Neil Osterweil

ATLANTA – A combination of the epidermal growth factor receptor–targeted agent osimertinib (Tagrisso) with selumetinib, an investigational inhibitor of MEK1/2, was safe and associated with partial responses in about one-third of patients with non–small cell lung cancer in the phase 1b TATTON trial.

Neil Osterweil/MDedge News

In the dose-finding phase of the trial, the objective response rate was 42% for 36 patients treated with the combination either as a second- or third-line therapy, or following prior therapy for the epidermal growth factor receptor (EGFR) T70M mutation. In the dose-expansion phase of the trial, the ORR was 34% for 47 patients treated regardless of mutational status, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute at Emory University, Atlanta.

“We conclude that combining osimertinib with intermittent selumetinib is feasible with manageable toxicity and has already demonstrated promising preliminary anticancer activity,” he said at the annual meeting of the American Association for Cancer Research.

The EGFR T790M mutation is the most common cause of resistance in patients with non–small cell lung cancer (NSCLC) bearing EGFR mutations who are treated with first- or second-generation, EGFR-targeted tyrosine kinase inhibitors (TKI). Up-regulation of the RAS/RAF/MEK/ERK signaling pathway has also been implicated in NSCLC resistance to EGFR-targeted TKIs.

Selumetinib is an oral, potent, and selective inhibitor of MEK1/2 with a short half-life.

In the phase 3 SELECT-1 trial, selumetinib in combination with docetaxel did not significantly improve progression-free survival, compared with docetaxel alone as second-line therapy for patients with KRAS-mutated NSCLC.

Therapeutic rationale

Invited discussant Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., said that there is sound rationale for combining osimertinib and selumetinib in EGFR-mutant NSCLC.

Neil Osterweil/MDedge News

In addition to the up-regulation of the RAS/RAF/MEK/ERK pathway noted before, resistance to osimertinib has been shown in models of EGFR-mutant NSCLC to develop from aberrant ERK signaling mediation in part by MEK1 amplification, and MEK kinase inhibitors can restore sensitivity to osimertinib in resistant cells, he said.

As previously reported, the TATTON investigators are evaluating in separate cohorts combinations of osimertinib with savolitinib, an investigational MET inhibitor for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents, or with selumetinib for patients with advanced EGFR-mutated NSCLC that had progressed on prior therapy, including EGFR-targeted TKIs, irrespective of T790M or KRAS status.

In part A, the dose-finding phase, patients received osimertinib 80 mg daily plus intermittent or continuous selumetinib. Asian patients received continuous selumetinib 25/50 mg twice daily, while other patients received continuous selumetinib 50/75 mg twice daily, or intermittent selumetinib 75 mg twice daily 4 days on, 3 days off or on days 1 and 4 of each week of treatment.

In part B, the dose-expansion phase, patients received osimertinib plus intermittent selumetinib 75 mg twice daily on the 4 days on/3 days off schedule.

An analysis of preliminary antitumor activity in part A showed an ORR in 15 of 36 patients (42%); all were partial responses (PR). In addition, 14 patients (39%) had stable disease at 6 weeks, 3 had progressive disease, 2 died, and 2 were not evaluable. The median duration of response was 16.6 months; 77% of the patients had responses lasting at least 12 months.

In part B, 16 of 47 patients enrolled (34%) had confirmed PR, and 16 had stable disease. Of the remaining patients, 11 had disease progression, 2 died, and 2 were not evaluable. The median duration of response in this group was 9.1 months, and 31% of patients remained in response at 12 months.

The most common treatment-related adverse events in the dose-finding phase were diarrhea in 75% of patients, nausea in 39% and fatigue in 33%. Dose-limiting toxicities occurred in six patients, all of whom had been treated with continuous selumetinib. These toxicities, all grade 3, include liver enzyme increases, diarrhea, asthenia, dizziness, nausea, and pneumonitis.

The most common treatment-related adverse events in the dose-expansion phase were diarrhea in 81%, stomatitis in 32%, and paronychia in 30% of patients.

Results ‘okay’

In his discussion, Dr. Herbst commented that the part A results “look okay, until you realize that the most of the activity is in those patients who are T790M-positive, who have not been exposed in this cohort to a third-generation T790M inhibitor.” Patients with the mutation who are treated with third-generation inhibitors would be expected to have a 78% response rate.

Part B included a few more patients with responses who were negative for T790M. “My thought here is that perhaps there is a biomarker” for selecting patients most likely to benefit from the combination, he said.

For MET-negative patients, the combination appears to have manageable toxicities with noncontinuous dosing of selumetinib, and there may be benefit to using it in the first-line setting in select patients, but that will require further trials and identification of suitable biomarkers, Dr. Herbst summarized.

TATTON was sponsored by AstraZeneca. Dr. Ramalingam reported receiving research support from the company and consulting/contracting with others. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and serving as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCE: Ramalingam SS et al. AACR 2019, Abstract CT034.

ATLANTA – A combination of the epidermal growth factor receptor–targeted agent osimertinib (Tagrisso) with selumetinib, an investigational inhibitor of MEK1/2, was safe and associated with partial responses in about one-third of patients with non–small cell lung cancer in the phase 1b TATTON trial.

Neil Osterweil/MDedge News

In the dose-finding phase of the trial, the objective response rate was 42% for 36 patients treated with the combination either as a second- or third-line therapy, or following prior therapy for the epidermal growth factor receptor (EGFR) T70M mutation. In the dose-expansion phase of the trial, the ORR was 34% for 47 patients treated regardless of mutational status, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute at Emory University, Atlanta.

“We conclude that combining osimertinib with intermittent selumetinib is feasible with manageable toxicity and has already demonstrated promising preliminary anticancer activity,” he said at the annual meeting of the American Association for Cancer Research.

The EGFR T790M mutation is the most common cause of resistance in patients with non–small cell lung cancer (NSCLC) bearing EGFR mutations who are treated with first- or second-generation, EGFR-targeted tyrosine kinase inhibitors (TKI). Up-regulation of the RAS/RAF/MEK/ERK signaling pathway has also been implicated in NSCLC resistance to EGFR-targeted TKIs.

Selumetinib is an oral, potent, and selective inhibitor of MEK1/2 with a short half-life.

In the phase 3 SELECT-1 trial, selumetinib in combination with docetaxel did not significantly improve progression-free survival, compared with docetaxel alone as second-line therapy for patients with KRAS-mutated NSCLC.

Therapeutic rationale

Invited discussant Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., said that there is sound rationale for combining osimertinib and selumetinib in EGFR-mutant NSCLC.

Neil Osterweil/MDedge News

In addition to the up-regulation of the RAS/RAF/MEK/ERK pathway noted before, resistance to osimertinib has been shown in models of EGFR-mutant NSCLC to develop from aberrant ERK signaling mediation in part by MEK1 amplification, and MEK kinase inhibitors can restore sensitivity to osimertinib in resistant cells, he said.

As previously reported, the TATTON investigators are evaluating in separate cohorts combinations of osimertinib with savolitinib, an investigational MET inhibitor for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents, or with selumetinib for patients with advanced EGFR-mutated NSCLC that had progressed on prior therapy, including EGFR-targeted TKIs, irrespective of T790M or KRAS status.

In part A, the dose-finding phase, patients received osimertinib 80 mg daily plus intermittent or continuous selumetinib. Asian patients received continuous selumetinib 25/50 mg twice daily, while other patients received continuous selumetinib 50/75 mg twice daily, or intermittent selumetinib 75 mg twice daily 4 days on, 3 days off or on days 1 and 4 of each week of treatment.

In part B, the dose-expansion phase, patients received osimertinib plus intermittent selumetinib 75 mg twice daily on the 4 days on/3 days off schedule.

An analysis of preliminary antitumor activity in part A showed an ORR in 15 of 36 patients (42%); all were partial responses (PR). In addition, 14 patients (39%) had stable disease at 6 weeks, 3 had progressive disease, 2 died, and 2 were not evaluable. The median duration of response was 16.6 months; 77% of the patients had responses lasting at least 12 months.

In part B, 16 of 47 patients enrolled (34%) had confirmed PR, and 16 had stable disease. Of the remaining patients, 11 had disease progression, 2 died, and 2 were not evaluable. The median duration of response in this group was 9.1 months, and 31% of patients remained in response at 12 months.

The most common treatment-related adverse events in the dose-finding phase were diarrhea in 75% of patients, nausea in 39% and fatigue in 33%. Dose-limiting toxicities occurred in six patients, all of whom had been treated with continuous selumetinib. These toxicities, all grade 3, include liver enzyme increases, diarrhea, asthenia, dizziness, nausea, and pneumonitis.

The most common treatment-related adverse events in the dose-expansion phase were diarrhea in 81%, stomatitis in 32%, and paronychia in 30% of patients.

Results ‘okay’

In his discussion, Dr. Herbst commented that the part A results “look okay, until you realize that the most of the activity is in those patients who are T790M-positive, who have not been exposed in this cohort to a third-generation T790M inhibitor.” Patients with the mutation who are treated with third-generation inhibitors would be expected to have a 78% response rate.

Part B included a few more patients with responses who were negative for T790M. “My thought here is that perhaps there is a biomarker” for selecting patients most likely to benefit from the combination, he said.

