establish atezolizumab and nab-paclitaxel as a new standard of care,” he said at the European Society for Medical Oncology Congress.

The results were published online in the New England Journal of Medicine to coincide with the presentation of the data.

Neil Osterweil/MDedge News

At a briefing prior to presentation of the data in a symposium, discussant Nadia Harbeck, MD, of the University of Munich Medical Center, a breast cancer specialist, confessed to being of envious of her colleagues in other oncology specialties in which immunotherapy has made great inroads.

“We have a lot of patients out there right now in clinical trials with immune therapy, but so far in breast cancer, we have not seen the tremendous effects we have seen in melanoma or lung cancer, so this is the first time we have a phase 3 trial proving that immune therapy in triple-negative breast cancer improves survival, and I think this is something that will change the way we practice in triple-negative breast cancer,” she said.

The rationale for using a PD-L1 inhibitor comes from the discovery that PD-L1 expression occurs primarily on tumor-infiltrating cells in TNBC rather than on tumor cells, which can inhibit immune responses directed against tumors.

The investigators enrolled 902 patients with previously untreated mTNBC and randomly assigned them to receive nab-paclitaxel 100 mg/m² intravenously on days 1, 8, and 15 of each 28-day cycle, plus either atezolizumab 804 mg intravenously or placebo on days 1 and 15 of each cycle.

Patients were stratified according to whether they received neoadjuvant or adjuvant taxane therapy, the presence of liver metastases at baseline, and PD-L1 expression at baseline.

Treatment was continued until disease progression or unacceptable toxicity.

The primary endpoints were PFS and OS in both the ITT and PD-L1–positive population.

In the ITT analysis, 1-year PFS rate was significantly improved in the atezolizumab arm, at 24% vs. 18% in the placebo arm. This translated into a stratified hazard ratio of 0.80 (P = .0025).

In the analysis restricted to the PD-L1-positive population (369 patients), the 1-year PFS rates were 29% for atezolizumab vs. 16% for placebo, translating into to an HR of 0.62 (P less than .0001).

As noted before, the interim OS analysis in the PD-L1 population showed a clinical benefit with atezolizumab, with a 2-year OS rate of 54% vs. 37%, respectively. The median OS in this analysis was 25 months with atezolizumab, vs. 15.5 months with placebo. The stratified HR favoring the PD-L1 inhibitor was 0.62, but because of the hierarchical statistical analysis design of the trial, formal testing of OS was not performed for the interim analysis.

Adverse events of any kind occurred in 99.3% of patients assigned to atezolizumab/nab-paclitaxel and 97.9% of those assigned to placebo/nab-paclitaxel.

Grade 1 or 2 immune-related hypothyroidism occurred more frequently with atezolizumab (17.3% vs. 4.3%), but none led to discontinuation of the drug regimen.

Six patients assigned to atezolizumab and three assigned to placebo died. Four of the deaths were deemed by investigators to be related to the trial regimen, include three deaths in the atezolizumab arm (from autoimmune hepatitis, mucosal inflammation, and septic shock), and one death in the placebo arm (from hepatic failure).

“A benefit with atezolizumab/nab-paclitaxel in patients with PD-L1–positive tumors that was shown in our trial provides evidence of the efficacy of immunotherapy in at least a subset of patients. It is important for patients’ PD-L1 expression status on tumor-infiltrating immune cells to be taken into consideration to inform treatment choices for patients with metastatic triple-negative breast cancer,” Dr. Schmid and his colleagues wrote in the study’s conclusion.

“I really do think that these results are going to make a very big difference,” said coinvestigator Hope S. Rugo, MD, a clinical professor of medicine and director of the Breast Oncology Clinical Trials Program at the University of California, San Francisco, Helen Diller Family Comprehensive Cancer Center.

“We believed from the phase 1 data and the less-than-exciting phase 2 data that there was clearly some role for immunotherapy in breast cancer but were really struggling as to what that role was. We knew for example that if they had a response, patients lived longer and really dramatically longer,” she said in an interview.

But unlike the clinical revolution brought about by the introduction of trastuzumab, in which clinicians had a biomarker and a large number of patients benefited, “here we have no biomarker and a small number of patients benefited, but the benefit is huge,” she said.

Neil Osterweil/MDedge News

Giuseppe Curigliano, MD, PhD, from the University of Milan and European Cancer Institute, Italy, the invited discussant at the symposium, agreed that the study “brings breast cancer into the immunotherapy era.”

Dr. Curigliano added, however, that the study was missing an arm – atezolizumab alone, which might be a good option for a subset of patients.

He also questioned whether nab-paclitaxel was the best partner for atezolizumab, vs. other drugs with known immunogenic effects, such as doxorubicin, cyclophosphamide, other taxanes, gemcitabine, or platinum salts.

The study was supported by F. Hoffmann–La Roche/Genentech. Dr. Schmid reported grant and nonfinancial support from Roche. Multiple coauthors reported financial relationships with Roche/Genentech and others. Dr. Harbeck has disclosed honoraria from and serving as a consultant for Roche and others. Dr. Rugo disclosed grants and nonfinancial support from F. Hoffmann–La Roche. Dr. Curigliano disclosed consulting/advising, speakers bureau participation, and travel/accommodations from Roche/Genentech.

SOURCE: Schmid P et al. N Engl J Med. 2018 Oct 20. doi: 10.1056/NEJMoa1809615.

The high price of chimeric antigen receptor (CAR) T-cell therapy for pediatric leukemia may prove cost effective if long-term survival benefits are realized, researchers reported.

utah778/Thinkstock

A cost-effectiveness analysis of the CAR T-cell therapy tisagenlecleucel suggests that the $475,000 price tag is in alignment with the lifetime benefits of the treatment. The findings were published in JAMA Pediatrics.

Tisagenlecleucel – marketed as Kymriah – is a one-dose treatment for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL) and the first CAR T-cell therapy approved by the Food and Drug Administration.

In this cost-effectiveness analysis, researchers used a decision analytic model that extrapolated the evidence from clinical trials over a patient’s lifetime to assess life-years gained, quality-adjusted life-years (QALYs) gained, and incremental costs per life-year and QALY gained. The comparator was the chemoimmunotherapeutic agent clofarabine.

While tisagenlecleucel has a list price of $475,000, researchers discounted the price by 3% and added several additional costs, such as hospital administration, pretreatment, and potential adverse events, to get to a total discounted cost of about $667,000. They estimated that 42.6% of patients were considered to be long-term survivors with tisagenlecleucel, 10.34 life-years would be gained, and 9.28 QALYs would be gained.

In comparison, clofarabine had a total discounted cost of approximately $337,000 (including an initial discounted price of $164,000 plus additional treatment and administrative costs), 10.8% of patients were long-term survivors, 2.43 life-years were gained, and 2.10 QALYs were gained in the model.

Overall, the mean incremental cost-effectiveness ratio was about $46,000 per QALY gained in this base-case model.

In analyses of different scenarios, such as a deeper discount, a different treatment start, or a different calculation of future treatment costs, the cost-effectiveness ratio varied from $37,000 to $78,000 per QALY gained.

“We acknowledge that considerable uncertainty remains around the long-term benefit of tisagenlecleucel owing to limited available evidence; however, with current evidence and assumptions, tisagenlecleucel meets commonly cited value thresholds over a patient lifetime horizon, assuming payment for treatment acquisition for responders at 1 month,” wrote Melanie D. Whittington, PhD, from the University of Colorado at Denver, Aurora, and her colleagues.

