Charles L. Cowey M.D.

Wolchok, J. D., V. Chiarion-Sileni, R. Gonzalez, P. Rutkowski, J. J. Grob, C. L. Cowey, C. D. Lao, J. Wagstaff, D. Schadendorf, P. F. Ferrucci, M. Smylie, R. Dummer, A. Hill, D. Hogg, J. Haanen, M. S. Carlino, O. Bechter, M. Maio, I. Marquez-Rodas, M. Guidoboni, G. McArthur, C. Lebbe, P. A. Ascierto, G. V. Long, J. Cebon, J. Sosman, M. A. Postow, M. K. Callahan, D. Walker, L. Rollin, R. Bhore, F. S. Hodi and J. Larkin (2017). “Overall survival with combined nivolumab and ipilimumab in advanced melanoma.” N Engl J Med 377(14): 1345-1356.

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Background Nivolumab combined with ipilimumab resulted in longer progression-free survival and a higher objective response rate than ipilimumab alone in a phase 3 trial involving patients with advanced melanoma. We now report 3-year overall survival outcomes in this trial. Methods We randomly assigned, in a 1:1:1 ratio, patients with previously untreated advanced melanoma to receive nivolumab at a dose of 1 mg per kilogram of body weight plus ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses, followed by nivolumab at a dose of 3 mg per kilogram every 2 weeks; nivolumab at a dose of 3 mg per kilogram every 2 weeks plus placebo; or ipilimumab at a dose of 3 mg per kilogram every 3 weeks for four doses plus placebo, until progression, the occurrence of unacceptable toxic effects, or withdrawal of consent. Randomization was stratified according to programmed death ligand 1 (PD-L1) status, BRAF mutation status, and metastasis stage. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group versus the ipilimumab group. Results At a minimum follow-up of 36 months, the median overall survival had not been reached in the nivolumab-plus-ipilimumab group and was 37.6 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.55 [P<0.001]; hazard ratio for death with nivolumab vs. ipilimumab, 0.65 [P<0.001]). The overall survival rate at 3 years was 58% in the nivolumab-plus-ipilimumab group and 52% in the nivolumab group, as compared with 34% in the ipilimumab group. The safety profile was unchanged from the initial report. Treatment-related adverse events of grade 3 or 4 occurred in 59% of the patients in the nivolumab-plus-ipilimumab group, in 21% of those in the nivolumab group, and in 28% of those in the ipilimumab group. Conclusions Among patients with advanced melanoma, significantly longer overall survival occurred with combination therapy with nivolumab plus ipilimumab or with nivolumab alone than with ipilimumab alone.

Weber, J., M. Mandala, M. Del Vecchio, H. J. Gogas, A. M. Arance, C. L. Cowey, S. Dalle, M. Schenker, V. Chiarion-Sileni, I. Marquez-Rodas, J. J. Grob, M. O. Butler, M. R. Middleton, M. Maio, V. Atkinson, P. Queirolo, R. Gonzalez, R. R. Kudchadkar, M. Smylie, N. Meyer, L. Mortier, M. B. Atkins, G. V. Long, S. Bhatia, C. Lebbe, P. Rutkowski, K. Yokota, N. Yamazaki, T. M. Kim, V. de Pril, J. Sabater, A. Qureshi, J. Larkin and P. A. Ascierto (2017). “Adjuvant nivolumab versus ipilimumab in resected stage iii or iv melanoma.” N Engl J Med: 2017 Sep [Epub ahead of print].

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Background Nivolumab and ipilimumab are immune checkpoint inhibitors that have been approved for the treatment of advanced melanoma. In the United States, ipilimumab has also been approved as adjuvant therapy for melanoma on the basis of recurrence-free and overall survival rates that were higher than those with placebo in a phase 3 trial. We wanted to determine the efficacy of nivolumab versus ipilimumab for adjuvant therapy in patients with resected advanced melanoma. Methods In this randomized, double-blind, phase 3 trial, we randomly assigned 906 patients (>/=15 years of age) who were undergoing complete resection of stage IIIB, IIIC, or IV melanoma to receive an intravenous infusion of either nivolumab at a dose of 3 mg per kilogram of body weight every 2 weeks (453 patients) or ipilimumab at a dose of 10 mg per kilogram every 3 weeks for four doses and then every 12 weeks (453 patients). The patients were treated for a period of up to 1 year or until disease recurrence, a report of unacceptable toxic effects, or withdrawal of consent. The primary end point was recurrence-free survival in the intention-to-treat population. Results At a minimum follow-up of 18 months, the 12-month rate of recurrence-free survival was 70.5% (95% confidence interval [CI], 66.1 to 74.5) in the nivolumab group and 60.8% (95% CI, 56.0 to 65.2) in the ipilimumab group (hazard ratio for disease recurrence or death, 0.65; 97.56% CI, 0.51 to 0.83; P<0.001). Treatment-related grade 3 or 4 adverse events were reported in 14.4% of the patients in the nivolumab group and in 45.9% of those in the ipilimumab group; treatment was discontinued because of any adverse event in 9.7% and 42.6% of the patients, respectively. Two deaths (0.4%) related to toxic effects were reported in the ipilimumab group more than 100 days after treatment. Conclusions Among patients undergoing resection of stage IIIB, IIIC, or IV melanoma, adjuvant therapy with nivolumab resulted in significantly longer recurrence-free survival and a lower rate of grade 3 or 4 adverse events than adjuvant therapy with ipilimumab.