For MET-negative patients, the combination appears to have manageable toxicities with noncontinuous dosing of selumetinib, and there may be benefit to using it in the first-line setting in select patients, but that will require further trials and identification of suitable biomarkers, Dr. Herbst summarized.

TATTON was sponsored by AstraZeneca. Dr. Ramalingam reported receiving research support from the company and consulting/contracting with others. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and serving as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCE: Ramalingam SS et al. AACR 2019, Abstract CT034.

ATLANTA – A combination of the epidermal growth factor receptor–targeted agent osimertinib (Tagrisso) with selumetinib, an investigational inhibitor of MEK1/2, was safe and associated with partial responses in about one-third of patients with non–small cell lung cancer in the phase 1b TATTON trial.

Neil Osterweil/MDedge News

In the dose-finding phase of the trial, the objective response rate was 42% for 36 patients treated with the combination either as a second- or third-line therapy, or following prior therapy for the epidermal growth factor receptor (EGFR) T70M mutation. In the dose-expansion phase of the trial, the ORR was 34% for 47 patients treated regardless of mutational status, reported Suresh S. Ramalingam, MD, from the Winship Cancer Institute at Emory University, Atlanta.

“We conclude that combining osimertinib with intermittent selumetinib is feasible with manageable toxicity and has already demonstrated promising preliminary anticancer activity,” he said at the annual meeting of the American Association for Cancer Research.

The EGFR T790M mutation is the most common cause of resistance in patients with non–small cell lung cancer (NSCLC) bearing EGFR mutations who are treated with first- or second-generation, EGFR-targeted tyrosine kinase inhibitors (TKI). Up-regulation of the RAS/RAF/MEK/ERK signaling pathway has also been implicated in NSCLC resistance to EGFR-targeted TKIs.

Selumetinib is an oral, potent, and selective inhibitor of MEK1/2 with a short half-life.

In the phase 3 SELECT-1 trial, selumetinib in combination with docetaxel did not significantly improve progression-free survival, compared with docetaxel alone as second-line therapy for patients with KRAS-mutated NSCLC.

Therapeutic rationale

Invited discussant Roy S. Herbst, MD, PhD, chief of medical oncology at Yale Cancer Center and Smilow Cancer Hospital in New Haven, Conn., said that there is sound rationale for combining osimertinib and selumetinib in EGFR-mutant NSCLC.

Neil Osterweil/MDedge News

In addition to the up-regulation of the RAS/RAF/MEK/ERK pathway noted before, resistance to osimertinib has been shown in models of EGFR-mutant NSCLC to develop from aberrant ERK signaling mediation in part by MEK1 amplification, and MEK kinase inhibitors can restore sensitivity to osimertinib in resistant cells, he said.

As previously reported, the TATTON investigators are evaluating in separate cohorts combinations of osimertinib with savolitinib, an investigational MET inhibitor for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents, or with selumetinib for patients with advanced EGFR-mutated NSCLC that had progressed on prior therapy, including EGFR-targeted TKIs, irrespective of T790M or KRAS status.

In part A, the dose-finding phase, patients received osimertinib 80 mg daily plus intermittent or continuous selumetinib. Asian patients received continuous selumetinib 25/50 mg twice daily, while other patients received continuous selumetinib 50/75 mg twice daily, or intermittent selumetinib 75 mg twice daily 4 days on, 3 days off or on days 1 and 4 of each week of treatment.

In part B, the dose-expansion phase, patients received osimertinib plus intermittent selumetinib 75 mg twice daily on the 4 days on/3 days off schedule.

An analysis of preliminary antitumor activity in part A showed an ORR in 15 of 36 patients (42%); all were partial responses (PR). In addition, 14 patients (39%) had stable disease at 6 weeks, 3 had progressive disease, 2 died, and 2 were not evaluable. The median duration of response was 16.6 months; 77% of the patients had responses lasting at least 12 months.

In part B, 16 of 47 patients enrolled (34%) had confirmed PR, and 16 had stable disease. Of the remaining patients, 11 had disease progression, 2 died, and 2 were not evaluable. The median duration of response in this group was 9.1 months, and 31% of patients remained in response at 12 months.

The most common treatment-related adverse events in the dose-finding phase were diarrhea in 75% of patients, nausea in 39% and fatigue in 33%. Dose-limiting toxicities occurred in six patients, all of whom had been treated with continuous selumetinib. These toxicities, all grade 3, include liver enzyme increases, diarrhea, asthenia, dizziness, nausea, and pneumonitis.

The most common treatment-related adverse events in the dose-expansion phase were diarrhea in 81%, stomatitis in 32%, and paronychia in 30% of patients.

Results ‘okay’

In his discussion, Dr. Herbst commented that the part A results “look okay, until you realize that the most of the activity is in those patients who are T790M-positive, who have not been exposed in this cohort to a third-generation T790M inhibitor.” Patients with the mutation who are treated with third-generation inhibitors would be expected to have a 78% response rate.

Part B included a few more patients with responses who were negative for T790M. “My thought here is that perhaps there is a biomarker” for selecting patients most likely to benefit from the combination, he said.

For MET-negative patients, the combination appears to have manageable toxicities with noncontinuous dosing of selumetinib, and there may be benefit to using it in the first-line setting in select patients, but that will require further trials and identification of suitable biomarkers, Dr. Herbst summarized.

TATTON was sponsored by AstraZeneca. Dr. Ramalingam reported receiving research support from the company and consulting/contracting with others. Dr. Herbst reported receiving research support from AstraZeneca, Eli Lilly, and Merck, and serving as a consultant for AstraZeneca, Eli Lilly, Genentech/Roche, Merck, NextCure, and Pfizer.

SOURCE: Ramalingam SS et al. AACR 2019, Abstract CT034.

ATLANTA – A novel chimeric antigen receptor (CAR) T-cell construct centered on HER2 as the target antigen was safe and showed early promise in the treatment of advanced sarcomas of bone and soft tissues in a phase I trial.

Neil Osterweil/MDedge News

One patient, a 16-year-old girl with advanced osteosarcoma metastatic to her lungs, had a complete response to the therapy that is ongoing out to nearly 3 years, reported Shoba A. Navai, MD, from Baylor College of Medicine in Houston.

A second patient, an 8-year-old boy with rhabdomyosarcoma metastatic to bone marrow, had a complete response lasting 12 months. Upon relapse he was re-enrolled, received additional CAR T-cell infusions, and had a second complete response that has been ongoing for 17 months.

“HER2 CAR T cells can induce objective clinical responses in some patients with sarcoma, and engagement of endogenous immunity may aid in generation of tumor responses. We are currently working to validate these findings in other patients who were treated,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

HER2 is a member of the human epidermal growth factor receptor family that is primarily expressed on the surface of tumor cells but is largely absent from nonmalignant tissues. HER2 can be expressed in a variety of sarcomas, including osteosarcoma, and HER2 expression in osteosarcoma correlates with worse overall survival.

Unlike HER2-positive breast cancers, however, HER2 expression levels in osteosarcoma are too low to be effectively targeted by anti-HER2 agents such as trastuzumab (Hereceptin).

But as Dr. Navai and colleagues have found, HER2 appears to be a valid target for CAR T-cell therapy in otherwise antigenically “cold” tumors – that is, tumors with few targetable antigens.
 

Old target, new weapon

They have developed a CAR T-cell construct using a HER2-directed antibody coupled with CD28 as the costimulatory molecule. As with other CAR T therapies, the patient’s T cells or selected T cell subsets are collected, transfected to express the antigen, and are then expanded and returned to the patient following lymphodepletion with either fludarabine alone or with cyclophosphamide.

Each patient received up to three infusions of autologous CAR T cells at a dose of 1 x 108 cells/m², and eligible patients received up to five additional infusions without additional lymphodepletion.

Dr. Navai presented data on 10 patients treated to date, including the two mentioned before; the boy with rhabdomyosarcoma was counted as two separate patients for the purpose of the efficacy analysis.

All patients had metastatic disease, including five with osteosarcoma, three with rhabdomyosarcoma, one with Ewing sarcoma, and one with synovial sarcoma.

The lymphodepletion regimens did their job, inducing neutropenia (defined as an absolute neutrophil count less than 500 per milliliter ) for up to 14 days.

Eight patients developed grade 1 or 2 cytokine release syndrome within 24 hours of CAR T-cell infusion, and all cases completely resolved with supportive care within 5 days of onset.

In nine patients, T cells were successfully expanded, with a median peak expansion on day 7.

In all 10 patients, CAR T cells were detected by quantitative polymerase chain reaction 6 weeks after infusion.

In addition to the two patients with complete remissions already described, three patients had stable disease. The remaining patients had disease progression. At the most recent analysis, five patients were still alive, and five had died.

The infusions were safe, with no dose-limiting toxicities reported. No patient required a transfusion, and there were no opportunistic, infections, no neurotoxicities, and no lasting pulmonary or cardiac toxicities, Dr. Navai reported.
 

Some fare better than others

Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, who moderated the briefing, commented that the study had “very small numbers, but is still very exciting.”

She noted that the patients who benefited most from the therapy either had minimal residual disease or bone marrow disease without visceral disease; she asked Dr. Navai how this could be addressed going forward.