The authors noted that the clinical trial evidence for tisagenlecleucel came from single-arm trials, which made selection of a comparator challenging. Clofarabine was chosen because it had the most similar baseline population characteristics, but they acknowledged that blinatumomab was also frequently used as a treatment for these patients.

“We suspect that tisagenlecleucel would remain cost effective, compared with blinatumomab,” they wrote. “A study conducted by other researchers found the incremental cost-effectiveness ratio of tisagenlecleucel versus blinatumomab was similar to the incremental cost-effectiveness ratio of tisagenlecleucel versus clofarabine [i.e., $3,000 more per QALY].”

The authors suggested that uncertainties in the evidence should be considered as payers are negotiating coverage and payment for tisagenlecleucel.

“Novel payment models consistent with the present evidence may reduce the risk and uncertainty in long-term value and be more closely aligned with ensuring high-value care,” they wrote. “Financing cures in the United States is challenging, owing to the high up-front price, rapid uptake, and uncertainty in long-term outcomes; however, innovative payment models are an opportunity to address some of these challenges and to promote patient access to novel and promising therapies.”

The study was funded by the Institute for Clinical and Economic Review, which receives some funding from the pharmaceutical industry. Four authors are employees of the Institute for Clinical and Economic Review.

SOURCE: Whittington MD et al. JAMA Pediatr. 2018 Oct 8. doi: 10.1001/jamapediatrics.2018.2530.

The high price of chimeric antigen receptor (CAR) T-cell therapy for pediatric leukemia may prove cost effective if long-term survival benefits are realized, researchers reported.

utah778/Thinkstock

A cost-effectiveness analysis of the CAR T-cell therapy tisagenlecleucel suggests that the $475,000 price tag is in alignment with the lifetime benefits of the treatment. The findings were published in JAMA Pediatrics.

Tisagenlecleucel – marketed as Kymriah – is a one-dose treatment for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL) and the first CAR T-cell therapy approved by the Food and Drug Administration.

In this cost-effectiveness analysis, researchers used a decision analytic model that extrapolated the evidence from clinical trials over a patient’s lifetime to assess life-years gained, quality-adjusted life-years (QALYs) gained, and incremental costs per life-year and QALY gained. The comparator was the chemoimmunotherapeutic agent clofarabine.

While tisagenlecleucel has a list price of $475,000, researchers discounted the price by 3% and added several additional costs, such as hospital administration, pretreatment, and potential adverse events, to get to a total discounted cost of about $667,000. They estimated that 42.6% of patients were considered to be long-term survivors with tisagenlecleucel, 10.34 life-years would be gained, and 9.28 QALYs would be gained.

In comparison, clofarabine had a total discounted cost of approximately $337,000 (including an initial discounted price of $164,000 plus additional treatment and administrative costs), 10.8% of patients were long-term survivors, 2.43 life-years were gained, and 2.10 QALYs were gained in the model.

Overall, the mean incremental cost-effectiveness ratio was about $46,000 per QALY gained in this base-case model.

In analyses of different scenarios, such as a deeper discount, a different treatment start, or a different calculation of future treatment costs, the cost-effectiveness ratio varied from $37,000 to $78,000 per QALY gained.

“We acknowledge that considerable uncertainty remains around the long-term benefit of tisagenlecleucel owing to limited available evidence; however, with current evidence and assumptions, tisagenlecleucel meets commonly cited value thresholds over a patient lifetime horizon, assuming payment for treatment acquisition for responders at 1 month,” wrote Melanie D. Whittington, PhD, from the University of Colorado at Denver, Aurora, and her colleagues.

The authors noted that the clinical trial evidence for tisagenlecleucel came from single-arm trials, which made selection of a comparator challenging. Clofarabine was chosen because it had the most similar baseline population characteristics, but they acknowledged that blinatumomab was also frequently used as a treatment for these patients.

“We suspect that tisagenlecleucel would remain cost effective, compared with blinatumomab,” they wrote. “A study conducted by other researchers found the incremental cost-effectiveness ratio of tisagenlecleucel versus blinatumomab was similar to the incremental cost-effectiveness ratio of tisagenlecleucel versus clofarabine [i.e., $3,000 more per QALY].”

The authors suggested that uncertainties in the evidence should be considered as payers are negotiating coverage and payment for tisagenlecleucel.

“Novel payment models consistent with the present evidence may reduce the risk and uncertainty in long-term value and be more closely aligned with ensuring high-value care,” they wrote. “Financing cures in the United States is challenging, owing to the high up-front price, rapid uptake, and uncertainty in long-term outcomes; however, innovative payment models are an opportunity to address some of these challenges and to promote patient access to novel and promising therapies.”

The study was funded by the Institute for Clinical and Economic Review, which receives some funding from the pharmaceutical industry. Four authors are employees of the Institute for Clinical and Economic Review.

SOURCE: Whittington MD et al. JAMA Pediatr. 2018 Oct 8. doi: 10.1001/jamapediatrics.2018.2530.

The high price of chimeric antigen receptor (CAR) T-cell therapy for pediatric leukemia may prove cost effective if long-term survival benefits are realized, researchers reported.

utah778/Thinkstock

A cost-effectiveness analysis of the CAR T-cell therapy tisagenlecleucel suggests that the $475,000 price tag is in alignment with the lifetime benefits of the treatment. The findings were published in JAMA Pediatrics.

Tisagenlecleucel – marketed as Kymriah – is a one-dose treatment for relapsed or refractory pediatric B-cell acute lymphoblastic leukemia (ALL) and the first CAR T-cell therapy approved by the Food and Drug Administration.

In this cost-effectiveness analysis, researchers used a decision analytic model that extrapolated the evidence from clinical trials over a patient’s lifetime to assess life-years gained, quality-adjusted life-years (QALYs) gained, and incremental costs per life-year and QALY gained. The comparator was the chemoimmunotherapeutic agent clofarabine.

While tisagenlecleucel has a list price of $475,000, researchers discounted the price by 3% and added several additional costs, such as hospital administration, pretreatment, and potential adverse events, to get to a total discounted cost of about $667,000. They estimated that 42.6% of patients were considered to be long-term survivors with tisagenlecleucel, 10.34 life-years would be gained, and 9.28 QALYs would be gained.

In comparison, clofarabine had a total discounted cost of approximately $337,000 (including an initial discounted price of $164,000 plus additional treatment and administrative costs), 10.8% of patients were long-term survivors, 2.43 life-years were gained, and 2.10 QALYs were gained in the model.

Overall, the mean incremental cost-effectiveness ratio was about $46,000 per QALY gained in this base-case model.

In analyses of different scenarios, such as a deeper discount, a different treatment start, or a different calculation of future treatment costs, the cost-effectiveness ratio varied from $37,000 to $78,000 per QALY gained.

“We acknowledge that considerable uncertainty remains around the long-term benefit of tisagenlecleucel owing to limited available evidence; however, with current evidence and assumptions, tisagenlecleucel meets commonly cited value thresholds over a patient lifetime horizon, assuming payment for treatment acquisition for responders at 1 month,” wrote Melanie D. Whittington, PhD, from the University of Colorado at Denver, Aurora, and her colleagues.

The authors noted that the clinical trial evidence for tisagenlecleucel came from single-arm trials, which made selection of a comparator challenging. Clofarabine was chosen because it had the most similar baseline population characteristics, but they acknowledged that blinatumomab was also frequently used as a treatment for these patients.

“We suspect that tisagenlecleucel would remain cost effective, compared with blinatumomab,” they wrote. “A study conducted by other researchers found the incremental cost-effectiveness ratio of tisagenlecleucel versus blinatumomab was similar to the incremental cost-effectiveness ratio of tisagenlecleucel versus clofarabine [i.e., $3,000 more per QALY].”

