‘Unprecedented’ overall survival of metastatic melanoma

CHICAGO – The combination of two immune checkpoint inhibitors, nivolumab and ipilimumab, has resulted in "unprecedented" 2-year overall survival rates for patients with metastatic melanoma, early study results show.

In an expanded phase I trial evaluating dosing, safety and efficacy of nivolumab and ipilimumab (Yervoy) either concurrently or in sequence, the 2-year overall survival for 53 patients in three concurrent dosing cohorts was 79%, reported Dr. Mario Sznol, a professor of medical oncology at Yale University, New Haven, Conn.

"We saw significant activity in patients with BRAF mutations, which means this is a very good option in addition to targeted therapy for patients who have BRAF mutations," Dr. Sznol said during a media briefing at the annual meeting of the American Society of Clinical Oncology.

"I almost feel like I’m looking at childhood leukemia survival curves, when we’re starting to approach an 80% plateau," commented Dr. Steven O’Day from the Beverly Hills (Calif.) Cancer Center, who moderated the briefing but was not involved in the study.

He cautioned that the study was small and that randomized, controlled phase III trials will be required before the full benefits of the combined therapies are evident.

Two checkpoints

Both agents are monoclonal antibodies directed against receptors in immune system checkpoints. Ipilimumab is a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor that acts at an early "brake" point in the immune response; nivolumab is a programmed cell death-1 (PD-1) inhibitor that serves as a late brake. By releasing the brakes, the drugs allow the immune system to operate full throttle against melanoma.

Ipilimumab is approved by the Food and Drug Administration for the treatment of metastatic melanoma. Nivolumab is an investigational agent that has been shown to have good antitumor activity in monotherapy.

"PD-1 and CTLA-4 both, as you\'ve heard before, are nonredundant checkpoints in T-cell differentiation and function, and there are several animal models that show synergy by combining these two agents," Dr. Sznol said in an oral abstract session.

As single agents, ipilimumab is associated with a 2-year overall survival rate of 24%, and nivolumab with a 2-year OS of 43%.

The investigators reported at ASCO 2013 and in the New England Journal of Medicine that the combined agents were associated with a 1-year OS of 82%.

Complex protocol

In the head-spinningly complex phase I dose-escalation study, patients with unresectable stage III or IV malignant melanoma were assigned to one of eight different dosing cohorts, looking at doses of nivolumab ranging from 0.3 to 10 mg/kg delivered in a 60 or 90 minute infusion every 2 or 3 weeks for up to 21 weeks, and to ipilimumab at doses ranging from 3 to 10 mg/kg delivered in 60- to 90-minute infusions every 3 weeks for 9 to 21 weeks of induction, followed by 84 to 96 weeks of maintenance therapy.

For the current report, Dr. Sznol and his colleagues looked at follow-up of 53 patients in dosing cohorts 1-3, all of whom received the drugs concurrently every 3 weeks for four doses, followed by nivolumab every 3 weeks for four doses, and then the combined agents every 12 weeks for eight doses. They also reported on a new, eighth cohort of 41 patients who received both drugs on the same induction schedule, followed by maintenance with nivolumab 3 mg/kg alone every 2 weeks until disease progression. This dosing schedule is being evaluated in phase II/III trials.

The overall response rate (ORR) for cohorts 1-3 was 42%, with 17% of patients having a complete response according to RECIST (Response Evaluation Criteria in Solid Tumors). In cohort 8, 40 of the 41 patients enrolled were evaluable for response, with an ORR of 43, and a 10% complete response rate (CRRs), although two of the CRRs were unconfirmed.

80% tumor shrinkage

In cohorts 1-3, 42% of patients had a reduction in tumor size of more than 80%, and many of these patients had complete or near-complete responses, Dr. Sznol said. Tumor shrinkage appeared similar in cohort 8, as shown on a waterfall plot, but Dr. Sznol did not report specifics about tumor dimensions in this group.

The median duration of responses in all four cohorts discussed has not been reached.