“The patients who seemed to have had responses both in this trial, as well as in our previous trial without lymphodepletion, tended to have less disease or more accessible disease. So we hypothesized that disease that’s in the bone marrow because it’s more accessible, or in the lungs, where also CAR T cells go after they are first infused, may be more amenable to treatment,” Dr. Navai said.

In contrast, larger tumors and more invasive disease may emit immune inhibitory signals that dampen the efficacy of CAR T cells, she added.

Development of the CAR T-cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai and Dr. Azad reported having no disclosures relevant to the work.

SOURCE: Navai SA et al. AACR 2019, Abstract LB-147.

ATLANTA – A novel chimeric antigen receptor (CAR) T-cell construct centered on HER2 as the target antigen was safe and showed early promise in the treatment of advanced sarcomas of bone and soft tissues in a phase I trial.

Neil Osterweil/MDedge News

One patient, a 16-year-old girl with advanced osteosarcoma metastatic to her lungs, had a complete response to the therapy that is ongoing out to nearly 3 years, reported Shoba A. Navai, MD, from Baylor College of Medicine in Houston.

A second patient, an 8-year-old boy with rhabdomyosarcoma metastatic to bone marrow, had a complete response lasting 12 months. Upon relapse he was re-enrolled, received additional CAR T-cell infusions, and had a second complete response that has been ongoing for 17 months.

“HER2 CAR T cells can induce objective clinical responses in some patients with sarcoma, and engagement of endogenous immunity may aid in generation of tumor responses. We are currently working to validate these findings in other patients who were treated,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

HER2 is a member of the human epidermal growth factor receptor family that is primarily expressed on the surface of tumor cells but is largely absent from nonmalignant tissues. HER2 can be expressed in a variety of sarcomas, including osteosarcoma, and HER2 expression in osteosarcoma correlates with worse overall survival.

Unlike HER2-positive breast cancers, however, HER2 expression levels in osteosarcoma are too low to be effectively targeted by anti-HER2 agents such as trastuzumab (Hereceptin).

But as Dr. Navai and colleagues have found, HER2 appears to be a valid target for CAR T-cell therapy in otherwise antigenically “cold” tumors – that is, tumors with few targetable antigens.
 

Old target, new weapon

They have developed a CAR T-cell construct using a HER2-directed antibody coupled with CD28 as the costimulatory molecule. As with other CAR T therapies, the patient’s T cells or selected T cell subsets are collected, transfected to express the antigen, and are then expanded and returned to the patient following lymphodepletion with either fludarabine alone or with cyclophosphamide.

Each patient received up to three infusions of autologous CAR T cells at a dose of 1 x 108 cells/m², and eligible patients received up to five additional infusions without additional lymphodepletion.

Dr. Navai presented data on 10 patients treated to date, including the two mentioned before; the boy with rhabdomyosarcoma was counted as two separate patients for the purpose of the efficacy analysis.

All patients had metastatic disease, including five with osteosarcoma, three with rhabdomyosarcoma, one with Ewing sarcoma, and one with synovial sarcoma.

The lymphodepletion regimens did their job, inducing neutropenia (defined as an absolute neutrophil count less than 500 per milliliter ) for up to 14 days.

Eight patients developed grade 1 or 2 cytokine release syndrome within 24 hours of CAR T-cell infusion, and all cases completely resolved with supportive care within 5 days of onset.

In nine patients, T cells were successfully expanded, with a median peak expansion on day 7.

In all 10 patients, CAR T cells were detected by quantitative polymerase chain reaction 6 weeks after infusion.

In addition to the two patients with complete remissions already described, three patients had stable disease. The remaining patients had disease progression. At the most recent analysis, five patients were still alive, and five had died.

The infusions were safe, with no dose-limiting toxicities reported. No patient required a transfusion, and there were no opportunistic, infections, no neurotoxicities, and no lasting pulmonary or cardiac toxicities, Dr. Navai reported.
 

Some fare better than others

Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, who moderated the briefing, commented that the study had “very small numbers, but is still very exciting.”

She noted that the patients who benefited most from the therapy either had minimal residual disease or bone marrow disease without visceral disease; she asked Dr. Navai how this could be addressed going forward.

“The patients who seemed to have had responses both in this trial, as well as in our previous trial without lymphodepletion, tended to have less disease or more accessible disease. So we hypothesized that disease that’s in the bone marrow because it’s more accessible, or in the lungs, where also CAR T cells go after they are first infused, may be more amenable to treatment,” Dr. Navai said.

In contrast, larger tumors and more invasive disease may emit immune inhibitory signals that dampen the efficacy of CAR T cells, she added.

Development of the CAR T-cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai and Dr. Azad reported having no disclosures relevant to the work.

SOURCE: Navai SA et al. AACR 2019, Abstract LB-147.

ATLANTA – A novel chimeric antigen receptor (CAR) T-cell construct centered on HER2 as the target antigen was safe and showed early promise in the treatment of advanced sarcomas of bone and soft tissues in a phase I trial.

Neil Osterweil/MDedge News

One patient, a 16-year-old girl with advanced osteosarcoma metastatic to her lungs, had a complete response to the therapy that is ongoing out to nearly 3 years, reported Shoba A. Navai, MD, from Baylor College of Medicine in Houston.

A second patient, an 8-year-old boy with rhabdomyosarcoma metastatic to bone marrow, had a complete response lasting 12 months. Upon relapse he was re-enrolled, received additional CAR T-cell infusions, and had a second complete response that has been ongoing for 17 months.

“HER2 CAR T cells can induce objective clinical responses in some patients with sarcoma, and engagement of endogenous immunity may aid in generation of tumor responses. We are currently working to validate these findings in other patients who were treated,” she said at a briefing at the annual meeting of the American Association for Cancer Research.

HER2 is a member of the human epidermal growth factor receptor family that is primarily expressed on the surface of tumor cells but is largely absent from nonmalignant tissues. HER2 can be expressed in a variety of sarcomas, including osteosarcoma, and HER2 expression in osteosarcoma correlates with worse overall survival.

Unlike HER2-positive breast cancers, however, HER2 expression levels in osteosarcoma are too low to be effectively targeted by anti-HER2 agents such as trastuzumab (Hereceptin).

But as Dr. Navai and colleagues have found, HER2 appears to be a valid target for CAR T-cell therapy in otherwise antigenically “cold” tumors – that is, tumors with few targetable antigens.
 

Old target, new weapon

They have developed a CAR T-cell construct using a HER2-directed antibody coupled with CD28 as the costimulatory molecule. As with other CAR T therapies, the patient’s T cells or selected T cell subsets are collected, transfected to express the antigen, and are then expanded and returned to the patient following lymphodepletion with either fludarabine alone or with cyclophosphamide.

Each patient received up to three infusions of autologous CAR T cells at a dose of 1 x 108 cells/m², and eligible patients received up to five additional infusions without additional lymphodepletion.

Dr. Navai presented data on 10 patients treated to date, including the two mentioned before; the boy with rhabdomyosarcoma was counted as two separate patients for the purpose of the efficacy analysis.

All patients had metastatic disease, including five with osteosarcoma, three with rhabdomyosarcoma, one with Ewing sarcoma, and one with synovial sarcoma.

The lymphodepletion regimens did their job, inducing neutropenia (defined as an absolute neutrophil count less than 500 per milliliter ) for up to 14 days.

Eight patients developed grade 1 or 2 cytokine release syndrome within 24 hours of CAR T-cell infusion, and all cases completely resolved with supportive care within 5 days of onset.

In nine patients, T cells were successfully expanded, with a median peak expansion on day 7.

In all 10 patients, CAR T cells were detected by quantitative polymerase chain reaction 6 weeks after infusion.

In addition to the two patients with complete remissions already described, three patients had stable disease. The remaining patients had disease progression. At the most recent analysis, five patients were still alive, and five had died.

The infusions were safe, with no dose-limiting toxicities reported. No patient required a transfusion, and there were no opportunistic, infections, no neurotoxicities, and no lasting pulmonary or cardiac toxicities, Dr. Navai reported.
 

Some fare better than others

Nilofer S. Azad, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, who moderated the briefing, commented that the study had “very small numbers, but is still very exciting.”

She noted that the patients who benefited most from the therapy either had minimal residual disease or bone marrow disease without visceral disease; she asked Dr. Navai how this could be addressed going forward.

“The patients who seemed to have had responses both in this trial, as well as in our previous trial without lymphodepletion, tended to have less disease or more accessible disease. So we hypothesized that disease that’s in the bone marrow because it’s more accessible, or in the lungs, where also CAR T cells go after they are first infused, may be more amenable to treatment,” Dr. Navai said.

In contrast, larger tumors and more invasive disease may emit immune inhibitory signals that dampen the efficacy of CAR T cells, she added.

Development of the CAR T-cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai and Dr. Azad reported having no disclosures relevant to the work.

SOURCE: Navai SA et al. AACR 2019, Abstract LB-147.

ATLANTA – The current standard of care for patients with advanced pancreatic cancer is chemotherapy continued until patients experience disease progression, unacceptable toxicities, clinical decline, or death.

