ASCO 2014: Ipilimumab/Nivolumab Combination Achieves Long-Term Survival for Patients With Advanced Melanoma
Concurrent treatment with ipilimumab (Yervoy) and nivolumab resulted in a 2-year survival rate of 79% for patients with advanced melanoma. “While this is a small trial, that is very impressive 2-year survival data,” noted Mario Sznol, MD, at a press briefing on progress in immunotherapy prior to the 2014 ASCO Annual Meeting in Chicago (Abstract LBA9003^). Dr. Sznol is lead author of the study and Professor of Medical Oncology at Yale School of Medicine in New Haven, Connecticut.
Nivolumab and ipilimumab are two distinct immune checkpoint inhibitors, with nivolumab targeting PD-1 and ipilimumab targeting CTLA-4. “It makes sense to combine them,” Dr. Sznol said. Both agents have demonstrated significant clinical activity as monotherapy in advanced melanoma. Ipilimumab is approved by the U.S. Food and Drug Administration for the treatment of metastatic melanoma.
New Cohort of Patients
Dr. Sznol reported updated data on safety, survival, and clinical activity for the initial 53 patients treated with concurrent combination treatment regimens in the phase I trial (previously reported at the 2013 ASCO Annual Meeting [Abstract 3003^] and published in The New England Journal of Medicine), as well as preliminary response data in a new cohort of 41 patients treated with the regimen used in the subsequent phase II/III trials.
The induction schedule was the same—nivolumab and ipilimumab every 3 weeks for four doses—but the initial 53 patients then received nivolumab every 3 weeks for four doses, followed by nivolumab and ipilimumab every 12 weeks for eight doses. In the new cohort, induction was followed by nivolumab at 3 mg/kg every 2 weeks for up to 2 years.
All 94 patients had stage III or IV melanoma and could have received up to three prior systemic therapies, although 55% had no prior systemic treatments.
Response Rates
“The 1-year overall survival rate was 85% and the 2-year survival rate now with further follow-up is 79%,” Dr. Sznol reported. During the past year, with further follow-up, the confirmed complete response rate for the initial 53 patients increased from 10% to 17%. “Probably the number of patients who had true complete responses is higher than that,” Dr. Sznol said, as suggested by the > 80% reduction in overall tumor measurements in 22 out of 53 patients (41.5%). “I can tell you that many of those patients had near complete responses,” he said.
The responses were durable, and 18 of the 22 objective responses (82%) were ongoing at time of analysis, with median duration of response not yet reached. Clinical responses were seen regardless of tumor BRAF mutation status or PD-L1 status and across all dose levels.
The activity of combination therapy was confirmed in the additional cohort of 41 patients. “The objective response rate was 43%, which was very similar to what we saw in the first 53 patients. So we feel very confident that the activity of this combination regiment is real,” Dr. Sznol stated.
“Certainly these early results with almost 80% 2-year survival are very impressive,” commented Steven O’Day, MD, Clinical Professor of Medicine at the University of Southern California, Keck School of Medicine, Los Angeles, and moderator of the ASCO press briefing on progress in immunotherapy. Along with concerns about toxicities, there are unresolved issues concerning sequencing. “If there is little cross-resistance between the agents, it is not absolutely clear that combining them vs sequencing them would be the best possible approach for patients in terms of toxicity and survival,” Dr. O’Day noted.
Increased Toxicity
Combining ipilimumab with nivolumab did result in increased toxicity compared to therapy with either single agent. Grade 3/4 side effects occurred in 58 of the 94 patients (62%). These events, however, “were manageable and reversible with algorithms that were established for ipilimumab,” Dr. Sznol stated. “In the vast majority of patients, all of the adverse events were reversible. There was one drug-related death in that last cohort of 41 patients, but it resulted from the consequences of colitis.”
Overall, there were no new safety signals reported with additional follow-up. “We feel fairly confident that these are adverse events that can be managed with a little bit of education and training. It certainly appears as though the activity of the regimen would justify the increased rate in adverse events,” Dr. Sznol said. He added that it is “very important not only to educate the physicians, but to educate the patients about what to look for, so they can call and alert us, and then we can manage the toxicities.”
Ongoing Trials
Enrollment has been completed for a phase III trial comparing nivolumab plus ipilimumab vs nivolumab or ipilimumab alone and a phase II trial comparing nivolumab plus ipilimumab to ipilimumab alone.
This current study was supported by Bristol-Myers Squibb and Ono Pharmaceutical. Dr. Sznol reported a consultant or advisory role with Symphogen, Anaeropharma, Bristol-Myers Squibb, Amgen, MedImmune, Nektar, and Genentech. For full disclosures of the study authors, view the study abstract at abstract.asco.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
