› Forums › General Melanoma Community › Nivolumab/Ipilimumab Combo in Advanced Melanoma – NEJM
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- June 7, 2013 at 7:13 pm
Research June 06, 2013Research June 06, 2013Score One for Nivolumab/Ipilimumab Combo in Advanced Melanoma
N. Engl. J. Med. 2013 Jun 02;[EPub Ahead of Print], JD Wolchok, H Kluger, MK Callahan, MA Postow, NA Rizvi, AM Lesokhin, NH Segal, CE Ariyan, R-A Gordon, K Reed, MM Burke, A Caldwell, SA Kronenberg, BU Agunwamba, X Zhang, I Lowy, HD Inzunza, WFeely, CE Horak, Q Hong, AJ Korman, JM Wigginton, A Gupta, M Sznol
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Researchers combined nivolumab plus ipilimumab in patients with advanced melanoma. Results demonstrated remarkable response rates, along with a manageable safety profile.
SUMMARY
PracticeUpdate Editorial Team
Background: In patients with melanoma, ipilimumab (an antibody against cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4]) prolongs overall survival, and nivolumab (an antibody against the programmed death 1 [PD-1] receptor) produced durable tumor regression in a phase 1 trial. On the basis of their distinct immunologic mechanisms of action and supportive preclinical data, we conducted a phase 1 trial of nivolumab combined with ipilimumab in patients with advanced melanoma.
Methods: We administered intravenous doses of nivolumab and ipilimumab in patients every 3 weeks for 4 doses, followed by nivolumab alone every 3 weeks for 4 doses (concurrent regimen). The combined treatment was subsequently administered every 12 weeks for up to 8 doses. In a sequenced regimen, patients previously treated with ipilimumab received nivolumab every 2 weeks for up to 48 doses.
Results: A total of 53 patients received concurrent therapy with nivolumab and ipilimumab, and 33 received sequenced treatment. The objective-response rate (according to modified World Health Organization criteria) for all patients in the concurrent-regimen group was 40%. Evidence of clinical activity (conventional, unconfirmed, or immune-related response or stable disease for ≥24 weeks) was observed in 65% of patients. At the maximum doses that were associated with an acceptable level of adverse events (nivolumab at a dose of 1 mg per kilogram of body weight and ipilimumab at a dose of 3 mg per kilogram), 53% of patients had an objective response, all with tumor reduction of 80% or more. Grade 3 or 4 adverse events related to therapy occurred in 53% of patients in the concurrent-regimen group but were qualitatively similar to previous experience with monotherapy and were generally reversible. Among patients in the sequenced-regimen group, 18% had grade 3 or 4 adverse events related to therapy and the objective-response rate was 20%.
Conclusions: Concurrent therapy with nivolumab and ipilimumab had a manageable safety profile and provided clinical activity that appears to be distinct from that in published data on monotherapy, with rapid and deep tumor regression in a substantial proportion of patients.
The New England Journal of MedicineNivolumab Plus Ipilimumab in Advanced Melanoma
N. Engl. J. Med. 2013 Jun 02;[EPub Ahead of Print], JD Wolchok, H Kluger, MK Callahan, MA Postow, NA Rizvi, AM Lesokhin, NH Segal, CE Ariyan, R-A Gordon, K Reed, MM Burke, A Caldwell, SA Kronenberg, BU Agunwamba, X Zhang, I Lowy, HD Inzunza, WFeely, CE Horak, Q Hong, AJ Korman, JM Wigginton, A Gupta, M Sznol
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Commentary by
Immunotherapeutic approaches to cancer continue to excite oncologists, and with good reason. A presentation by Jedd Wolchok of Memorial Sloan-Kettering Cancer Center presented at the ASCO 2013 meeting, and published simultaneously in The New England Journal of Medicine, focused on the combination of ipilimumab, an FDA-approved CTLA-4 antagonist, and nivolumab, an investigational PD-1 inhibitor, for the treatment of patients with advanced melanoma. Both drugs affect the immune system by reducing the so-called "brake mechanism" by interfering with T-cell inhibitory checkpoints, which normally prevent innate immunosurveillance of cancer cells. By targeting two different points along this pathway, preclinical studies had demonstrated additive benefits over one drug alone.
In this phase I study, the results were dramatic: a 40% response rate, clinical activity in 60% of patients, many complete/near complete responses, and very long duration of response. The concurrent administration of these agents appeared to be superior to a sequential approach, and the maximal tolerated dose of the combination was established. Given the fact that other PD-1 antibodies have also shown impressive activity, as seen with lambrolizumab in an article published in the same issue of NEJM, and the promising results of this approach in common cancers such as non–small cell lung cancer, we appear to be entering an era when the ultimate personalized therapy—a patient's own uniquely specific immune system—provides tangible, long-lasting benefit against cancer.