Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study

Abstract

Purpose The clinical activity observed in a phase I dose-escalation study of concurrent therapy with nivolumab (NIVO) and ipilimumab (IPI) in patients with previously treated or untreated advanced melanoma led to subsequent clinical development, including randomized trials. Here, we report long-term follow-up data from study CA209-004, including 3-year overall survival (OS). Patients and Methods Concurrent cohorts 1, 2, 2a, and 3 received escalating doses of NIVO plus IPI once every 3 weeks for four doses, followed by NIVO once every 3 weeks for four doses, then NIVO plus IPI once every 12 weeks for eight doses. An expansion cohort (cohort 8) received concurrent NIVO 1 mg/kg plus IPI 3 mg/kg once every 3 weeks for four doses, followed by NIVO 3 mg/kg once every 2 weeks, which is the dose and schedule used in phase II and III studies and now approved for patients with unresectable or metastatic melanoma. Results Among all concurrent cohorts (N = 94) at a follow-up of 30.3 to 55.0 months, the 3-year OS rate was 63% and median OS had not been reached. Objective response rate by modified WHO criteria was 42%, and median duration of response was 22.3 months. Incidence of grade 3 and 4 treatment-related adverse events was 59%. The most common grade 3 and 4 treatment-related adverse events were increases in lipase (15%), alanine aminotransferase (12%), and aspartate aminotransferase (11%). One treatment-related death (1.1%) occurred in a patient who had multiorgan failure 70 days after the last dose of NIVO plus IPI. Conclusion This is the longest follow-up for NIVO plus IPI combination therapy in patients with advanced melanoma. The 3-year OS rate of 63% is the highest observed for this patient population and provides additional evidence for the durable clinical activity of immune checkpoint inhibitors in the treatment of advanced melanoma.

Trial registration: ClinicalTrials.gov NCT01024231.

Fig 1.

(A and B) Kaplan-Meier curves of (A) overall survival (OS) and (B) progression-free survival (PFS) for all concurrent cohorts (N = 94). Symbols indicate censored observations.

Fig 2.

Swimmer plots showing time to first response and duration of response in accordance with modified WHO criteria for responders who received concurrent nivolumab plus ipilimumab in each individual cohort.

Fig 3.

(A) Proportion of patients with treatment-related grade 3 and 4 adverse events (AEs) over time for cohorts 1 to 3 and cohort 8*. (B and C) Proportion of patients with treatment-related select grade 3 and 4 AEs over time for (B) cohorts 1 to 3 and (C) cohort 8*. The percentage at each time point shows the number of patients experiencing at least one grade 3 and 4 AE divided by all treated patients (n = 53 for cohorts 1 to 3; n = 41 for cohort 8). *One treatment-related death (1.1%) occurred in a patient who had multiorgan failure subsequent to enterocolitis, sepsis, and pancreatitis, 70 days after the last dose of nivolumab plus ipilimumab treatment in cohort 8.

Fig A1.

Dosing regimen for Study CA209-004 concurrent cohorts. In cohorts 1-3, patients were eligible for reinduction if they experienced investigator-assessed clinical benefit without unacceptable toxicity. Reinduction followed the dose and schedule of the initial 4 doses of nivolumab and ipilimumab, followed by 4 doses of nivolumab. Patients in cohort 8 were ineligible for reinduction.

Fig A2.

Overall survival (OS) by patient subgroups. Overall survival by (A) baseline LDH, (B) M-stage at study entry, (C) treatment-related AEs leading to discontinuation, (D) tumor response, (E) BRAF status, and (F) PD-L1 status in all concurrent cohorts. One-, 2-, and 3-year OS rates are shown in table insets. AE, adverse event; LDH, lactate dehydrogenase; ULN, upper limit of normal.