But a subset of patients with pancreatic cancer – approximately 5%-8% – have pathogenic mutations in homologous recombination genes such as BRCA1, BRCA2, or PALB2. The resulting homologous recombination deficiencies (HRD) make their cancers especially sensitive to platinum-based chemotherapy and, potentially, to poly (ADP-ribose) polymerase (PARP) inhibitors.

Now, investigators at the University of Pennsylvania, Philadelphia, are proposing to upend the conventional approach by treating patients with advanced pancreatic cancer and HRD with a novel strategy consisting of induction chemotherapy, followed by maintenance with the PARP inhibitor rucaparib (Rubraca).

In a video interview at the annual meeting of the American Society for Cancer Research, Kim A. Reiss Binder, MD, of the University of Pennsylvania, describes the rationale for treating this subset of patients with this novel strategy, outlines the promising progression-free and overall survival results in a clinical study, and discusses the potential for chemotherapy and PARP inhibitors in neoadjuvant or adjuvant settings for some patients with pancreatic cancer.

The study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Dr. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.

ATLANTA – The current standard of care for patients with advanced pancreatic cancer is chemotherapy continued until patients experience disease progression, unacceptable toxicities, clinical decline, or death.

But a subset of patients with pancreatic cancer – approximately 5%-8% – have pathogenic mutations in homologous recombination genes such as BRCA1, BRCA2, or PALB2. The resulting homologous recombination deficiencies (HRD) make their cancers especially sensitive to platinum-based chemotherapy and, potentially, to poly (ADP-ribose) polymerase (PARP) inhibitors.

Now, investigators at the University of Pennsylvania, Philadelphia, are proposing to upend the conventional approach by treating patients with advanced pancreatic cancer and HRD with a novel strategy consisting of induction chemotherapy, followed by maintenance with the PARP inhibitor rucaparib (Rubraca).

In a video interview at the annual meeting of the American Society for Cancer Research, Kim A. Reiss Binder, MD, of the University of Pennsylvania, describes the rationale for treating this subset of patients with this novel strategy, outlines the promising progression-free and overall survival results in a clinical study, and discusses the potential for chemotherapy and PARP inhibitors in neoadjuvant or adjuvant settings for some patients with pancreatic cancer.

The study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Dr. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.

ATLANTA – The current standard of care for patients with advanced pancreatic cancer is chemotherapy continued until patients experience disease progression, unacceptable toxicities, clinical decline, or death.

But a subset of patients with pancreatic cancer – approximately 5%-8% – have pathogenic mutations in homologous recombination genes such as BRCA1, BRCA2, or PALB2. The resulting homologous recombination deficiencies (HRD) make their cancers especially sensitive to platinum-based chemotherapy and, potentially, to poly (ADP-ribose) polymerase (PARP) inhibitors.

Now, investigators at the University of Pennsylvania, Philadelphia, are proposing to upend the conventional approach by treating patients with advanced pancreatic cancer and HRD with a novel strategy consisting of induction chemotherapy, followed by maintenance with the PARP inhibitor rucaparib (Rubraca).

In a video interview at the annual meeting of the American Society for Cancer Research, Kim A. Reiss Binder, MD, of the University of Pennsylvania, describes the rationale for treating this subset of patients with this novel strategy, outlines the promising progression-free and overall survival results in a clinical study, and discusses the potential for chemotherapy and PARP inhibitors in neoadjuvant or adjuvant settings for some patients with pancreatic cancer.

The study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Dr. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.

ATLANTA – Adult survivors of childhood cancers are at significantly greater risk than the general population for late-term complications related to therapy, including secondary cancers, cardiovascular disease, and cerebrovascular complications, including ischemic and hemorrhagic strokes.

In particular, childhood cancer survivors have an approximately eightfold higher risk for stroke, compared with their siblings, with a history of cranial irradiation being a strong, dose-dependent risk factor for stroke.

Researchers at St. Jude Children’s Research Hospital in Memphis, Tenn., are conducting a retrospective cohort study with prospective clinical follow-up and ongoing enrollment of childhood cancer survivors who are 5 or more years out of therapy.

The study includes publicly available, whole-genome sequencing data on 4,500 participants. Sifting through these data, Yadav Sapkota, PhD, a clinical research scientist at St. Jude, and his colleagues have identified a genetic variant strongly associated with stroke risk in survivors of European ancestry, and they have replicated the finding in survivors of African ancestry.

In a video interview at the annual meeting of the American Association for Cancer Research, Dr. Sapkota describes his group’s findings and potential research and clinical implications.

The study was sponsored by the National Cancer Institute and ALSAC, the fundraising and awareness organization of St. Jude. Dr. Sapkota declared no conflict of interest.

ATLANTA – Adult survivors of childhood cancers are at significantly greater risk than the general population for late-term complications related to therapy, including secondary cancers, cardiovascular disease, and cerebrovascular complications, including ischemic and hemorrhagic strokes.

In particular, childhood cancer survivors have an approximately eightfold higher risk for stroke, compared with their siblings, with a history of cranial irradiation being a strong, dose-dependent risk factor for stroke.

Researchers at St. Jude Children’s Research Hospital in Memphis, Tenn., are conducting a retrospective cohort study with prospective clinical follow-up and ongoing enrollment of childhood cancer survivors who are 5 or more years out of therapy.

The study includes publicly available, whole-genome sequencing data on 4,500 participants. Sifting through these data, Yadav Sapkota, PhD, a clinical research scientist at St. Jude, and his colleagues have identified a genetic variant strongly associated with stroke risk in survivors of European ancestry, and they have replicated the finding in survivors of African ancestry.

In a video interview at the annual meeting of the American Association for Cancer Research, Dr. Sapkota describes his group’s findings and potential research and clinical implications.

The study was sponsored by the National Cancer Institute and ALSAC, the fundraising and awareness organization of St. Jude. Dr. Sapkota declared no conflict of interest.

ATLANTA – Adult survivors of childhood cancers are at significantly greater risk than the general population for late-term complications related to therapy, including secondary cancers, cardiovascular disease, and cerebrovascular complications, including ischemic and hemorrhagic strokes.

In particular, childhood cancer survivors have an approximately eightfold higher risk for stroke, compared with their siblings, with a history of cranial irradiation being a strong, dose-dependent risk factor for stroke.

Researchers at St. Jude Children’s Research Hospital in Memphis, Tenn., are conducting a retrospective cohort study with prospective clinical follow-up and ongoing enrollment of childhood cancer survivors who are 5 or more years out of therapy.

The study includes publicly available, whole-genome sequencing data on 4,500 participants. Sifting through these data, Yadav Sapkota, PhD, a clinical research scientist at St. Jude, and his colleagues have identified a genetic variant strongly associated with stroke risk in survivors of European ancestry, and they have replicated the finding in survivors of African ancestry.

In a video interview at the annual meeting of the American Association for Cancer Research, Dr. Sapkota describes his group’s findings and potential research and clinical implications.

The study was sponsored by the National Cancer Institute and ALSAC, the fundraising and awareness organization of St. Jude. Dr. Sapkota declared no conflict of interest.

ATLANTA – About 10%-25% of patients with epithelial growth factor receptor–(EGFR) mutant non–small cell lung cancer (NSCLC) have tumors with either MET amplification or another MET-based mechanism that leads to drug resistance.

In the TATTON trial, investigators are evaluating a combination of the EGFR-targeted tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents.

In a video interview at the annual meeting of the American Association for Cancer Research, Lecia Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston, discusses early results with the osimertinib/savolitinib combination in patients with disease progression after a first and/or second-generation EGFR TKI, or after a third-generation agent.

Dr. Sequist said results of TATTON suggest that it may be possible to overcome MET-driven drug-resistance mechanisms.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company.

ATLANTA – About 10%-25% of patients with epithelial growth factor receptor–(EGFR) mutant non–small cell lung cancer (NSCLC) have tumors with either MET amplification or another MET-based mechanism that leads to drug resistance.

In the TATTON trial, investigators are evaluating a combination of the EGFR-targeted tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents.

In a video interview at the annual meeting of the American Association for Cancer Research, Lecia Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston, discusses early results with the osimertinib/savolitinib combination in patients with disease progression after a first and/or second-generation EGFR TKI, or after a third-generation agent.

Dr. Sequist said results of TATTON suggest that it may be possible to overcome MET-driven drug-resistance mechanisms.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company.

ATLANTA – About 10%-25% of patients with epithelial growth factor receptor–(EGFR) mutant non–small cell lung cancer (NSCLC) have tumors with either MET amplification or another MET-based mechanism that leads to drug resistance.

In the TATTON trial, investigators are evaluating a combination of the EGFR-targeted tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso) with savolitinib, an investigational MET inhibitor, for safety and activity against MET-driven NSCLC in patients with disease that has progressed on one or more prior EGFR-targeted agents.

In a video interview at the annual meeting of the American Association for Cancer Research, Lecia Sequist, MD, from the Massachusetts General Hospital Cancer Center in Boston, discusses early results with the osimertinib/savolitinib combination in patients with disease progression after a first and/or second-generation EGFR TKI, or after a third-generation agent.

Dr. Sequist said results of TATTON suggest that it may be possible to overcome MET-driven drug-resistance mechanisms.

The TATTON trial is sponsored by AstraZeneca. Dr. Sequist reported serving as an advisory board member and receiving research support and honoraria from the company.