Grade 3 or 4 toxicities occurred in 62% of patients, with gastrointestinal side effects and elevated liver function tests occurring in 14% each, and increases in serum lipase in 15% and amylase in 6%. No new safety signals have emerged over 22 months of follow-up of patients in the initial cohorts, Dr. Sznol noted.

Dr. Jeffrey Weber of the Moffit Cancer Center in Tampa, Fla., the invited discussant, who has treated patients using the drugs in combination, commented that "Yes, you do see a large rate of patients with asymptomatic liver-function abnormalities that get better, and then you can retreat them."

Grade 3 elevated lipase or amylase may not require treatment, and grade 4 events may resolve with treatment interruption. Much of the toxicity occurs early with the concurrent regimen, and lessens during maintenance with nivolumab alone, he added.

Of the 94 patients in cohorts 1-3 and 8, 22 (23%) discontinued therapy due to treatment-related adverse events. One patient died from multiorgan failure associated with treatment-induced colitis; this patient was in cohort 8.

The study is supported by Bristol-Myers Squibb, Medarex, and Ono Pharma USA. Dr. Sznol disclosed consultant/advisory relationships with Bristol-Myers Squibb and several other companies. Dr. Weber disclosed consulting/advising, and received honoraria and research funding from Bristol-Myers Squibb and other companies. Dr. O’Day has received grants for research support from Bristol-Myers Squibb and Medarex, and he has served on the speakers bureau for Bristol-Myers Squibb.

CHICAGO – The combination of two immune checkpoint inhibitors, nivolumab and ipilimumab, has resulted in "unprecedented" 2-year overall survival rates for patients with metastatic melanoma, early study results show.

In an expanded phase I trial evaluating dosing, safety and efficacy of nivolumab and ipilimumab (Yervoy) either concurrently or in sequence, the 2-year overall survival for 53 patients in three concurrent dosing cohorts was 79%, reported Dr. Mario Sznol, a professor of medical oncology at Yale University, New Haven, Conn.

"We saw significant activity in patients with BRAF mutations, which means this is a very good option in addition to targeted therapy for patients who have BRAF mutations," Dr. Sznol said during a media briefing at the annual meeting of the American Society of Clinical Oncology.

"I almost feel like I’m looking at childhood leukemia survival curves, when we’re starting to approach an 80% plateau," commented Dr. Steven O’Day from the Beverly Hills (Calif.) Cancer Center, who moderated the briefing but was not involved in the study.

He cautioned that the study was small and that randomized, controlled phase III trials will be required before the full benefits of the combined therapies are evident.

Two checkpoints

Both agents are monoclonal antibodies directed against receptors in immune system checkpoints. Ipilimumab is a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor that acts at an early "brake" point in the immune response; nivolumab is a programmed cell death-1 (PD-1) inhibitor that serves as a late brake. By releasing the brakes, the drugs allow the immune system to operate full throttle against melanoma.

Ipilimumab is approved by the Food and Drug Administration for the treatment of metastatic melanoma. Nivolumab is an investigational agent that has been shown to have good antitumor activity in monotherapy.

"PD-1 and CTLA-4 both, as you\'ve heard before, are nonredundant checkpoints in T-cell differentiation and function, and there are several animal models that show synergy by combining these two agents," Dr. Sznol said in an oral abstract session.

As single agents, ipilimumab is associated with a 2-year overall survival rate of 24%, and nivolumab with a 2-year OS of 43%.

The investigators reported at ASCO 2013 and in the New England Journal of Medicine that the combined agents were associated with a 1-year OS of 82%.

Complex protocol

In the head-spinningly complex phase I dose-escalation study, patients with unresectable stage III or IV malignant melanoma were assigned to one of eight different dosing cohorts, looking at doses of nivolumab ranging from 0.3 to 10 mg/kg delivered in a 60 or 90 minute infusion every 2 or 3 weeks for up to 21 weeks, and to ipilimumab at doses ranging from 3 to 10 mg/kg delivered in 60- to 90-minute infusions every 3 weeks for 9 to 21 weeks of induction, followed by 84 to 96 weeks of maintenance therapy.