The authors suggested that uncertainties in the evidence should be considered as payers are negotiating coverage and payment for tisagenlecleucel.

“Novel payment models consistent with the present evidence may reduce the risk and uncertainty in long-term value and be more closely aligned with ensuring high-value care,” they wrote. “Financing cures in the United States is challenging, owing to the high up-front price, rapid uptake, and uncertainty in long-term outcomes; however, innovative payment models are an opportunity to address some of these challenges and to promote patient access to novel and promising therapies.”

The study was funded by the Institute for Clinical and Economic Review, which receives some funding from the pharmaceutical industry. Four authors are employees of the Institute for Clinical and Economic Review.

SOURCE: Whittington MD et al. JAMA Pediatr. 2018 Oct 8. doi: 10.1001/jamapediatrics.2018.2530.

CHICAGO – Novel antibodies are improving outcomes in relapsed and refractory acute lymphoblastic leukemia (ALL), and the hope is that they will also show benefit in the up-front treatment setting and thereby improve overall outcomes, according to Anjali Advani, MD.

“It has been a really exciting time in ALL because several drugs have now been FDA approved: blinatumomab, inotuzumab, and now – for patients who are less than 26 years of age – we actually have CAR [chimeric antigen receptor] T cells that have been approved,” Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic said at the American Society of Hematology Meeting on Hematologic Malignancies.

At the time of relapse, however, the only known cure is allogeneic bone marrow transplant. That may change as more data regarding CAR T cells become available, but the typical goal at this time is to get patients into remission and then to transplant, she said.
 

Blinatumomab

“Blinatumomab is a very interesting antibody,” Dr. Advani said, explaining that it is a bispecific, T cell–engaging antibody with an anti-CD3 arm that engages the T cell and an anti-CD19 antibody that engages the B lymphoblast.

“Basically this drug then acts as a bridge between the lymphoblast and the T cell to lead to proliferation of the cytotoxic T cell and apoptosis of the lymphoblast,” she said. “It’s interesting because it’s an antibody but it actually works through the immune system through the T cells.”

The largest study to date of blinatumomab in the relapsed/refractory ALL setting showed a 43% complete remission (CR) or CR with partial hematological recovery of peripheral blood counts (CRi) in 189 treated patients with Philadelphia chromosome–negative ALL. It also demonstrated and a 39% rate of salvage status 2 or higher, she said, noting that the response was impressive given that about 30% of participants had a prior transplant (Lancet. 2015 Jan 1;16[1]:57-66).

Of the responders, 40% went on to allogeneic transplant. This was a “fairly impressive” rate given the 30% prior-transplant rate, Dr. Advani said.

“There also was a high minimal residual disease response in those patients achieving CR,” she said, adding that the only significant predictor of response was bone marrow blast count; patients with 50% or more blasts in the bone marrow had a reduced likelihood of responding to blinatumomab.

The agent was approved by the Food and Drug Administration in December 2014 based on these phase 2 findings.

Adverse events mainly included toxicities that are expected in leukemia patients; the most frequent were febrile neutropenia, neutropenia, and anemia. Two patients developed cytokine release syndrome, and about half of the blinatumomab-treated patients experienced neurological events, although the majority of those were grade 1 or 2 and were easily manageable, she noted.

Blinatumomab was further evaluated in the phase 3 TOWER study (NCT02013167), which compared it with standard-of-care chemotherapy regimens. This study showed much higher response rates with blinatumomab than with the chemotherapy regimens (CR with full, partial, or incomplete hematologic recovery, 44% vs. 25%, respectively), Dr. Advani said (N Engl J Med. 2017 Mar 2;376[9]:836-47).

“The main things to remember [are that blinatumomab is] generally very well tolerated and it has been shown to be superior over standard chemotherapy,” she said. “I think it’s a very good drug to use as a bridge to transplant.”

One setting where blinatumomab perhaps should not be used is in patients with central nervous system disease, she noted.

“There is some concern, at least theoretically, that if you have to use concurrent intrathecal chemo along with blinatumomab, there could be some neurotoxicity,” Dr. Advani said, adding that there are no clear data in that setting because patients with CNS disease were not included in the trials.

Patients with high tumor burden may also be poor candidates for blinatumomab because they tend to have lower response rates.

“That doesn’t mean you can’t use it, but you have to kind of think about what the best option would be,” she said.

Additionally, patients treated with CAR T-cell therapy may develop CD19 loss or CD19-negative disease, and blinatumomab should be avoided in these patients.

“The nice thing ... is you don’t have to worry about veno-occlusive disease [VOD] in patients who are proceeding to transplant,” she said, explaining that no increased risk of VOD was seen in these trials.
 

Inotuzumab

Inotuzumab, which was approved in 2017, differs from blinatumomab in that it is an anti-CD22-calicheamicin conjugate; however, it also showed high response rates in the initial phase 2 trial in relapsed/refractory ALL. The overall response rate was 57%, with 18% achieving a complete response and 63% achieving complete molecular remission.

Of 49 treated patients, 22 patients proceeded to allogeneic transplant, and 5 of those developed VOD.

“Interestingly, four out of five of these patients had received a clofarabine-based preparative regimen, and this likely explains why there was a higher risk of VOD in this study,” she said, noting that the VOD risk has been lower in subsequent studies of inotuzumab.

The international INO-VATE ALL study (NCT01564784) that led to FDA approval was similar in design to the TOWER study in that it compared inotuzumab with standard chemotherapy regimens, and response rates were clearly higher (81% vs. 33%) with inotuzumab (N Engl J Med. 2016 Aug 25;375[8]:740-53).

The VOD risk in the INO-VATE trial was 11%, and it seemed to be higher in those who received dual alkylator–conditioning regimens, which are commonly used in Europe.

Longer-term outcomes after transplant in INO-VATE participants show that median survival has not been reached.

“It’s encouraging that with longer follow-up these patients actually look like they’re doing well,” Dr. Advani said, adding that inotuzumab is a good treatment option for relapsed patients with high disease burden or with CNS disease.

The continuous hookup required for this treatment may be problematic for some younger and older patients, but it is generally not an issue, she noted.

It is important, though, to give as few cycles prior to transplant as possible and to “really think about the preparative regimen to decrease the risk of VOD.”
 

CAR T-cell therapy

As for CAR T-cell therapy in the relapsed/refractory ALL setting, tisagenlecleucel was approved in 2017 for those up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse.

Approval was based on a single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had prior transplant. The confirmed overall remission rate was 82%, with a 63% CR rate and 19% CRi rate.

“This is a very exciting area,” Dr. Advani said. “There are multiple trials being done in adults with ALL to really look at the older subgroup of patients.”
 

Overall outcomes

“These treatments we have now really seem to be effective in the relapse setting, but the problem is that once patients relapse and then go to transplant, their overall survival is still poor,” Dr. Advani said. “So the question is how can we improve the up-front treatment of patients so that hopefully they don’t relapse, and hopefully we also can send a smaller number of patients to transplant.”

Two trials seek to address this, she said.

The A041501 study (NCT03150693) is comparing C10403 chemotherapy with C10403 induction followed by two cycles of inotuzumab before continuing with chemotherapy in adults under age 40 years with previously untreated B ALL.

The primary objective is improved 3-year event-free survival, she said, adding that minimal residual disease (MRD) testing will be used and that CD20-positive patients will receive rituximab, as is now standard.