ATLANTA – Sarcomas of bone and soft tissues are considered to be “antigenically cold” tumors, with few identifiable mutations that may be susceptible to targeted therapies.

Some sarcoma subtypes such as osteosarcoma and rhabomyosarcoma, however, frequently express the human epidermal growth factor receptor 2 on tumor surfaces. Although HER2 expression in these tumors is at too low a level for HER2-targeted therapies such as trastuzumab (Herceptin), HER2 appears to be an opportunistic target for chimeric antigen receptor (CAR) T-cell therapy, according to Shoba Navai, MD, from Baylor College of Medicine, Houston.

In a video interview at the 2019 annual meeting of the American Association for Cancer Research, Dr. Navai describes her team’s early experience using a HER2-targeted CAR-T cell construct and preinfusion lymphodepletion in patients with advanced sarcomas.

Development of the CAR-T cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai reported having no disclosures.

ATLANTA – Sarcomas of bone and soft tissues are considered to be “antigenically cold” tumors, with few identifiable mutations that may be susceptible to targeted therapies.

Some sarcoma subtypes such as osteosarcoma and rhabomyosarcoma, however, frequently express the human epidermal growth factor receptor 2 on tumor surfaces. Although HER2 expression in these tumors is at too low a level for HER2-targeted therapies such as trastuzumab (Herceptin), HER2 appears to be an opportunistic target for chimeric antigen receptor (CAR) T-cell therapy, according to Shoba Navai, MD, from Baylor College of Medicine, Houston.

In a video interview at the 2019 annual meeting of the American Association for Cancer Research, Dr. Navai describes her team’s early experience using a HER2-targeted CAR-T cell construct and preinfusion lymphodepletion in patients with advanced sarcomas.

Development of the CAR-T cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai reported having no disclosures.

ATLANTA – Sarcomas of bone and soft tissues are considered to be “antigenically cold” tumors, with few identifiable mutations that may be susceptible to targeted therapies.

Some sarcoma subtypes such as osteosarcoma and rhabomyosarcoma, however, frequently express the human epidermal growth factor receptor 2 on tumor surfaces. Although HER2 expression in these tumors is at too low a level for HER2-targeted therapies such as trastuzumab (Herceptin), HER2 appears to be an opportunistic target for chimeric antigen receptor (CAR) T-cell therapy, according to Shoba Navai, MD, from Baylor College of Medicine, Houston.

In a video interview at the 2019 annual meeting of the American Association for Cancer Research, Dr. Navai describes her team’s early experience using a HER2-targeted CAR-T cell construct and preinfusion lymphodepletion in patients with advanced sarcomas.

Development of the CAR-T cell construct is supported by the Cancer Prevention & Research Institute of Texas, Stand Up to Cancer, the St. Baldrick’s Foundation, Cookies for Kids’ Cancer, Alex’s Lemonade Stand, and a grant from the National Institutes of Health. Dr. Navai reported having no disclosures.

For women with metastatic hormone receptor–positive breast cancer, the addition of the selective estrogen receptor modifier fulvestrant (Faslodex) to the aromatase inhibitor anastrozole (Arimidex and generics) resulted in a small but significant improvement in overall survival, according to final results from a randomized phase 3 trial.

Among 694 patients randomized for whom data were available, the hazard ratio for death with the combination when compared with anastrozole alone was 0.82 (P = .03), reported Rita S. Mehta, MD, from the University of California (Irvine) Medical Center and her colleagues.

The benefit of the combination was highest for patients without prior exposure to adjuvant endocrine therapy.

“Furthermore, sequential therapy with anastrozole and fulvestrant (45% of patients crossed over to fulvestrant alone) did not negate the significance of the long-term overall survival benefit with the combination therapy as compared with anastrozole,” the investigators wrote in The New England Journal of Medicine.

The current report is the final survival analysis of the trial. The primary results were reported in 2012 (N Engl J Med. 2012; 367:435-44). A total of 707 postmenopausal women with previously untreated metastatic disease were randomly assigned to receive either 1 mg of anastrozole orally every day with crossover to fulvestrant alone strongly encouraged if the disease progressed or to anastrozole and fulvestrant in combination. Randomization was stratified according to prior adjuvant tamoxifen use. A total of 694 women had data available for analysis.

The primary analysis, conducted at a median follow-up of 35 months, showed a median progression-free survival (PFS) with anastrozole alone of 13.5 months, compared with 15.0 months for anastrozole/fulvestrant (HR for progression or death 0.80; P = .007). Respective median overall survival was 41.3 months and 47.7 months (HR for death 0.81; P = .05).

The current, final analysis, conducted at a median follow-up of 7 years in patients who did not have disease progression, showed 261 deaths among 345 women (76%) in the anastrozole-only group, compared with 247 deaths among 349 women (71%) in the combination group (HR for death 0.82; P = .03).

Overall survival was longer for those women who had not previously received tamoxifen who were treated with the combination, at a median of 52.2 months versus 40.3 months for women not previously treated with tamoxifen who received anastrozole alone (hazard ratio, 0.73; 95% confidence interval, 0.58-0.92). In contrast, there was no significant difference in OS between the two treatment groups in women who had previously received tamoxifen.

Approximately 45% of patients initially randomized to anastrozole alone were crossed over to fulvestrant.

The incidence of long-term toxic effects and treatment-related deaths was similar between the groups. Previously reported treatment-related deaths with the combination included pulmonary emboli in two patients and a cerebrovascular ischemic event in one patients.

At the time of data cutoff for the final report, 15% of patients in the combination-therapy group and 13% in the anastrozole-only group had experienced grade 3 toxicities.

The study was supported by National Cancer Institute grants and by AstraZeneca. Dr. Mehta reported institutional and personal grants from AstraZeneca and others. Multiple coauthors reported similar relationships.

SOURCE: Mehta RS et al. N Engl J Med. 2019;380:1226-34.

For women with metastatic hormone receptor–positive breast cancer, the addition of the selective estrogen receptor modifier fulvestrant (Faslodex) to the aromatase inhibitor anastrozole (Arimidex and generics) resulted in a small but significant improvement in overall survival, according to final results from a randomized phase 3 trial.

Among 694 patients randomized for whom data were available, the hazard ratio for death with the combination when compared with anastrozole alone was 0.82 (P = .03), reported Rita S. Mehta, MD, from the University of California (Irvine) Medical Center and her colleagues.

The benefit of the combination was highest for patients without prior exposure to adjuvant endocrine therapy.

“Furthermore, sequential therapy with anastrozole and fulvestrant (45% of patients crossed over to fulvestrant alone) did not negate the significance of the long-term overall survival benefit with the combination therapy as compared with anastrozole,” the investigators wrote in The New England Journal of Medicine.

The current report is the final survival analysis of the trial. The primary results were reported in 2012 (N Engl J Med. 2012; 367:435-44). A total of 707 postmenopausal women with previously untreated metastatic disease were randomly assigned to receive either 1 mg of anastrozole orally every day with crossover to fulvestrant alone strongly encouraged if the disease progressed or to anastrozole and fulvestrant in combination. Randomization was stratified according to prior adjuvant tamoxifen use. A total of 694 women had data available for analysis.

The primary analysis, conducted at a median follow-up of 35 months, showed a median progression-free survival (PFS) with anastrozole alone of 13.5 months, compared with 15.0 months for anastrozole/fulvestrant (HR for progression or death 0.80; P = .007). Respective median overall survival was 41.3 months and 47.7 months (HR for death 0.81; P = .05).

The current, final analysis, conducted at a median follow-up of 7 years in patients who did not have disease progression, showed 261 deaths among 345 women (76%) in the anastrozole-only group, compared with 247 deaths among 349 women (71%) in the combination group (HR for death 0.82; P = .03).

Overall survival was longer for those women who had not previously received tamoxifen who were treated with the combination, at a median of 52.2 months versus 40.3 months for women not previously treated with tamoxifen who received anastrozole alone (hazard ratio, 0.73; 95% confidence interval, 0.58-0.92). In contrast, there was no significant difference in OS between the two treatment groups in women who had previously received tamoxifen.

Approximately 45% of patients initially randomized to anastrozole alone were crossed over to fulvestrant.

The incidence of long-term toxic effects and treatment-related deaths was similar between the groups. Previously reported treatment-related deaths with the combination included pulmonary emboli in two patients and a cerebrovascular ischemic event in one patients.

At the time of data cutoff for the final report, 15% of patients in the combination-therapy group and 13% in the anastrozole-only group had experienced grade 3 toxicities.

The study was supported by National Cancer Institute grants and by AstraZeneca. Dr. Mehta reported institutional and personal grants from AstraZeneca and others. Multiple coauthors reported similar relationships.

SOURCE: Mehta RS et al. N Engl J Med. 2019;380:1226-34.

For women with metastatic hormone receptor–positive breast cancer, the addition of the selective estrogen receptor modifier fulvestrant (Faslodex) to the aromatase inhibitor anastrozole (Arimidex and generics) resulted in a small but significant improvement in overall survival, according to final results from a randomized phase 3 trial.

Among 694 patients randomized for whom data were available, the hazard ratio for death with the combination when compared with anastrozole alone was 0.82 (P = .03), reported Rita S. Mehta, MD, from the University of California (Irvine) Medical Center and her colleagues.