For the current report, Dr. Sznol and his colleagues looked at follow-up of 53 patients in dosing cohorts 1-3, all of whom received the drugs concurrently every 3 weeks for four doses, followed by nivolumab every 3 weeks for four doses, and then the combined agents every 12 weeks for eight doses. They also reported on a new, eighth cohort of 41 patients who received both drugs on the same induction schedule, followed by maintenance with nivolumab 3 mg/kg alone every 2 weeks until disease progression. This dosing schedule is being evaluated in phase II/III trials.

The overall response rate (ORR) for cohorts 1-3 was 42%, with 17% of patients having a complete response according to RECIST (Response Evaluation Criteria in Solid Tumors). In cohort 8, 40 of the 41 patients enrolled were evaluable for response, with an ORR of 43, and a 10% complete response rate (CRRs), although two of the CRRs were unconfirmed.

80% tumor shrinkage

In cohorts 1-3, 42% of patients had a reduction in tumor size of more than 80%, and many of these patients had complete or near-complete responses, Dr. Sznol said. Tumor shrinkage appeared similar in cohort 8, as shown on a waterfall plot, but Dr. Sznol did not report specifics about tumor dimensions in this group.

The median duration of responses in all four cohorts discussed has not been reached.

Grade 3 or 4 toxicities occurred in 62% of patients, with gastrointestinal side effects and elevated liver function tests occurring in 14% each, and increases in serum lipase in 15% and amylase in 6%. No new safety signals have emerged over 22 months of follow-up of patients in the initial cohorts, Dr. Sznol noted.

Dr. Jeffrey Weber of the Moffit Cancer Center in Tampa, Fla., the invited discussant, who has treated patients using the drugs in combination, commented that "Yes, you do see a large rate of patients with asymptomatic liver-function abnormalities that get better, and then you can retreat them."

Grade 3 elevated lipase or amylase may not require treatment, and grade 4 events may resolve with treatment interruption. Much of the toxicity occurs early with the concurrent regimen, and lessens during maintenance with nivolumab alone, he added.

Of the 94 patients in cohorts 1-3 and 8, 22 (23%) discontinued therapy due to treatment-related adverse events. One patient died from multiorgan failure associated with treatment-induced colitis; this patient was in cohort 8.

The study is supported by Bristol-Myers Squibb, Medarex, and Ono Pharma USA. Dr. Sznol disclosed consultant/advisory relationships with Bristol-Myers Squibb and several other companies. Dr. Weber disclosed consulting/advising, and received honoraria and research funding from Bristol-Myers Squibb and other companies. Dr. O’Day has received grants for research support from Bristol-Myers Squibb and Medarex, and he has served on the speakers bureau for Bristol-Myers Squibb.

CHICAGO – The combination of two immune checkpoint inhibitors, nivolumab and ipilimumab, has resulted in "unprecedented" 2-year overall survival rates for patients with metastatic melanoma, early study results show.

In an expanded phase I trial evaluating dosing, safety and efficacy of nivolumab and ipilimumab (Yervoy) either concurrently or in sequence, the 2-year overall survival for 53 patients in three concurrent dosing cohorts was 79%, reported Dr. Mario Sznol, a professor of medical oncology at Yale University, New Haven, Conn.

"We saw significant activity in patients with BRAF mutations, which means this is a very good option in addition to targeted therapy for patients who have BRAF mutations," Dr. Sznol said during a media briefing at the annual meeting of the American Society of Clinical Oncology.

"I almost feel like I’m looking at childhood leukemia survival curves, when we’re starting to approach an 80% plateau," commented Dr. Steven O’Day from the Beverly Hills (Calif.) Cancer Center, who moderated the briefing but was not involved in the study.

He cautioned that the study was small and that randomized, controlled phase III trials will be required before the full benefits of the combined therapies are evident.

Two checkpoints

Both agents are monoclonal antibodies directed against receptors in immune system checkpoints. Ipilimumab is a cytotoxic T-lymphocyte antigen-4 (CTLA-4) inhibitor that acts at an early "brake" point in the immune response; nivolumab is a programmed cell death-1 (PD-1) inhibitor that serves as a late brake. By releasing the brakes, the drugs allow the immune system to operate full throttle against melanoma.