The phase 3 E1910 study (NCT02003222) is evaluating up-front blinatumomab in patients aged 30-70 years with newly diagnosed BCR-ABL–negative B-lineage ALL. This trial was complicated by the recent approval of blinatumomab for MRD-positive disease, which rendered randomization of MRD-positive patients unethical. MRD-negative patients will be randomized, however.

“The hope is that, by incorporating blinatumomab up front, this will again improve outcomes for patients,” she said.

Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.

sworcester@mdedge.com

CHICAGO – Novel antibodies are improving outcomes in relapsed and refractory acute lymphoblastic leukemia (ALL), and the hope is that they will also show benefit in the up-front treatment setting and thereby improve overall outcomes, according to Anjali Advani, MD.

“It has been a really exciting time in ALL because several drugs have now been FDA approved: blinatumomab, inotuzumab, and now – for patients who are less than 26 years of age – we actually have CAR [chimeric antigen receptor] T cells that have been approved,” Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic said at the American Society of Hematology Meeting on Hematologic Malignancies.

At the time of relapse, however, the only known cure is allogeneic bone marrow transplant. That may change as more data regarding CAR T cells become available, but the typical goal at this time is to get patients into remission and then to transplant, she said.
 

Blinatumomab

“Blinatumomab is a very interesting antibody,” Dr. Advani said, explaining that it is a bispecific, T cell–engaging antibody with an anti-CD3 arm that engages the T cell and an anti-CD19 antibody that engages the B lymphoblast.

“Basically this drug then acts as a bridge between the lymphoblast and the T cell to lead to proliferation of the cytotoxic T cell and apoptosis of the lymphoblast,” she said. “It’s interesting because it’s an antibody but it actually works through the immune system through the T cells.”

The largest study to date of blinatumomab in the relapsed/refractory ALL setting showed a 43% complete remission (CR) or CR with partial hematological recovery of peripheral blood counts (CRi) in 189 treated patients with Philadelphia chromosome–negative ALL. It also demonstrated and a 39% rate of salvage status 2 or higher, she said, noting that the response was impressive given that about 30% of participants had a prior transplant (Lancet. 2015 Jan 1;16[1]:57-66).

Of the responders, 40% went on to allogeneic transplant. This was a “fairly impressive” rate given the 30% prior-transplant rate, Dr. Advani said.

“There also was a high minimal residual disease response in those patients achieving CR,” she said, adding that the only significant predictor of response was bone marrow blast count; patients with 50% or more blasts in the bone marrow had a reduced likelihood of responding to blinatumomab.

The agent was approved by the Food and Drug Administration in December 2014 based on these phase 2 findings.

Adverse events mainly included toxicities that are expected in leukemia patients; the most frequent were febrile neutropenia, neutropenia, and anemia. Two patients developed cytokine release syndrome, and about half of the blinatumomab-treated patients experienced neurological events, although the majority of those were grade 1 or 2 and were easily manageable, she noted.

Blinatumomab was further evaluated in the phase 3 TOWER study (NCT02013167), which compared it with standard-of-care chemotherapy regimens. This study showed much higher response rates with blinatumomab than with the chemotherapy regimens (CR with full, partial, or incomplete hematologic recovery, 44% vs. 25%, respectively), Dr. Advani said (N Engl J Med. 2017 Mar 2;376[9]:836-47).

“The main things to remember [are that blinatumomab is] generally very well tolerated and it has been shown to be superior over standard chemotherapy,” she said. “I think it’s a very good drug to use as a bridge to transplant.”

One setting where blinatumomab perhaps should not be used is in patients with central nervous system disease, she noted.

“There is some concern, at least theoretically, that if you have to use concurrent intrathecal chemo along with blinatumomab, there could be some neurotoxicity,” Dr. Advani said, adding that there are no clear data in that setting because patients with CNS disease were not included in the trials.

Patients with high tumor burden may also be poor candidates for blinatumomab because they tend to have lower response rates.

“That doesn’t mean you can’t use it, but you have to kind of think about what the best option would be,” she said.

Additionally, patients treated with CAR T-cell therapy may develop CD19 loss or CD19-negative disease, and blinatumomab should be avoided in these patients.

“The nice thing ... is you don’t have to worry about veno-occlusive disease [VOD] in patients who are proceeding to transplant,” she said, explaining that no increased risk of VOD was seen in these trials.
 

Inotuzumab

Inotuzumab, which was approved in 2017, differs from blinatumomab in that it is an anti-CD22-calicheamicin conjugate; however, it also showed high response rates in the initial phase 2 trial in relapsed/refractory ALL. The overall response rate was 57%, with 18% achieving a complete response and 63% achieving complete molecular remission.

Of 49 treated patients, 22 patients proceeded to allogeneic transplant, and 5 of those developed VOD.

“Interestingly, four out of five of these patients had received a clofarabine-based preparative regimen, and this likely explains why there was a higher risk of VOD in this study,” she said, noting that the VOD risk has been lower in subsequent studies of inotuzumab.

The international INO-VATE ALL study (NCT01564784) that led to FDA approval was similar in design to the TOWER study in that it compared inotuzumab with standard chemotherapy regimens, and response rates were clearly higher (81% vs. 33%) with inotuzumab (N Engl J Med. 2016 Aug 25;375[8]:740-53).

The VOD risk in the INO-VATE trial was 11%, and it seemed to be higher in those who received dual alkylator–conditioning regimens, which are commonly used in Europe.

Longer-term outcomes after transplant in INO-VATE participants show that median survival has not been reached.

“It’s encouraging that with longer follow-up these patients actually look like they’re doing well,” Dr. Advani said, adding that inotuzumab is a good treatment option for relapsed patients with high disease burden or with CNS disease.

The continuous hookup required for this treatment may be problematic for some younger and older patients, but it is generally not an issue, she noted.

It is important, though, to give as few cycles prior to transplant as possible and to “really think about the preparative regimen to decrease the risk of VOD.”
 

CAR T-cell therapy

As for CAR T-cell therapy in the relapsed/refractory ALL setting, tisagenlecleucel was approved in 2017 for those up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse.

Approval was based on a single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had prior transplant. The confirmed overall remission rate was 82%, with a 63% CR rate and 19% CRi rate.

“This is a very exciting area,” Dr. Advani said. “There are multiple trials being done in adults with ALL to really look at the older subgroup of patients.”
 

Overall outcomes

“These treatments we have now really seem to be effective in the relapse setting, but the problem is that once patients relapse and then go to transplant, their overall survival is still poor,” Dr. Advani said. “So the question is how can we improve the up-front treatment of patients so that hopefully they don’t relapse, and hopefully we also can send a smaller number of patients to transplant.”

Two trials seek to address this, she said.

The A041501 study (NCT03150693) is comparing C10403 chemotherapy with C10403 induction followed by two cycles of inotuzumab before continuing with chemotherapy in adults under age 40 years with previously untreated B ALL.

The primary objective is improved 3-year event-free survival, she said, adding that minimal residual disease (MRD) testing will be used and that CD20-positive patients will receive rituximab, as is now standard.

The phase 3 E1910 study (NCT02003222) is evaluating up-front blinatumomab in patients aged 30-70 years with newly diagnosed BCR-ABL–negative B-lineage ALL. This trial was complicated by the recent approval of blinatumomab for MRD-positive disease, which rendered randomization of MRD-positive patients unethical. MRD-negative patients will be randomized, however.

“The hope is that, by incorporating blinatumomab up front, this will again improve outcomes for patients,” she said.

Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.

sworcester@mdedge.com

CHICAGO – Novel antibodies are improving outcomes in relapsed and refractory acute lymphoblastic leukemia (ALL), and the hope is that they will also show benefit in the up-front treatment setting and thereby improve overall outcomes, according to Anjali Advani, MD.

“It has been a really exciting time in ALL because several drugs have now been FDA approved: blinatumomab, inotuzumab, and now – for patients who are less than 26 years of age – we actually have CAR [chimeric antigen receptor] T cells that have been approved,” Dr. Advani, a hematologist and director of the inpatient leukemia program at the Cleveland Clinic said at the American Society of Hematology Meeting on Hematologic Malignancies.

At the time of relapse, however, the only known cure is allogeneic bone marrow transplant. That may change as more data regarding CAR T cells become available, but the typical goal at this time is to get patients into remission and then to transplant, she said.
 

Blinatumomab

“Blinatumomab is a very interesting antibody,” Dr. Advani said, explaining that it is a bispecific, T cell–engaging antibody with an anti-CD3 arm that engages the T cell and an anti-CD19 antibody that engages the B lymphoblast.

“Basically this drug then acts as a bridge between the lymphoblast and the T cell to lead to proliferation of the cytotoxic T cell and apoptosis of the lymphoblast,” she said. “It’s interesting because it’s an antibody but it actually works through the immune system through the T cells.”

The largest study to date of blinatumomab in the relapsed/refractory ALL setting showed a 43% complete remission (CR) or CR with partial hematological recovery of peripheral blood counts (CRi) in 189 treated patients with Philadelphia chromosome–negative ALL. It also demonstrated and a 39% rate of salvage status 2 or higher, she said, noting that the response was impressive given that about 30% of participants had a prior transplant (Lancet. 2015 Jan 1;16[1]:57-66).

Of the responders, 40% went on to allogeneic transplant. This was a “fairly impressive” rate given the 30% prior-transplant rate, Dr. Advani said.

“There also was a high minimal residual disease response in those patients achieving CR,” she said, adding that the only significant predictor of response was bone marrow blast count; patients with 50% or more blasts in the bone marrow had a reduced likelihood of responding to blinatumomab.

The agent was approved by the Food and Drug Administration in December 2014 based on these phase 2 findings.

Adverse events mainly included toxicities that are expected in leukemia patients; the most frequent were febrile neutropenia, neutropenia, and anemia. Two patients developed cytokine release syndrome, and about half of the blinatumomab-treated patients experienced neurological events, although the majority of those were grade 1 or 2 and were easily manageable, she noted.

Blinatumomab was further evaluated in the phase 3 TOWER study (NCT02013167), which compared it with standard-of-care chemotherapy regimens. This study showed much higher response rates with blinatumomab than with the chemotherapy regimens (CR with full, partial, or incomplete hematologic recovery, 44% vs. 25%, respectively), Dr. Advani said (N Engl J Med. 2017 Mar 2;376[9]:836-47).

“The main things to remember [are that blinatumomab is] generally very well tolerated and it has been shown to be superior over standard chemotherapy,” she said. “I think it’s a very good drug to use as a bridge to transplant.”

One setting where blinatumomab perhaps should not be used is in patients with central nervous system disease, she noted.

“There is some concern, at least theoretically, that if you have to use concurrent intrathecal chemo along with blinatumomab, there could be some neurotoxicity,” Dr. Advani said, adding that there are no clear data in that setting because patients with CNS disease were not included in the trials.

Patients with high tumor burden may also be poor candidates for blinatumomab because they tend to have lower response rates.

“That doesn’t mean you can’t use it, but you have to kind of think about what the best option would be,” she said.

Additionally, patients treated with CAR T-cell therapy may develop CD19 loss or CD19-negative disease, and blinatumomab should be avoided in these patients.

“The nice thing ... is you don’t have to worry about veno-occlusive disease [VOD] in patients who are proceeding to transplant,” she said, explaining that no increased risk of VOD was seen in these trials.
 

Inotuzumab

Inotuzumab, which was approved in 2017, differs from blinatumomab in that it is an anti-CD22-calicheamicin conjugate; however, it also showed high response rates in the initial phase 2 trial in relapsed/refractory ALL. The overall response rate was 57%, with 18% achieving a complete response and 63% achieving complete molecular remission.

Of 49 treated patients, 22 patients proceeded to allogeneic transplant, and 5 of those developed VOD.

“Interestingly, four out of five of these patients had received a clofarabine-based preparative regimen, and this likely explains why there was a higher risk of VOD in this study,” she said, noting that the VOD risk has been lower in subsequent studies of inotuzumab.

The international INO-VATE ALL study (NCT01564784) that led to FDA approval was similar in design to the TOWER study in that it compared inotuzumab with standard chemotherapy regimens, and response rates were clearly higher (81% vs. 33%) with inotuzumab (N Engl J Med. 2016 Aug 25;375[8]:740-53).

The VOD risk in the INO-VATE trial was 11%, and it seemed to be higher in those who received dual alkylator–conditioning regimens, which are commonly used in Europe.

Longer-term outcomes after transplant in INO-VATE participants show that median survival has not been reached.

“It’s encouraging that with longer follow-up these patients actually look like they’re doing well,” Dr. Advani said, adding that inotuzumab is a good treatment option for relapsed patients with high disease burden or with CNS disease.

The continuous hookup required for this treatment may be problematic for some younger and older patients, but it is generally not an issue, she noted.

It is important, though, to give as few cycles prior to transplant as possible and to “really think about the preparative regimen to decrease the risk of VOD.”
 

CAR T-cell therapy

As for CAR T-cell therapy in the relapsed/refractory ALL setting, tisagenlecleucel was approved in 2017 for those up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse.

Approval was based on a single-arm trial of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had prior transplant. The confirmed overall remission rate was 82%, with a 63% CR rate and 19% CRi rate.

“This is a very exciting area,” Dr. Advani said. “There are multiple trials being done in adults with ALL to really look at the older subgroup of patients.”
 

Overall outcomes

“These treatments we have now really seem to be effective in the relapse setting, but the problem is that once patients relapse and then go to transplant, their overall survival is still poor,” Dr. Advani said. “So the question is how can we improve the up-front treatment of patients so that hopefully they don’t relapse, and hopefully we also can send a smaller number of patients to transplant.”

Two trials seek to address this, she said.

The A041501 study (NCT03150693) is comparing C10403 chemotherapy with C10403 induction followed by two cycles of inotuzumab before continuing with chemotherapy in adults under age 40 years with previously untreated B ALL.

The primary objective is improved 3-year event-free survival, she said, adding that minimal residual disease (MRD) testing will be used and that CD20-positive patients will receive rituximab, as is now standard.

The phase 3 E1910 study (NCT02003222) is evaluating up-front blinatumomab in patients aged 30-70 years with newly diagnosed BCR-ABL–negative B-lineage ALL. This trial was complicated by the recent approval of blinatumomab for MRD-positive disease, which rendered randomization of MRD-positive patients unethical. MRD-negative patients will be randomized, however.

“The hope is that, by incorporating blinatumomab up front, this will again improve outcomes for patients,” she said.

Dr. Advani reported consultancy for Pfizer; research funding from Genzyme, Novartis, Pfizer, and Sigma Tau; and honoraria from Genzyme, Pfizer, and Sigma Tau. She is also on the speakers bureau for Sigma Tau.

sworcester@mdedge.com

The Food and Drug Administration has granted priority review to an anti-CD20, chemotherapy-free combination – ibrutinib plus obinutuzumab – for the frontline treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).

The agency will review the combination in previously untreated adults.