Schadendorf, D., J. D. Wolchok, F. S. Hodi, V. Chiarion-Sileni, R. Gonzalez, P. Rutkowski, J. J. Grob, C. L. Cowey, C. D. Lao, J. Chesney, C. Robert, K. Grossmann, D. McDermott, D. Walker, R. Bhore, J. Larkin and M. A. Postow (2017). “Efficacy and safety outcomes in patients with advanced melanoma who discontinued treatment with nivolumab and ipilimumab because of adverse events: A pooled analysis of randomized phase ii and iii trials.” J Clin Oncol: 2017 Aug [Epub ahead of print].

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Purpose Approximately 40% of patients with advanced melanoma who received nivolumab combined with ipilimumab in clinical trials discontinued treatment because of adverse events (AEs). We conducted a retrospective analysis to assess the efficacy and safety of nivolumab plus ipilimumab in patients who discontinued treatment because of AEs. Methods Data were pooled from phase II and III trials of patients who received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, every 3 weeks for four doses, followed by nivolumab monotherapy 3 mg/kg every 2 weeks (N = 409). Efficacy was assessed in all randomly assigned patients who discontinued because of AEs during the induction phase (n = 96) and in those who did not discontinue because of AEs (n = 233). Safety was assessed in treated patients who discontinued because of AEs (n = 176) at any time and in those who did not discontinue because of AEs (n = 231). Results At a minimum follow-up of 18 months, median progression-free survival was 8.4 months for patients who discontinued treatment because of AEs during the induction phase and 10.8 months for patients who did not discontinue because of AEs ( P = .97). Median overall survival had not been reached in either group ( P = .23). The objective response rate was 58.3% for patients who discontinued because of AEs during the induction phase and 50.2% for patients who did not discontinue. The vast majority of grade 3 or 4 AEs occurred during the induction phase, with most resolving after appropriate management. Conclusion Efficacy outcomes seemed similar between patients who discontinued nivolumab plus ipilimumab treatment because of AEs during the induction phase and those who did not discontinue because of AEs. Therefore, even after discontinuation, many patients may continue to derive benefit from combination therapy.

Schadendorf, D., J. Larkin, J. Wolchok, F. S. Hodi, V. Chiarion-Sileni, R. Gonzalez, P. Rutkowski, J. J. Grob, C. L. Cowey, C. Lao, J. Wagstaff, M. K. Callahan, M. A. Postow, M. Smylie, P. F. Ferrucci, R. Dummer, A. Hill, F. Taylor, J. Sabater, D. Walker, S. Kotapati, A. Abernethy and G. V. Long (2017). “Health-related quality of life results from the phase iii checkmate 067 study.” Eur J Cancer 82: 80-91.

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BACKGROUND: Nivolumab, a monoclonal antibody of immune checkpoint programmed death 1 on T cells (PD-1), combined with ipilimumab, an immune checkpoint cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor, as combination therapy on the one hand and nivolumab as monotherapy on the other, have both demonstrated improved efficacy compared with ipilimumab alone in the CheckMate 067 study. However, the combination resulted in a higher frequency of grade 3/4 adverse events (AEs), which could result in diminished health-related quality of life (HRQoL). Here we report analyses of HRQoL for patients with advanced melanoma in clinical trial CheckMate 067. PATIENTS AND METHODS: HRQoL was assessed at weeks 1 and 5 per 6-week cycle for the first 6 months, once every 6 weeks thereafter, and at two follow-up visits using the European Organization for Research and Treatment of Care Core Quality of Life Questionnaire and the EuroQoL Five Dimensions Questionnaire. In addition to the randomised population, patient subgroups, including BRAF mutation status, partial or complete response, treatment-related AEs of grade 3/4, and those who discontinued due to any reason and due to an AE, were investigated. RESULTS: Nivolumab and ipilimumab combination and nivolumab alone both maintained HRQoL, and no clinically meaningful deterioration was observed over time compared with ipilimumab. In addition, similar results were observed across patient subgroups, and no clinically meaningful changes in HRQoL were observed during follow-up visits for patients who discontinued due to any cause. CONCLUSION: These results further support the clinical benefit of nivolumab monotherapy and nivolumab and ipilimumab combination therapy in patients with advanced melanoma. The finding that the difference in grade 3/4 AEs between the arms did not translate into clinically meaningful differences in the reported HRQoL may be relevant in the clinical setting.

Cowey, C. L., L. Mahnke, J. Espirito, C. Helwig, D. Oksen and M. Bharmal (2017). “Real-world treatment outcomes in patients with metastatic merkel cell carcinoma treated with chemotherapy in the USA.” Future Oncol: 2017 Jun [Epub ahead of print].

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AIM: This retrospective study of patients in the USA with metastatic Merkel cell carcinoma (mMCC) aimed to assess patient responses to second-line and later (2L+) and first-line (1L) chemotherapy. PATIENTS & METHODS: Out of 686 patients with MCC identified in The US Oncology Network, 20 and 67 patients with mMCC qualified for the 2L+ and 1L study, respectively; the primary analysis population was restricted to immunocompetent patients. RESULTS: In the 2L+ primary analysis population, objective response rate (ORR) was 28.6%, median duration of response (DOR) was 1.7 months and median progression-free survival was 2.2 months. In the 1L primary analysis population, ORR was 29.4%, median DOR was 6.7 months and median progression-free survival was 4.6 months. CONCLUSION: The low ORR and brief DOR underscore the need for novel therapies.