Nivolumab/Ipilimumab Combo Active in Sarcoma

Sandra P. D’Angelo, MD

Dual checkpoint inhibition with nivolumab (Opdivo) plus ipilimumab (Yervoy) induced an objective response rate (ORR) of 16% (90% CI, 7-29) in patients with heavily treated, unselected, metastatic sarcoma, according to findings from the phase II ALLIANCE A091401 trial presented at the 2017 ASCO Annual Meeting.

Single-agent nivolumab demonstrated “minimal” activity, according to researchers, with an ORR of 5% (90% CI, 1-15). The clinical benefit rate was 29% (90% CI, 17-43) with the combination and 18% (90% CI, 1-32) with monotherapy.

Thirty-eight patients from each group were evaluable for efficacy. Median overall survival (OS) was 14.3 months in the combination arm (95% CI, 9.6-not evaluable) and median progression-free survival (PFS) was 4.4 months (95% CI, 2.3-6.3). At 12 months, 54% of patients were still alive. OS was 10.7 months (95% CI, 5.5-15.4) and PFS was 2.1 months (95% CI, 1.4-4.4) in the monotherapy arm, and 40% of patients remained alive at 12 months.

“Nivolumab at 3 mg/kg with ipilimumab at 1 mg/kg was safe and well-tolerated despite higher grade 3 or 4 treatment-related adverse events compared to monotherapy,” said Sandra P. D’Angelo, MD, a medical oncologist specializing in soft tissue and bone sarcomas with Memorial Sloan Kettering Cancer Center. “The survival at 1 year for the combination cohort exceeds expectations for this patient population.”

She added that investigators observed responses in patients with uterine and non-uterine leiomyosarcoma, myxofibrosarcoma, undifferentiated pleomorphic sarcoma, and angiosarcoma.

Eligible patients with advanced sarcoma were randomly assigned in a noncomparative fashion to 3 mg/kg of nivolumab every 2 weeks (n = 42) or 3 mg/kg of nivolumab with 1 mg/kg of ipilimumab (Yervoy) every 3 weeks for 4 doses, followed by 3 mg/kg of nivolumab every 2 weeks (n = 43). Patients remained on treatment for 2 years, or until progression or unacceptable toxicity.

Four patients crossed over to the combination arm, and 7% of patients in that arm remain on-study.

In the monotherapy arm, there were 3 partial responses (8%), 15 patients with stable disease (39%), and 20 (53%) with progressive disease. There were no complete responses. Two patients on monotherapy had confirmed partial response. Seven patients had complete or partial response, including 6 confirmed, with the combination.

Median time to response in the combination arm was 6.6 weeks.

“Of note, [for] the 2 patients with complete responses, it occurred at month 6 and month 8 on treatment,” D’Angelo said. “There was only 1 patient who had evidence of progressive disease and subsequent partial response, therefore the concept of pseudoprogression in this particular cohort of sarcoma patients may not be something that’s applicable.”

Median time to response was 8.6 weeks in the monotherapy arm. One patient stayed on treatment for 12 months and had an unconfirmed partial response that was not durable.

D’Angelo said, at a median follow-up of 14 months, 71% of patients in the combination arm experienced progression, 47% of patients are still alive, and 55% received off-protocol therapy. In the monotherapy arm, 89% of patients experienced progression, 32% of patients were still alive, and 55% received off-protocol therapy.

Forty-two patients from each group were included in the safety assessment. All patients experienced adverse events (AEs).

The rate for grade 3/4 AEs was slightly higher in the combination arm (48% vs 40%). Incidence of treatment-related AEs was nearly identical, but the patients in the combination arm experienced grade 3/4 treatment-related AEs at twice the rate as patients assigned to monotherapy (14% vs 7%). There were 11 deaths (5 monotherapy, 6 combination), none related to treatment.

In the monotherapy arm, 86% of discontinuations were due to progression compared with 74% in the combination arm. Fifteen percent of patients in the combination arm discontinued due to AEs compared with 2% on monotherapy.

D’Angelo SP, Mahoney MR, Van Tine BA, et al. A multi-center phase II study of nivolumab +/- ipilimumab for patients with metastatic sarcoma (Alliance A091401). J Clin Oncol. 35, 2017 (suppl; abstr 11007).