Metastatic melanoma and kidney cancer are difficult for both patients and physicians, since there are limited treatment options that extend survival. That is slowly changing.
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New combined immunotherapy treatments have the potential to improve survival in advanced kidney cancer and melanoma, according to the results of the CheckMate 069 and 016 trials that Cleveland Clinic researchers presented at the 2015 American Society of Clinical Oncology (ASCO) annual meeting.
In the two studies, a combination regimen of nivolumab and ipilimumab, both of which are immune checkpoint inhibitors, produced a high response rate and improved progression-free survival. The two drugs temporarily inhibit modulating mechanisms in the immune system, enabling a full-force immune response against cancer cells. Nivolumab and ipilimumab have each been used as monotherapy, but combining them is a new approach.
Marc Ernstoff, MD
At the ASCO meeting, researchers presented updated results of the phase II CheckMate 069 study, in which the ipilimumab-nivolumab combination treatment was tested against ipilimumab monotherapy in advanced melanoma patients. The initial results were published in the New England Journal of Medicine and were presented at the annual meeting of the American Association for Cancer Research in April.
In the study, 142 patients with metastatic or unresectable melanoma (BRAF V600 wild-type and BRAF V600 mutation-positive tumors) who had not previously been treated were randomized in a 2:1 ratio to either nivolumab and ipilimumab treatment (NIVO + IPI) or ipilimumab monotherapy plus placebo (IPI). The primary endpoint was the rate of objective response among patients with BRAF V600 wild-type tumors. The primary endpoint was restricted to these patients (n = 110) because of their need for new treatment options.
The results showed that 22 percent of the 95 patients who received NIVO + IPI achieved a complete response, versus 0 percent in the IPI group. The objective response rate (ORR) in BRAF wild-type patients was 60 percent (44 of 73) for NIVO + IPI, compared with 11 percent (4 of 37) for IPI.
“To say we now have a treatment that can produce complete remission in 22 percent of metastatic melanoma patients is a game-changer,” said Marc Ernstoff, MD, Co-Director of Cleveland Clinic’s Melanoma Program and a coauthor of the study. Progression-free survival (PFS) in BRAF wild-type melanoma patients on the combination therapy was also improved, with a median PFS of 8.9 months for the combination treatment versus 4.7 months for ipilimumab monotherapy. The combination therapy’s ORR and PFS benefits were observed irrespective of BRAF status, tumor PD-L1 status and prognostic factors.
Grade 3 and 4 adverse events affected more patients (54 percent) in the NIVO + IPI arm than in the IPI arm, where the grade 3 and 4 adverse event rate was 24 percent.
“Cancer patients and cancer physicians are willing to tolerate a certain level of toxicity if the benefit is significant, and with this treatment, 22 percent of stage IV patients experienced a complete disappearance of their tumors,” Dr. Ernstoff said. The newest data from the study shows promising survival curves during extended follow-up of the CheckMate 069 patients, indicating that the treatment could be a candidate for FDA licensing.
Brian Rini, MD
In CheckMate 016, a phase I study whose results were presented as a poster at this year’s ASCO, Brian Rini, MD, of Cleveland Clinic’s Department of Hematology and Medical Oncology, and fellow researchers tested the combination of nivolumab and ipilimumab in metastatic kidney cancer. In this study, patients with metastatic kidney cancer were randomized to three treatment arms that tested nivolumab plus ipilimumab at different dosages. In the treatment arm with the highest dosage — nivolumab at 3 mg/kg plus ipilimumab at 3 mg/kg — treatment was halted because of early toxicity.
The other two treatment arms, with 47 patients each, showed that the combination therapy produced durable responses and encouraging progression-free survival, according to Dr. Rini, who specializes in renal and prostate cancer research. Patients in these two treatment arms received either nivolumab at 3 mg/kg plus ipilimumab at 1 mg/kg (N3 + I1) or nivolumab at 1 mg/kg plus ipilimumab at 3 mg/kg (N1 + I3).
“There was a high response rate, as well as a reasonable duration of disease control and progression-free survival in the study,” Dr. Rini said. “Clearly the combination treatment showed clinical activity.”
Patients showed an overall response rate of 38 percent for N3 + I1 and 43 percent for N1 + I3. The median progression-free survival was 30.3 weeks for N3 + I1 and 36 weeks for N1 + I3. Treatment-related grade 3 and 4 adverse events occurred in 34 percent of N3 + I1 patients and in 64 percent of N1 + I3 patients.
A phase III trial testing the combination of nivolumab plus ipilimumab in kidney cancer is now accruing patients, according to Dr. Rini. Cleveland Clinic researchers will participate in this study as well.
“What we can conclude from the phase I study is that the combination of nivolumab plus ipilimumab is active in kidney cancer, and worthy of further study,” Dr. Rini said.
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