The benefit of the combination was highest for patients without prior exposure to adjuvant endocrine therapy.

“Furthermore, sequential therapy with anastrozole and fulvestrant (45% of patients crossed over to fulvestrant alone) did not negate the significance of the long-term overall survival benefit with the combination therapy as compared with anastrozole,” the investigators wrote in The New England Journal of Medicine.

The current report is the final survival analysis of the trial. The primary results were reported in 2012 (N Engl J Med. 2012; 367:435-44). A total of 707 postmenopausal women with previously untreated metastatic disease were randomly assigned to receive either 1 mg of anastrozole orally every day with crossover to fulvestrant alone strongly encouraged if the disease progressed or to anastrozole and fulvestrant in combination. Randomization was stratified according to prior adjuvant tamoxifen use. A total of 694 women had data available for analysis.

The primary analysis, conducted at a median follow-up of 35 months, showed a median progression-free survival (PFS) with anastrozole alone of 13.5 months, compared with 15.0 months for anastrozole/fulvestrant (HR for progression or death 0.80; P = .007). Respective median overall survival was 41.3 months and 47.7 months (HR for death 0.81; P = .05).

The current, final analysis, conducted at a median follow-up of 7 years in patients who did not have disease progression, showed 261 deaths among 345 women (76%) in the anastrozole-only group, compared with 247 deaths among 349 women (71%) in the combination group (HR for death 0.82; P = .03).

Overall survival was longer for those women who had not previously received tamoxifen who were treated with the combination, at a median of 52.2 months versus 40.3 months for women not previously treated with tamoxifen who received anastrozole alone (hazard ratio, 0.73; 95% confidence interval, 0.58-0.92). In contrast, there was no significant difference in OS between the two treatment groups in women who had previously received tamoxifen.

Approximately 45% of patients initially randomized to anastrozole alone were crossed over to fulvestrant.

The incidence of long-term toxic effects and treatment-related deaths was similar between the groups. Previously reported treatment-related deaths with the combination included pulmonary emboli in two patients and a cerebrovascular ischemic event in one patients.

At the time of data cutoff for the final report, 15% of patients in the combination-therapy group and 13% in the anastrozole-only group had experienced grade 3 toxicities.

The study was supported by National Cancer Institute grants and by AstraZeneca. Dr. Mehta reported institutional and personal grants from AstraZeneca and others. Multiple coauthors reported similar relationships.

SOURCE: Mehta RS et al. N Engl J Med. 2019;380:1226-34.

Taking a deep dive into plasma cell-free DNA in patients with advanced non–small cell lung cancer may reveal targetable mutations and cancer resistance mechanisms in tumors, even when tissue biopsy samples are not adequate for genotyping, investigators say,

Noninvasive tumor genotyping of plasma cell-free DNA (cfDNA) with ultra-deep next generation sequencing (NGS) in plasma samples from 127 patients identified known oncogenic drivers with a sensitivity of 75% and ruled out the presence of driver mutations with a specificity of 100% in patients with tissue samples indicating no mutations, reported Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, and his colleagues.

“These results reveal the potential utility of NGS assays that use cfDNA as input for detecting actionable driver alterations and both de novo and emergent resistance mechanisms in the clinical setting,” they wrote. The report is in Annals of Oncology.

Although the researchers did not directly assess clinical utility, the results suggest that NGS-based analysis of cfDNA may help guide treatment selection, they added.

Ultra-deep NGS is a kind of obsessive-compulsive form of sequencing in which the same genomic region is read repeatedly – in this study, 50,000 times over – with filtering of somatic mutations attributable to clonal hematopoiesis. The technique allows for detection of rare genetic alterations that can be missed by other methods.

“More recent studies employing plasma cfDNA NGS have shown promise in detecting a broader variety of genetic alterations with similar sensitivity to that of digital PCR, with potential to change clinical practice,” Dr. Li and his colleagues wrote.

They conducted a systematic study of a novel cfDNA assay in patients whose cancers had oncogenic driver mutations, those who were driver negative on tissue-based NGS, and those whose tumors had unknown mutational status.

A total of 127 patients from three centers (MSKCC, the Dana-Farber Cancer Center in Boston, and the University of Texas MD Anderson Cancer Center in Houston) were available for assessment.

Ultra-deep NGS was performed on cfDNA and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50,000 times raw-target coverage filtering somatic mutations attributable to clonal hematopoiesis.

Plasma NGS was able to detect driver mutations with variant allele frequencies ranging from as low as 0.14% to as high as 52%.

In 21 of 22 patients, plasma digital drop polymerase chain reaction (ddPCR) results for EGFR or KRAS mutations were nearly identical to those of NGS, with high concordance for variant allele frequencies (r = .98).

In analyses blinded to tissue genotyping results in 91 patients, plasma NGS detected de novo known oncogenic driver alterations in 68 samples, for a sensitivity of 75%, and in 19 of 19 patients who were driver negative by tissue sequencing, plasma NGS also showed an absence of mutations, for a specificity of 100%.

Furthermore, plasma NGS identified four KRAS mutations in plasma from 17 patients for whom tissues samples were not adequate for genotyping, and the plasma-based technique was able to identify potential resistance mutations in samples from 23 patients with EGFR mutations whose tumors had required resistance to targeted therapy.

“The sensitivity of detection by NGS was comparable to that of established ddPCR methods. Its high concordance with tissue genotyping and the detection of drivers in settings where tissue biopsy had failed or was not feasible lend credence to the potential clinical use of plasma cfDNA NGS and the development of cfDNA-guided intervention studies,” the investigators wrote.

The study was supported by Illumina. Authors from MSKCC and MD Anderson were supported by National Institutes of Health grants. Dr. Li received consulting/advisory board fees from Genentech, Thermo-Fisher Scientific, and Guardant Health outside of the submitted work. Multiple coauthors reported similar relationships, and eight coauthors were current or former employees of Illumina.

SOURCE: Source: Li BT et al. Ann Oncol. doi: 10.1093/annonc/mdz046.

Taking a deep dive into plasma cell-free DNA in patients with advanced non–small cell lung cancer may reveal targetable mutations and cancer resistance mechanisms in tumors, even when tissue biopsy samples are not adequate for genotyping, investigators say,

Noninvasive tumor genotyping of plasma cell-free DNA (cfDNA) with ultra-deep next generation sequencing (NGS) in plasma samples from 127 patients identified known oncogenic drivers with a sensitivity of 75% and ruled out the presence of driver mutations with a specificity of 100% in patients with tissue samples indicating no mutations, reported Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, and his colleagues.

“These results reveal the potential utility of NGS assays that use cfDNA as input for detecting actionable driver alterations and both de novo and emergent resistance mechanisms in the clinical setting,” they wrote. The report is in Annals of Oncology.

Although the researchers did not directly assess clinical utility, the results suggest that NGS-based analysis of cfDNA may help guide treatment selection, they added.

Ultra-deep NGS is a kind of obsessive-compulsive form of sequencing in which the same genomic region is read repeatedly – in this study, 50,000 times over – with filtering of somatic mutations attributable to clonal hematopoiesis. The technique allows for detection of rare genetic alterations that can be missed by other methods.

“More recent studies employing plasma cfDNA NGS have shown promise in detecting a broader variety of genetic alterations with similar sensitivity to that of digital PCR, with potential to change clinical practice,” Dr. Li and his colleagues wrote.

They conducted a systematic study of a novel cfDNA assay in patients whose cancers had oncogenic driver mutations, those who were driver negative on tissue-based NGS, and those whose tumors had unknown mutational status.

A total of 127 patients from three centers (MSKCC, the Dana-Farber Cancer Center in Boston, and the University of Texas MD Anderson Cancer Center in Houston) were available for assessment.

Ultra-deep NGS was performed on cfDNA and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50,000 times raw-target coverage filtering somatic mutations attributable to clonal hematopoiesis.

Plasma NGS was able to detect driver mutations with variant allele frequencies ranging from as low as 0.14% to as high as 52%.

In 21 of 22 patients, plasma digital drop polymerase chain reaction (ddPCR) results for EGFR or KRAS mutations were nearly identical to those of NGS, with high concordance for variant allele frequencies (r = .98).

In analyses blinded to tissue genotyping results in 91 patients, plasma NGS detected de novo known oncogenic driver alterations in 68 samples, for a sensitivity of 75%, and in 19 of 19 patients who were driver negative by tissue sequencing, plasma NGS also showed an absence of mutations, for a specificity of 100%.

Furthermore, plasma NGS identified four KRAS mutations in plasma from 17 patients for whom tissues samples were not adequate for genotyping, and the plasma-based technique was able to identify potential resistance mutations in samples from 23 patients with EGFR mutations whose tumors had required resistance to targeted therapy.

“The sensitivity of detection by NGS was comparable to that of established ddPCR methods. Its high concordance with tissue genotyping and the detection of drivers in settings where tissue biopsy had failed or was not feasible lend credence to the potential clinical use of plasma cfDNA NGS and the development of cfDNA-guided intervention studies,” the investigators wrote.

The study was supported by Illumina. Authors from MSKCC and MD Anderson were supported by National Institutes of Health grants. Dr. Li received consulting/advisory board fees from Genentech, Thermo-Fisher Scientific, and Guardant Health outside of the submitted work. Multiple coauthors reported similar relationships, and eight coauthors were current or former employees of Illumina.

