Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL).

Melanoma/Skin Cancers
Session Type and Session Title: 
Clinical Science Symposium, PD1/PDL1: An Effective Target in Melanoma
Abstract Number: 
J Clin Oncol 31, 2013 (suppl; abstr 9012^)
Jedd D. Wolchok, Harriet M. Kluger, Margaret K. Callahan, Michael Andrew Postow, Ruth Ann Gordon, Neil Howard Segal, Naiyer A. Rizvi, Alexander M. Lesokhin, Kathleen Reed, Matthew M. Burke, Anne Caldwell, Stephanie Anne Kronenberg, Blessing Agunwamba, William Feely, Quan Hong, Christine E. Horak, Alan J. Korman, Jon M. Wigginton, Ashok Kumar Gupta, Mario Sznol; Memorial Sloan-Kettering Cancer Center, New York, NY; Yale School of Medicine; Yale Cancer Center, New Haven, CT; Memorial-Sloan Kettering Cancer Center, New York, NY; Bristol-Myers Squibb, Princeton, NJ; Bristol-Myers Squibb, Redwood City, CA

Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).

Abstract Disclosures


Background: CTLA-4 and PD-1 are critical immune checkpoint receptors. In MEL pts, ipilimumab (anti-CTLA-4) prolonged survival in two phase III trials, and nivolumab (anti-PD-1) produced an objective response rate (ORR) of 31% (n=106) in a phase I trial. PD-1 is induced by CTLA-4 blockade, and combined blockade of CTLA-4/PD-1 showed enhanced antitumor activity in murine models. Thus, we initiated the first phase 1 study to evaluate nivolumab/ipilimumab combination therapy. Methods: MEL pts with ≤3 prior therapies received IV nivolumab and ipilimumab concurrently, q3 wk × 4 doses, followed by nivolumab alone q3 wk × 4 (Table). At wk 24, combined treatment was continued q12 wk × 8 in pts with disease control and no DLT. In two sequenced-regimen cohorts, pts with prior standard ipilimumab therapy were treated with nivolumab (q2 wk × 48). Results: As of Dec. 6, 2012, 69 pts were treated. We report efficacy data on 37 pts with concurrent therapy in completed cohorts 1-3 (Table); ORR was 38% (95% CI: 23-55). In cohort 2 (MTD), ORR was 47% and 41% of pts had ≥80% tumor reduction at 12 wk (Table) with some pts showing rapid responses, prompt symptom resolution, and durable CRs. Related adverse events (rAEs) for concurrent therapy were similar in nature with some higher in frequency than those typically seen for the monotherapies and were generally manageable using immunosuppressants. Cohort 3 exceeded the MTD (DLT: gr 3-4 ↑ lipase). At the MTD, gr 3-4 rAEs occurred in 59% of pts and included uveitis/choroiditis, colitis, and reversible lab abnormalities. Conclusions: Nivolumab and ipilimumab can be combined with a manageable safety profile. Clinical activity for concurrent therapy appears to exceed that of published monotherapy data, with rapid and deep tumor responses (≥80% tumor reduction at 12 wk) in 30% (11/37) of pts. A phase III trial is planned to compare concurrent combination dosing with each monotherapy. Clinical trial information: NCT01024231.

Cohort Ipilimumab (mg/kg) +
nivolumab (mg/kg)
na CRb
ORR (%)
[95% CI]
≥80% Tumor reduction
at 12 wk (%)
1 3 + 0.3 14 1 2 21 [5-51] 4/14 (29)
2 3 + 1 17 3 5 47 [23-72] 7/17 (41)
3 3 + 3 6 0 3 50 [12-88] 0/6 (0)
2a 1 + 3 12 Ongoing
6 Prior + 1 14 Ongoing
7 Prior + 3 6 Ongoing

Total treated; bmWHO criteria.