Ipilimumab is approved by the Food and Drug Administration for the treatment of metastatic melanoma. Nivolumab is an investigational agent that has been shown to have good antitumor activity in monotherapy.

"PD-1 and CTLA-4 both, as you\'ve heard before, are nonredundant checkpoints in T-cell differentiation and function, and there are several animal models that show synergy by combining these two agents," Dr. Sznol said in an oral abstract session.

As single agents, ipilimumab is associated with a 2-year overall survival rate of 24%, and nivolumab with a 2-year OS of 43%.

The investigators reported at ASCO 2013 and in the New England Journal of Medicine that the combined agents were associated with a 1-year OS of 82%.

Complex protocol

In the head-spinningly complex phase I dose-escalation study, patients with unresectable stage III or IV malignant melanoma were assigned to one of eight different dosing cohorts, looking at doses of nivolumab ranging from 0.3 to 10 mg/kg delivered in a 60 or 90 minute infusion every 2 or 3 weeks for up to 21 weeks, and to ipilimumab at doses ranging from 3 to 10 mg/kg delivered in 60- to 90-minute infusions every 3 weeks for 9 to 21 weeks of induction, followed by 84 to 96 weeks of maintenance therapy.

For the current report, Dr. Sznol and his colleagues looked at follow-up of 53 patients in dosing cohorts 1-3, all of whom received the drugs concurrently every 3 weeks for four doses, followed by nivolumab every 3 weeks for four doses, and then the combined agents every 12 weeks for eight doses. They also reported on a new, eighth cohort of 41 patients who received both drugs on the same induction schedule, followed by maintenance with nivolumab 3 mg/kg alone every 2 weeks until disease progression. This dosing schedule is being evaluated in phase II/III trials.

The overall response rate (ORR) for cohorts 1-3 was 42%, with 17% of patients having a complete response according to RECIST (Response Evaluation Criteria in Solid Tumors). In cohort 8, 40 of the 41 patients enrolled were evaluable for response, with an ORR of 43, and a 10% complete response rate (CRRs), although two of the CRRs were unconfirmed.

80% tumor shrinkage

In cohorts 1-3, 42% of patients had a reduction in tumor size of more than 80%, and many of these patients had complete or near-complete responses, Dr. Sznol said. Tumor shrinkage appeared similar in cohort 8, as shown on a waterfall plot, but Dr. Sznol did not report specifics about tumor dimensions in this group.

The median duration of responses in all four cohorts discussed has not been reached.

Grade 3 or 4 toxicities occurred in 62% of patients, with gastrointestinal side effects and elevated liver function tests occurring in 14% each, and increases in serum lipase in 15% and amylase in 6%. No new safety signals have emerged over 22 months of follow-up of patients in the initial cohorts, Dr. Sznol noted.

Dr. Jeffrey Weber of the Moffit Cancer Center in Tampa, Fla., the invited discussant, who has treated patients using the drugs in combination, commented that "Yes, you do see a large rate of patients with asymptomatic liver-function abnormalities that get better, and then you can retreat them."

Grade 3 elevated lipase or amylase may not require treatment, and grade 4 events may resolve with treatment interruption. Much of the toxicity occurs early with the concurrent regimen, and lessens during maintenance with nivolumab alone, he added.

Of the 94 patients in cohorts 1-3 and 8, 22 (23%) discontinued therapy due to treatment-related adverse events. One patient died from multiorgan failure associated with treatment-induced colitis; this patient was in cohort 8.

The study is supported by Bristol-Myers Squibb, Medarex, and Ono Pharma USA. Dr. Sznol disclosed consultant/advisory relationships with Bristol-Myers Squibb and several other companies. Dr. Weber disclosed consulting/advising, and received honoraria and research funding from Bristol-Myers Squibb and other companies. Dr. O’Day has received grants for research support from Bristol-Myers Squibb and Medarex, and he has served on the speakers bureau for Bristol-Myers Squibb.