SOURCE: Source: Li BT et al. Ann Oncol. doi: 10.1093/annonc/mdz046.

Taking a deep dive into plasma cell-free DNA in patients with advanced non–small cell lung cancer may reveal targetable mutations and cancer resistance mechanisms in tumors, even when tissue biopsy samples are not adequate for genotyping, investigators say,

Noninvasive tumor genotyping of plasma cell-free DNA (cfDNA) with ultra-deep next generation sequencing (NGS) in plasma samples from 127 patients identified known oncogenic drivers with a sensitivity of 75% and ruled out the presence of driver mutations with a specificity of 100% in patients with tissue samples indicating no mutations, reported Bob T. Li, MD, MPH, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York, and his colleagues.

“These results reveal the potential utility of NGS assays that use cfDNA as input for detecting actionable driver alterations and both de novo and emergent resistance mechanisms in the clinical setting,” they wrote. The report is in Annals of Oncology.

Although the researchers did not directly assess clinical utility, the results suggest that NGS-based analysis of cfDNA may help guide treatment selection, they added.

Ultra-deep NGS is a kind of obsessive-compulsive form of sequencing in which the same genomic region is read repeatedly – in this study, 50,000 times over – with filtering of somatic mutations attributable to clonal hematopoiesis. The technique allows for detection of rare genetic alterations that can be missed by other methods.

“More recent studies employing plasma cfDNA NGS have shown promise in detecting a broader variety of genetic alterations with similar sensitivity to that of digital PCR, with potential to change clinical practice,” Dr. Li and his colleagues wrote.

They conducted a systematic study of a novel cfDNA assay in patients whose cancers had oncogenic driver mutations, those who were driver negative on tissue-based NGS, and those whose tumors had unknown mutational status.

A total of 127 patients from three centers (MSKCC, the Dana-Farber Cancer Center in Boston, and the University of Texas MD Anderson Cancer Center in Houston) were available for assessment.

Ultra-deep NGS was performed on cfDNA and matched white blood cells using a hybrid capture panel covering 37 lung cancer-related genes sequenced to 50,000 times raw-target coverage filtering somatic mutations attributable to clonal hematopoiesis.

Plasma NGS was able to detect driver mutations with variant allele frequencies ranging from as low as 0.14% to as high as 52%.

In 21 of 22 patients, plasma digital drop polymerase chain reaction (ddPCR) results for EGFR or KRAS mutations were nearly identical to those of NGS, with high concordance for variant allele frequencies (r = .98).

In analyses blinded to tissue genotyping results in 91 patients, plasma NGS detected de novo known oncogenic driver alterations in 68 samples, for a sensitivity of 75%, and in 19 of 19 patients who were driver negative by tissue sequencing, plasma NGS also showed an absence of mutations, for a specificity of 100%.

Furthermore, plasma NGS identified four KRAS mutations in plasma from 17 patients for whom tissues samples were not adequate for genotyping, and the plasma-based technique was able to identify potential resistance mutations in samples from 23 patients with EGFR mutations whose tumors had required resistance to targeted therapy.

“The sensitivity of detection by NGS was comparable to that of established ddPCR methods. Its high concordance with tissue genotyping and the detection of drivers in settings where tissue biopsy had failed or was not feasible lend credence to the potential clinical use of plasma cfDNA NGS and the development of cfDNA-guided intervention studies,” the investigators wrote.

The study was supported by Illumina. Authors from MSKCC and MD Anderson were supported by National Institutes of Health grants. Dr. Li received consulting/advisory board fees from Genentech, Thermo-Fisher Scientific, and Guardant Health outside of the submitted work. Multiple coauthors reported similar relationships, and eight coauthors were current or former employees of Illumina.

SOURCE: Source: Li BT et al. Ann Oncol. doi: 10.1093/annonc/mdz046.

For patients older than 65 years with newly diagnosed acute myeloid leukemia (AML) who were ineligible for standard induction therapy, adding the investigational pan-histone deacetylase (pan-HDAC) inhibitor pracinostat to azacitidine resulted in better complete remission and overall survival rates than azacitidine alone, results of a multicenter phase 2 trial showed.

Among 50 patients treated with the combination, 26 (52%) achieved the primary endpoint of either a complete remission (CR), CR with incomplete recovery of blood counts (CRi), or morphologic leukemia-free state (MLFS).

The median overall survival (OS) was 19.1 months, which compares favorably with historical data on similar patients treated with single-agent azacitidine, reported Guillermo Garcia-Manero, MD, from the University of Texas MD Anderson Cancer Center in Houston and his colleagues.

“[T]his study shows that pracinostat in combination with azacitidine has the potential to be a safe and effective regimen in the frontline treatment of older patients with AML unfit for [induction chemotherapy],” they wrote in Blood Advances.

Pracinostat is an oral pan-HDAC inhibitor that has been shown to have modest activity against AML as a single agent, but synergistic activity when combined with hypomethylating agent azacitidine, a standard of care for older patients with AML in the trial.

The investigators enrolled 50 patients with a median age of 75 years (range, 66-84 years). The cohort included 33 patients with de novo AML, 12 with AML secondary to myelodysplasia syndrome or myleoproliferative neoplasia, and five with therapy-related AML.

The patients were treated with pracinostat 60 mg daily for 3 days each week for 3 consecutive weeks in addition to azacitidine 75 mg/m² daily for 7 days in a 28-day cycle.

As noted, 26 patients reached the clinical endpoint, including 21 with a CR, 2 with a CRi, and 3 with MLFS. Additionally, two patients had a partial response (PR) and four had a PR with incomplete recovery of blood counts.

The median OS was 19.1 months, and the median progression-free survival (PFS) was 12.6 months. The 1-year OS rate was 62%. The 60-day mortality rate was 10%.

The authors noted that the survival data were superior to those seen in the phase 3 AZA-AML-001 study, which compared azacitidine therapy with conventional regimens in patients older than 65 years with newly diagnosed AML who were not eligible for stem cell transplants. In that trial, median OS was 10.4 months, the CR rate was 19.5% (vs. 49% in the present study), the 1-year OS rate was 46.5%, and the 60-day mortality rate was 16.2%.

They acknowledged, however, that the validity of the comparison is limited by their study’s small sample size, potential differences between the study populations, and lack of a control group in the present study. The investigators also found that clearance rates of baseline somatic mutations correlated with response to treatment.

Grade 3 or greater treatment-emergent adverse events occurred in 43 of the 50 patients, including infections, thrombocytopenias, and febrile neutropenias.

“On the basis of these encouraging results, a phase 3, multicenter, double-blind, randomized study of pracinostat vs. placebo with azacitidine (NCT03151408) is currently ongoing to confirm superiority of the combination in this difficult-to-treat AML population,” the investigators wrote.

The study was supported by research funding from MEI Pharma, which helped develop pracinostat. Dr. Garcia-Manero reported having no disclosures. Multiple coauthors reported financial relationships with MEI and others. One coauthor is an MEI employee.

SOURCE: Garcia-Manero G et al. Blood Adv. 2019 Feb 26;3(4):508-18.

For patients older than 65 years with newly diagnosed acute myeloid leukemia (AML) who were ineligible for standard induction therapy, adding the investigational pan-histone deacetylase (pan-HDAC) inhibitor pracinostat to azacitidine resulted in better complete remission and overall survival rates than azacitidine alone, results of a multicenter phase 2 trial showed.

Among 50 patients treated with the combination, 26 (52%) achieved the primary endpoint of either a complete remission (CR), CR with incomplete recovery of blood counts (CRi), or morphologic leukemia-free state (MLFS).

The median overall survival (OS) was 19.1 months, which compares favorably with historical data on similar patients treated with single-agent azacitidine, reported Guillermo Garcia-Manero, MD, from the University of Texas MD Anderson Cancer Center in Houston and his colleagues.

“[T]his study shows that pracinostat in combination with azacitidine has the potential to be a safe and effective regimen in the frontline treatment of older patients with AML unfit for [induction chemotherapy],” they wrote in Blood Advances.

Pracinostat is an oral pan-HDAC inhibitor that has been shown to have modest activity against AML as a single agent, but synergistic activity when combined with hypomethylating agent azacitidine, a standard of care for older patients with AML in the trial.

The investigators enrolled 50 patients with a median age of 75 years (range, 66-84 years). The cohort included 33 patients with de novo AML, 12 with AML secondary to myelodysplasia syndrome or myleoproliferative neoplasia, and five with therapy-related AML.

The patients were treated with pracinostat 60 mg daily for 3 days each week for 3 consecutive weeks in addition to azacitidine 75 mg/m² daily for 7 days in a 28-day cycle.

As noted, 26 patients reached the clinical endpoint, including 21 with a CR, 2 with a CRi, and 3 with MLFS. Additionally, two patients had a partial response (PR) and four had a PR with incomplete recovery of blood counts.

The median OS was 19.1 months, and the median progression-free survival (PFS) was 12.6 months. The 1-year OS rate was 62%. The 60-day mortality rate was 10%.