Ibrutinib (Imbruvica) is already approved as a single agent for adults with CLL/SLL for all lines of therapy and in combination with bendamustine and rituximab. Obinutuzumab (Gazyva) has been approved for patients with previously untreated CLL, in combination with chlorambucil.

The current application, which is sponsored by Janssen and Pharmacyclics, is based on results from the phase 3 iLLUMINATE trial. Preliminary results announced by Janssen and Pharmacyclics showed that ibrutinib plus obinutuzumab had statistically significant better progression-free survival, compared with chlorambucil plus obinutuzumab, as assessed by an independent review committee.

Complete results from the trial will be presented at an upcoming medical meeting, according to the sponsors.

mschneider@mdedge.com

The Food and Drug Administration has granted priority review to an anti-CD20, chemotherapy-free combination – ibrutinib plus obinutuzumab – for the frontline treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).

The agency will review the combination in previously untreated adults.

Ibrutinib (Imbruvica) is already approved as a single agent for adults with CLL/SLL for all lines of therapy and in combination with bendamustine and rituximab. Obinutuzumab (Gazyva) has been approved for patients with previously untreated CLL, in combination with chlorambucil.

The current application, which is sponsored by Janssen and Pharmacyclics, is based on results from the phase 3 iLLUMINATE trial. Preliminary results announced by Janssen and Pharmacyclics showed that ibrutinib plus obinutuzumab had statistically significant better progression-free survival, compared with chlorambucil plus obinutuzumab, as assessed by an independent review committee.

Complete results from the trial will be presented at an upcoming medical meeting, according to the sponsors.

mschneider@mdedge.com

The Food and Drug Administration has granted priority review to an anti-CD20, chemotherapy-free combination – ibrutinib plus obinutuzumab – for the frontline treatment of chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL).

The agency will review the combination in previously untreated adults.

Ibrutinib (Imbruvica) is already approved as a single agent for adults with CLL/SLL for all lines of therapy and in combination with bendamustine and rituximab. Obinutuzumab (Gazyva) has been approved for patients with previously untreated CLL, in combination with chlorambucil.

The current application, which is sponsored by Janssen and Pharmacyclics, is based on results from the phase 3 iLLUMINATE trial. Preliminary results announced by Janssen and Pharmacyclics showed that ibrutinib plus obinutuzumab had statistically significant better progression-free survival, compared with chlorambucil plus obinutuzumab, as assessed by an independent review committee.

Complete results from the trial will be presented at an upcoming medical meeting, according to the sponsors.

mschneider@mdedge.com

TORONTO – Concurrent atezolizumab immunotherapy and chemoradiation followed by atezolizumab consolidation and maintenance was safe and showed promising efficacy in patients with locally advanced non–small cell lung cancer (LA-NSCLC) in the phase 2 DETERRED trial.

In part 1 of the single-institution study, 10 patients underwent chemoradiation therapy (CRT) with low-dose carboplatin/paclitaxel followed by high-dose consolidation chemotherapy plus atezolizumab and atezolizumab maintenance for 1 year. Six patients in this group (60%) experienced grade 3 or higher adverse events (AEs). In part 2 of the study, 30 patients received concurrent atezolizumab and CRT followed by the same consolidation and maintenance used in part 1, and 17 (57%) experienced grade 3 or higher AEs, Steven H. Lin, MD, reported at the World Conference on Lung Cancer.

Grade 3 or higher AEs were associated with atezolizumab in 30% and 23% of patients in part 1 and part 2, respectively. In part 1 these included dyspnea, arthralgia, and a grade 5 tracheoesophageal fistula, and in part 2 included diarrhea, pneumonitis, nephritis, fatigue, respiratory failure, and heart failure in one patient each, and fatigue in three patients.

Grade 2 radiation pneumonitis was seen in two patients in each group, Dr. Lin of the University of Texas MD Anderson Cancer Center, Houston, said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.

Withdrawals caused by toxicity occurred in three and four patients in part 1 and 2, respectively.

Four patients in part 1 progressed with disease during atezolizumab maintenance and five have died from either tracheoesophageal fistula or grade 5 toxicity. In part 2, six have progressed and five have died, most caused by cancer progression, he said.

Preliminary survival data show a median progression-free survival of 20.1 months in part 1, whereas progression-free survival was not reached in part 2. Median overall survival at 1 year was 60% versus 77% in parts 1 and 2, respectively.

Consolidation immunotherapy with durvalumab after CRT has been the standard of care for LA-NSCLC as established by the phase 3 PACIFIC trial, but evidence from that trial also suggested timing of the start of immunotherapy may be important.

“If patients were randomized less than 14 days after starting durvalumab there was a trend, or suggestion, that there was potentially an improvement in progression-free survival, compared with patients who started durvalumab outside of this window,” Dr. Lin said, noting that this is also supported by some preclinical evidence showing that the effectiveness of immunotherapies may be enhanced when combined with concurrent CRT.

The DETERRED trial evaluated the safety and preliminary efficacy of this approach followed by consolidation full-dose carboplatin/paclitaxel with atezolizumab and maintenance atezolizumab for up to 1 year for LA-NSCLC.

Patients, who had a median age of 66.5 years, were enrolled between February 2016 and April 2018; 15% had stage II disease, 50% had stage IIIA, and 35% had stage IIIB. Most (58%) had adenocarcinoma.

In part 1, standard chemoradiation including low-dose carboplatin/paclitaxel was given for 6 weeks. After CRT completion, patients were given consolidated high-dose chemotherapy with carboplatin/paclitaxel and intravenous atezolizumab was started at that point at a dose of 1,200 mg every 3 weeks for up to 1 year from the first dose. Part 2 was initiated based on the safety data in part 1 showing no concerning toxicities. In part 2, atezolizumab was given concurrently with CRT followed by the same consolidated regimen and maintenance.

“So the take-home message from this study is that the concurrent immunotherapy with atezolizumab and chemoradiation therapy can be administered safely,” Dr. Lin said, adding that grade 3+ pneumonitis is low and not significantly increased with the addition of concurrent atezolizumab with CRT.

Early efficacy analyses also show promising results, but further follow-up is needed, he said.

Trials now being planned include a phase 3 trial comparing the DETERRED and PACIFIC regimens, a phase 1 study comparing durvalumab with radiation to replace chemotherapy in programmed death–ligand 1–high locoregionally advanced NSCLC, and a phase 1 study of nivolumab with radiation to replace chemotherapy in locoregionally advanced NSCLC, he noted.

The DETERRED trial was supported by Genentech. Dr. Lin has received research grants from STCube Pharmaceuticals, Hitachi Chemical Diagnostics, Genentech, New River Labs, and BeyondSpring Pharmaceuticals, and is an advisory board member for AstraZeneca and New River Labs.

sworcester@mdedge.com

SOURCE: Lin SH et al. WCLC 2018, Abstract OA01.06.

TORONTO – Concurrent atezolizumab immunotherapy and chemoradiation followed by atezolizumab consolidation and maintenance was safe and showed promising efficacy in patients with locally advanced non–small cell lung cancer (LA-NSCLC) in the phase 2 DETERRED trial.

In part 1 of the single-institution study, 10 patients underwent chemoradiation therapy (CRT) with low-dose carboplatin/paclitaxel followed by high-dose consolidation chemotherapy plus atezolizumab and atezolizumab maintenance for 1 year. Six patients in this group (60%) experienced grade 3 or higher adverse events (AEs). In part 2 of the study, 30 patients received concurrent atezolizumab and CRT followed by the same consolidation and maintenance used in part 1, and 17 (57%) experienced grade 3 or higher AEs, Steven H. Lin, MD, reported at the World Conference on Lung Cancer.

