Nivolumab plus ipilimumab in advanced melanoma

Abstract

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. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical; ClinicalTrials.gov number, NCT01024231.).

Figure 1. Clinical activity of concurrent and sequenced regimens of nivolumab and ipilimumab

Representative spider plots show changes from baseline in the tumor burden, measured as the sum of products of perpendicular diameters of all target lesions, in patients who received the concurrent regimen of 1 mg/kg nivolumab + 3 mg/kg ipilimumab, the maximum tolerated dose, (panel A) and in patients who received the sequenced regimen of 1 mg/kg nivolumab after prior ipilimumab therapy (panel C). Red triangles indicate the first occurrence of a new lesion. Representative waterfall plots show maximum percentage response in baseline target lesions in all patients who received the concurrent regimen (panel B) or the sequenced regimen (panel D). For sequenced regimen cohorts (panel D), “*” denotes patients who had radiographic progression with prior ipilimumab treatment.

Figure 2. Tumor regressions of patients who received concurrent nivolumab and ipilimumab

In Panel A, regression of tumors in a 52-year old patient who received 1 mg/kg nivolumab + 3 mg/kg ipilimumab, the maximum tolerated dose. This patient presented with extensive neck, mediastinal, axillary, abdominal and pelvic lymphadenopathy, bilateral pulmonary nodules, small bowel metastasis, peritoneal implants and diffuse subcutaneous nodules. Baseline lactate dehydrogenase (LDH) was 2.25 × upper limit of normal, hemoglobin was 9.7 g/dL, and symptoms included nausea and vomiting. Within 4 weeks of treatment the LDH normalized, symptoms improved (appetite increased, nausea decreased), and cutaneous lesions were regressing. At week-12 scans, there was marked reduction in all areas of disease. Arrows denote location of metastatic disease. In Panel B, regression of tumors in a 61-year-old patient who received 0.3 mg/kg nivolumab + 3 mg/kg ipilimumab. The patient presented with stage IV (M1c) melanoma of an unknown primary site, metastatic to the stomach and the mesentery. LDH was 225 and hemoglobin was 9.6 g/dL after a recent transfusion. Twelve weeks after the initiation of study treatment, a CT scan showed an 86% reduction in the bulky disease burden.