The authors noted that the survival data were superior to those seen in the phase 3 AZA-AML-001 study, which compared azacitidine therapy with conventional regimens in patients older than 65 years with newly diagnosed AML who were not eligible for stem cell transplants. In that trial, median OS was 10.4 months, the CR rate was 19.5% (vs. 49% in the present study), the 1-year OS rate was 46.5%, and the 60-day mortality rate was 16.2%.

They acknowledged, however, that the validity of the comparison is limited by their study’s small sample size, potential differences between the study populations, and lack of a control group in the present study. The investigators also found that clearance rates of baseline somatic mutations correlated with response to treatment.

Grade 3 or greater treatment-emergent adverse events occurred in 43 of the 50 patients, including infections, thrombocytopenias, and febrile neutropenias.

“On the basis of these encouraging results, a phase 3, multicenter, double-blind, randomized study of pracinostat vs. placebo with azacitidine (NCT03151408) is currently ongoing to confirm superiority of the combination in this difficult-to-treat AML population,” the investigators wrote.

The study was supported by research funding from MEI Pharma, which helped develop pracinostat. Dr. Garcia-Manero reported having no disclosures. Multiple coauthors reported financial relationships with MEI and others. One coauthor is an MEI employee.

SOURCE: Garcia-Manero G et al. Blood Adv. 2019 Feb 26;3(4):508-18.

For patients older than 65 years with newly diagnosed acute myeloid leukemia (AML) who were ineligible for standard induction therapy, adding the investigational pan-histone deacetylase (pan-HDAC) inhibitor pracinostat to azacitidine resulted in better complete remission and overall survival rates than azacitidine alone, results of a multicenter phase 2 trial showed.

Among 50 patients treated with the combination, 26 (52%) achieved the primary endpoint of either a complete remission (CR), CR with incomplete recovery of blood counts (CRi), or morphologic leukemia-free state (MLFS).

The median overall survival (OS) was 19.1 months, which compares favorably with historical data on similar patients treated with single-agent azacitidine, reported Guillermo Garcia-Manero, MD, from the University of Texas MD Anderson Cancer Center in Houston and his colleagues.

“[T]his study shows that pracinostat in combination with azacitidine has the potential to be a safe and effective regimen in the frontline treatment of older patients with AML unfit for [induction chemotherapy],” they wrote in Blood Advances.

Pracinostat is an oral pan-HDAC inhibitor that has been shown to have modest activity against AML as a single agent, but synergistic activity when combined with hypomethylating agent azacitidine, a standard of care for older patients with AML in the trial.

The investigators enrolled 50 patients with a median age of 75 years (range, 66-84 years). The cohort included 33 patients with de novo AML, 12 with AML secondary to myelodysplasia syndrome or myleoproliferative neoplasia, and five with therapy-related AML.

The patients were treated with pracinostat 60 mg daily for 3 days each week for 3 consecutive weeks in addition to azacitidine 75 mg/m² daily for 7 days in a 28-day cycle.

As noted, 26 patients reached the clinical endpoint, including 21 with a CR, 2 with a CRi, and 3 with MLFS. Additionally, two patients had a partial response (PR) and four had a PR with incomplete recovery of blood counts.

The median OS was 19.1 months, and the median progression-free survival (PFS) was 12.6 months. The 1-year OS rate was 62%. The 60-day mortality rate was 10%.

The authors noted that the survival data were superior to those seen in the phase 3 AZA-AML-001 study, which compared azacitidine therapy with conventional regimens in patients older than 65 years with newly diagnosed AML who were not eligible for stem cell transplants. In that trial, median OS was 10.4 months, the CR rate was 19.5% (vs. 49% in the present study), the 1-year OS rate was 46.5%, and the 60-day mortality rate was 16.2%.

They acknowledged, however, that the validity of the comparison is limited by their study’s small sample size, potential differences between the study populations, and lack of a control group in the present study. The investigators also found that clearance rates of baseline somatic mutations correlated with response to treatment.

Grade 3 or greater treatment-emergent adverse events occurred in 43 of the 50 patients, including infections, thrombocytopenias, and febrile neutropenias.

“On the basis of these encouraging results, a phase 3, multicenter, double-blind, randomized study of pracinostat vs. placebo with azacitidine (NCT03151408) is currently ongoing to confirm superiority of the combination in this difficult-to-treat AML population,” the investigators wrote.

The study was supported by research funding from MEI Pharma, which helped develop pracinostat. Dr. Garcia-Manero reported having no disclosures. Multiple coauthors reported financial relationships with MEI and others. One coauthor is an MEI employee.

SOURCE: Garcia-Manero G et al. Blood Adv. 2019 Feb 26;3(4):508-18.

SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.

Neil Osterweil/MDedge News

Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.

“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.

The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.

In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.

The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.

The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.

The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.

Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.

Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.

Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.

The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.

The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.

The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.

The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.

SOURCE: Diab A et al. ASCO-SITC, Abstract 26.

SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.

Neil Osterweil/MDedge News

Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.

“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.

The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.

In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.

The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.

The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.

The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.

Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.

Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.

Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.

The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.

The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.

The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.

The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.

SOURCE: Diab A et al. ASCO-SITC, Abstract 26.

SAN FRANCISCO – A combination of two novel immune-stimulating agents has shown early evidence of efficacy against malignant melanoma, leiomyosarcoma, and triple-negative breast cancer in a phase 1b, dose-escalating study.

Neil Osterweil/MDedge News

Among 11 evaluable patients enrolled in a trial of NKTR-262, a small molecule agonist of toll-like receptors (TLR) 7/8, and bempegaldesleukin, an interleukin-2 pathway agonist, 2 had a partial response and 3 had stable disease, reported Adi Diab, MD, from the University of Texas MD Anderson Cancer Center, Houston, and his colleagues.

Patients tolerated the combination well, and there have been no serious adverse events or dose-limiting toxicities.

“Pharmacodynamic data demonstrate both activation of the systemic adaptive and the local innate immune system, and we have seen early evidence of clinical activity in patients who are refractory to checkpoint inhibitors with immunotherapy regimens,” Dr. Diab said at the American Society of Clinical Oncology (ASCO) – Society for Immunotherapy of Cancer (SITC): Clinical Immuno-Oncology Symposium.

NKTR-262 is injected into tumors and is designed to be retained in the tumor microenvironment where it helps to activate antigen-presenting cells, such as dendritic cells, and primes development of new, antigen-specific cytotoxic T cells. Bempegaldesleukin is a cytokine that works within the IL-2 pathway to increase CD8-positive T cells and natural killer (NK) cells in the tumor microenvironment.

The rationale for the combination is that NKTR-262 can activate innate immunity in cells surrounding the tumor microenvironment and activate the machinery of antigen-presenting cells, and bempegaldesleukin can prime and boost a systemic tumor immune response that can ultimately mediate antitumor activity in distant lesions, Dr. Adib said.

In preclinical models, the combination of these agents led to a robust antitumor effect that also involved distant lesions through mediation of the abscopal effect, in which treatment of a tumor activates an immune response against distant tumor cells as well, Dr. Diab said.

The REVEAL study is an ongoing, phase 1b/2 trial looking at the combination in melanoma, Merkel cell carcinoma, triple-negative breast cancer (TNBC), ovarian cancer, renal cell carcinoma, colorectal cancer, urothelial carcinoma, and sarcoma.

The primary goal of the study is to evaluate safety and determine the optimal phase 2 dose of the combination, evaluate biomarkers of response, and assess antitumor activity. As of Jan. 23, 2019, 13 patients were enrolled and evaluable for safety, and 11 were evaluable for the preliminary efficacy analysis.

The most common treatment-related adverse events (TRAEs) with the combination were transient grade 1 or 2 flu-like symptoms, rash, fatigue, pruritus, and nausea. One patients developed grade 3 maculopapular rash and leukocytosis.

Most of the TRAEs are attributable to bempegaldesleukin. There were no immune-mediated AEs and no TRAEs resulted in study discontinuation.

Tumor biopsies obtained 24 hours after injection of NKTR-262 confirmed the activation of TLR 7/8 and robust induction of type 1 interferon, interferon-alpha, and interferon-beta gene-related signatures necessary for optimal antigen presentation.

Dr. Diab noted that in a different trial of bempegaldesleukin monotherapy there was no significant increase in the type 1 interferon gene signature, but the agent did promote activation of the adaptive immune system.

The complementary nature of the two novel agents could also be demonstrated in evaluation of peripheral blood samples, which showed that, although there was no proliferation of T or NK cells following NKTR-262 injection, the addition of bempegaldesleukin resulted in the proliferation of both effector T cells and NK cells to enhance the systemic immune response.

The preliminary efficacy analysis showed that two of five patients with stage IV melanoma who experienced disease progression on prior immune checkpoint inhibitors had partial responses, including one who had a 100% reduction in target lesions and the other with a 50% reduction. In addition, two patients with heavily pretreated leiomyosarcoma had stable disease as the best response, as did the single patient with TNBC.

The maximum tolerated dose of the combination has not been identified, and the investigators are continuing to enroll patients.

The REVEAL study is supported by Nektar Therapeutics. Dr. Diab reported institutional research funding, consulting fees, and advisory board participation from Nektar, Bristol-Myers Squib, Idera Pharmaceuticals, Jounce Therapeutics, and Array BioPharma.

SOURCE: Diab A et al. ASCO-SITC, Abstract 26.