Grade 3 or higher AEs were associated with atezolizumab in 30% and 23% of patients in part 1 and part 2, respectively. In part 1 these included dyspnea, arthralgia, and a grade 5 tracheoesophageal fistula, and in part 2 included diarrhea, pneumonitis, nephritis, fatigue, respiratory failure, and heart failure in one patient each, and fatigue in three patients.

Grade 2 radiation pneumonitis was seen in two patients in each group, Dr. Lin of the University of Texas MD Anderson Cancer Center, Houston, said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.

Withdrawals caused by toxicity occurred in three and four patients in part 1 and 2, respectively.

Four patients in part 1 progressed with disease during atezolizumab maintenance and five have died from either tracheoesophageal fistula or grade 5 toxicity. In part 2, six have progressed and five have died, most caused by cancer progression, he said.

Preliminary survival data show a median progression-free survival of 20.1 months in part 1, whereas progression-free survival was not reached in part 2. Median overall survival at 1 year was 60% versus 77% in parts 1 and 2, respectively.

Consolidation immunotherapy with durvalumab after CRT has been the standard of care for LA-NSCLC as established by the phase 3 PACIFIC trial, but evidence from that trial also suggested timing of the start of immunotherapy may be important.

“If patients were randomized less than 14 days after starting durvalumab there was a trend, or suggestion, that there was potentially an improvement in progression-free survival, compared with patients who started durvalumab outside of this window,” Dr. Lin said, noting that this is also supported by some preclinical evidence showing that the effectiveness of immunotherapies may be enhanced when combined with concurrent CRT.

The DETERRED trial evaluated the safety and preliminary efficacy of this approach followed by consolidation full-dose carboplatin/paclitaxel with atezolizumab and maintenance atezolizumab for up to 1 year for LA-NSCLC.

Patients, who had a median age of 66.5 years, were enrolled between February 2016 and April 2018; 15% had stage II disease, 50% had stage IIIA, and 35% had stage IIIB. Most (58%) had adenocarcinoma.

In part 1, standard chemoradiation including low-dose carboplatin/paclitaxel was given for 6 weeks. After CRT completion, patients were given consolidated high-dose chemotherapy with carboplatin/paclitaxel and intravenous atezolizumab was started at that point at a dose of 1,200 mg every 3 weeks for up to 1 year from the first dose. Part 2 was initiated based on the safety data in part 1 showing no concerning toxicities. In part 2, atezolizumab was given concurrently with CRT followed by the same consolidated regimen and maintenance.

“So the take-home message from this study is that the concurrent immunotherapy with atezolizumab and chemoradiation therapy can be administered safely,” Dr. Lin said, adding that grade 3+ pneumonitis is low and not significantly increased with the addition of concurrent atezolizumab with CRT.

Early efficacy analyses also show promising results, but further follow-up is needed, he said.

Trials now being planned include a phase 3 trial comparing the DETERRED and PACIFIC regimens, a phase 1 study comparing durvalumab with radiation to replace chemotherapy in programmed death–ligand 1–high locoregionally advanced NSCLC, and a phase 1 study of nivolumab with radiation to replace chemotherapy in locoregionally advanced NSCLC, he noted.

The DETERRED trial was supported by Genentech. Dr. Lin has received research grants from STCube Pharmaceuticals, Hitachi Chemical Diagnostics, Genentech, New River Labs, and BeyondSpring Pharmaceuticals, and is an advisory board member for AstraZeneca and New River Labs.

sworcester@mdedge.com

SOURCE: Lin SH et al. WCLC 2018, Abstract OA01.06.

TORONTO – Concurrent atezolizumab immunotherapy and chemoradiation followed by atezolizumab consolidation and maintenance was safe and showed promising efficacy in patients with locally advanced non–small cell lung cancer (LA-NSCLC) in the phase 2 DETERRED trial.

In part 1 of the single-institution study, 10 patients underwent chemoradiation therapy (CRT) with low-dose carboplatin/paclitaxel followed by high-dose consolidation chemotherapy plus atezolizumab and atezolizumab maintenance for 1 year. Six patients in this group (60%) experienced grade 3 or higher adverse events (AEs). In part 2 of the study, 30 patients received concurrent atezolizumab and CRT followed by the same consolidation and maintenance used in part 1, and 17 (57%) experienced grade 3 or higher AEs, Steven H. Lin, MD, reported at the World Conference on Lung Cancer.

Grade 3 or higher AEs were associated with atezolizumab in 30% and 23% of patients in part 1 and part 2, respectively. In part 1 these included dyspnea, arthralgia, and a grade 5 tracheoesophageal fistula, and in part 2 included diarrhea, pneumonitis, nephritis, fatigue, respiratory failure, and heart failure in one patient each, and fatigue in three patients.

Grade 2 radiation pneumonitis was seen in two patients in each group, Dr. Lin of the University of Texas MD Anderson Cancer Center, Houston, said at the meeting, which was sponsored by the International Association for the Study of Lung Cancer.

Withdrawals caused by toxicity occurred in three and four patients in part 1 and 2, respectively.

Four patients in part 1 progressed with disease during atezolizumab maintenance and five have died from either tracheoesophageal fistula or grade 5 toxicity. In part 2, six have progressed and five have died, most caused by cancer progression, he said.

Preliminary survival data show a median progression-free survival of 20.1 months in part 1, whereas progression-free survival was not reached in part 2. Median overall survival at 1 year was 60% versus 77% in parts 1 and 2, respectively.

Consolidation immunotherapy with durvalumab after CRT has been the standard of care for LA-NSCLC as established by the phase 3 PACIFIC trial, but evidence from that trial also suggested timing of the start of immunotherapy may be important.

“If patients were randomized less than 14 days after starting durvalumab there was a trend, or suggestion, that there was potentially an improvement in progression-free survival, compared with patients who started durvalumab outside of this window,” Dr. Lin said, noting that this is also supported by some preclinical evidence showing that the effectiveness of immunotherapies may be enhanced when combined with concurrent CRT.

The DETERRED trial evaluated the safety and preliminary efficacy of this approach followed by consolidation full-dose carboplatin/paclitaxel with atezolizumab and maintenance atezolizumab for up to 1 year for LA-NSCLC.

Patients, who had a median age of 66.5 years, were enrolled between February 2016 and April 2018; 15% had stage II disease, 50% had stage IIIA, and 35% had stage IIIB. Most (58%) had adenocarcinoma.

In part 1, standard chemoradiation including low-dose carboplatin/paclitaxel was given for 6 weeks. After CRT completion, patients were given consolidated high-dose chemotherapy with carboplatin/paclitaxel and intravenous atezolizumab was started at that point at a dose of 1,200 mg every 3 weeks for up to 1 year from the first dose. Part 2 was initiated based on the safety data in part 1 showing no concerning toxicities. In part 2, atezolizumab was given concurrently with CRT followed by the same consolidated regimen and maintenance.

“So the take-home message from this study is that the concurrent immunotherapy with atezolizumab and chemoradiation therapy can be administered safely,” Dr. Lin said, adding that grade 3+ pneumonitis is low and not significantly increased with the addition of concurrent atezolizumab with CRT.

Early efficacy analyses also show promising results, but further follow-up is needed, he said.

Trials now being planned include a phase 3 trial comparing the DETERRED and PACIFIC regimens, a phase 1 study comparing durvalumab with radiation to replace chemotherapy in programmed death–ligand 1–high locoregionally advanced NSCLC, and a phase 1 study of nivolumab with radiation to replace chemotherapy in locoregionally advanced NSCLC, he noted.

The DETERRED trial was supported by Genentech. Dr. Lin has received research grants from STCube Pharmaceuticals, Hitachi Chemical Diagnostics, Genentech, New River Labs, and BeyondSpring Pharmaceuticals, and is an advisory board member for AstraZeneca and New River Labs.

sworcester@mdedge.com

SOURCE: Lin SH et al. WCLC 2018, Abstract OA01.06.

Epacadostat, a highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme, was well tolerated when combined with pembrolizumab and demonstrated encouraging antitumor activity in multiple types of advanced solid tumors, according to the results of a phase l/ll trial.

Tumors may evade immunosurveillance through upregulation of the IDO1 enzyme, and thus there is a great interest in developing combination therapies that can target various immune evasion pathways to improve therapeutic response and outcomes. In this study, the authors evaluated the investigational agent epacadostat combined with pembrolizumab in 62 patients with advanced solid tumors.

In the dose escalation phase, patents received increasing doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, epacadostat at 50, 100, or 300 mg was given twice per day, plus pembrolizumab 200 mg every 3 weeks. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached.

Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck, reported Tara C. Mitchell, MD, of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, and her colleagues. The report is in the Journal of Clinical Oncology.

The authors observed that there was antitumor activity at all epacadostat doses and in several tumor types. A complete response was achieved by 8 patients (treatment naive melanoma [5 patients] and previously treated for advanced/ metastatic melanoma, endometrial adenocarcinoma [EA], or urothelial carcinoma [UC] [1 patient each]), while 17 patients achieved a partial response (treatment-naive melanoma [6 patients], non–small cell lung cancer [NSCLC] [5 patients], renal cell carcinoma [RCC] and UC [2 patients each], and EA and squamous cell carcinoma of the head and neck [1 patient each]).

Most patients (n = 52, 84%) experienced treatment-related adverse events (TRAEs), the most frequently observed being fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%). Grade 3/4 TRAEs occurred in 24% of patients, and 7 patients (11%) discontinued their treatment because of TRAEs. There were no deaths associated with TRAEs.

“The safety profile observed with epacadostat plus pembrolizumab compares favorably with studies of other combination immunotherapies,” wrote Dr. Mitchell and her colleagues. “Although not powered to evaluate efficacy, the phase I portion of this study showed that epacadostat plus pembrolizumab had encouraging and durable antitumor activity,” they said.

SOURCE: Mitchell TC et al. J Clin Oncol. 2018 Sep 28. doi: 10.1200/JCO.2018.78.9602.

Epacadostat, a highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme, was well tolerated when combined with pembrolizumab and demonstrated encouraging antitumor activity in multiple types of advanced solid tumors, according to the results of a phase l/ll trial.

Tumors may evade immunosurveillance through upregulation of the IDO1 enzyme, and thus there is a great interest in developing combination therapies that can target various immune evasion pathways to improve therapeutic response and outcomes. In this study, the authors evaluated the investigational agent epacadostat combined with pembrolizumab in 62 patients with advanced solid tumors.

In the dose escalation phase, patents received increasing doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, epacadostat at 50, 100, or 300 mg was given twice per day, plus pembrolizumab 200 mg every 3 weeks. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached.

Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck, reported Tara C. Mitchell, MD, of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, and her colleagues. The report is in the Journal of Clinical Oncology.

The authors observed that there was antitumor activity at all epacadostat doses and in several tumor types. A complete response was achieved by 8 patients (treatment naive melanoma [5 patients] and previously treated for advanced/ metastatic melanoma, endometrial adenocarcinoma [EA], or urothelial carcinoma [UC] [1 patient each]), while 17 patients achieved a partial response (treatment-naive melanoma [6 patients], non–small cell lung cancer [NSCLC] [5 patients], renal cell carcinoma [RCC] and UC [2 patients each], and EA and squamous cell carcinoma of the head and neck [1 patient each]).

Most patients (n = 52, 84%) experienced treatment-related adverse events (TRAEs), the most frequently observed being fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%). Grade 3/4 TRAEs occurred in 24% of patients, and 7 patients (11%) discontinued their treatment because of TRAEs. There were no deaths associated with TRAEs.

“The safety profile observed with epacadostat plus pembrolizumab compares favorably with studies of other combination immunotherapies,” wrote Dr. Mitchell and her colleagues. “Although not powered to evaluate efficacy, the phase I portion of this study showed that epacadostat plus pembrolizumab had encouraging and durable antitumor activity,” they said.

SOURCE: Mitchell TC et al. J Clin Oncol. 2018 Sep 28. doi: 10.1200/JCO.2018.78.9602.

Epacadostat, a highly selective oral inhibitor of the indoleamine 2,3-dioxygenase 1 (IDO1) enzyme, was well tolerated when combined with pembrolizumab and demonstrated encouraging antitumor activity in multiple types of advanced solid tumors, according to the results of a phase l/ll trial.

Tumors may evade immunosurveillance through upregulation of the IDO1 enzyme, and thus there is a great interest in developing combination therapies that can target various immune evasion pathways to improve therapeutic response and outcomes. In this study, the authors evaluated the investigational agent epacadostat combined with pembrolizumab in 62 patients with advanced solid tumors.

In the dose escalation phase, patents received increasing doses of oral epacadostat (25, 50, 100, or 300 mg) twice per day plus intravenous pembrolizumab 2 mg/kg or 200 mg every 3 weeks. During the safety expansion, epacadostat at 50, 100, or 300 mg was given twice per day, plus pembrolizumab 200 mg every 3 weeks. The maximum tolerated dose of epacadostat in combination with pembrolizumab was not reached.

Objective responses (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) occurred in 12 (55%) of 22 patients with melanoma and in patients with non–small-cell lung cancer, renal cell carcinoma, endometrial adenocarcinoma, urothelial carcinoma, and squamous cell carcinoma of the head and neck, reported Tara C. Mitchell, MD, of the Abramson Cancer Center, University of Pennsylvania, Philadelphia, and her colleagues. The report is in the Journal of Clinical Oncology.

The authors observed that there was antitumor activity at all epacadostat doses and in several tumor types. A complete response was achieved by 8 patients (treatment naive melanoma [5 patients] and previously treated for advanced/ metastatic melanoma, endometrial adenocarcinoma [EA], or urothelial carcinoma [UC] [1 patient each]), while 17 patients achieved a partial response (treatment-naive melanoma [6 patients], non–small cell lung cancer [NSCLC] [5 patients], renal cell carcinoma [RCC] and UC [2 patients each], and EA and squamous cell carcinoma of the head and neck [1 patient each]).

Most patients (n = 52, 84%) experienced treatment-related adverse events (TRAEs), the most frequently observed being fatigue (36%), rash (36%), arthralgia (24%), pruritus (23%), and nausea (21%). Grade 3/4 TRAEs occurred in 24% of patients, and 7 patients (11%) discontinued their treatment because of TRAEs. There were no deaths associated with TRAEs.

“The safety profile observed with epacadostat plus pembrolizumab compares favorably with studies of other combination immunotherapies,” wrote Dr. Mitchell and her colleagues. “Although not powered to evaluate efficacy, the phase I portion of this study showed that epacadostat plus pembrolizumab had encouraging and durable antitumor activity,” they said.

SOURCE: Mitchell TC et al. J Clin Oncol. 2018 Sep 28. doi: 10.1200/JCO.2018.78.9602.