The combination of the checkpoint inhibitor nivolumab with the anti-CTLA (cytotoxic T-lymphocyte antigen)-4 ipilimumab results in durable responses in patients with advanced small-cell lung cancer (SCLC) or advanced non–small-cell lung cancer (NSCLC), according to the results of 2 separate clinical studies presented at ASCO 2016.
The combination of nivolumab and ipilimumab is already approved for the treatment of patients with metastatic melanoma, and has demonstrated encouraging clinical benefit across a range of tumor types.
In the CheckMate 032 trial, which included patients with advanced SCLC whose disease progressed after platinum-based chemotherapy, the objective response rate (ORR) with the combination of 1-mg/kg nivolumab plus 3-mg/kg ipilimumab was 23%, reported Scott J. Antonia, MD, PhD, Department Chair of the Thoracic Oncology Department, H. Lee Moffitt Cancer Center, Tampa, FL.
Although patients with SCLC often respond to first-line chemotherapy, recurrence is the rule.
“SCLC has been a very stubborn disease, not for lack of trying,” said Dr Antonia.
“There really has been only trivial progress made over the past 30, maybe 40, years for this disease,” he noted.
Nivolumab as a single agent has limited efficacy in SCLC, because there are few tumor-infiltrating lymphocytes present in SCLC tumors, Dr Antonia explained, providing the rationale for combining it with ipilimumab.
CheckMate 032 enrolled 216 patients with advanced SCLC who received ≥1 previous treatments, including platinum-based chemotherapy. Patients were not selected on the basis of PD ligand 1 (PD-L1) expression. A total of 98 patients received 3-mg/kg nivolumab twice weekly (N3); 61 patients received nivolumab 1 mg/kg plus ipilimumab 3 mg/kg for 4 cycles (N1 + I3); and 54 patients received N3 plus 1 mg/kg of ipilimumab for 4 cycles (N3 + I1). Approximately 50% of the patients received ≥2 previous treatment regimens.
The ORR was 10% in the nivolumab monotherapy arm, which improved to 23% for the N1 + I3 regimen and 19% for N3 + I1. The response rates were similar in patients with platinum-sensitive disease and in those with platinum-refractory disease.
“These responses are rapid. The majority of responding patients did so by the time of their first restaging CT [computed tomography] scan,” Dr Antonia said. “The responses appear to be durable in many of the patients.” Responsiveness did not require PD-L1 expression.
The combination had the most favorable impact on overall survival (OS), although the data are early, said Dr Antonia. The median OS was 7.7 months in the N1 + I3 arm and 6.0 months for N3 + I1 compared with 4.4 months in the nivolumab monotherapy arm. The 1-year OS rates were 33% for nivolumab monotherapy, 43% for N1 + I3, and 35% for N3 + I1.
“The toxicity that we saw was reminiscent of what we’re seeing with these drugs in other diseases,” he said. In the combination arms, 79% of patients experienced any toxicity. In the N1 + I3 arm, 30% had grade 3 or 4 toxicity, and in the N3 + I1 arm, 19% had grade 3 or 4 toxicity. Only 7% to 11% of the patients in the combination arms discontinued treatment because of toxicity. Among patients who received the combination, 3 treatment-related deaths occurred.
In the phase 1 CheckMate 012 study of patients with advanced NSCLC, the combination of nivolumab and ipilimumab in the frontline setting produced ORRs as high as 47%, said Matthew D. Hellmann, MD, a thoracic medical oncologist at Memorial Sloan Kettering Cancer Center, New York, NY.
Dr Hellmann reported data from 77 patients with stage IIIb/IV NSCLC with any histology who had no previous chemotherapy for advanced disease. The patients received nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks (N = 38), or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks (N = 39). (Other arms in the study with more frequent ipilimumab dosing had high rates of discontinuation; long-term follow-up data were not provided for these other cohorts.)
The rates of treatment-related adverse events leading to discontinuation were 11% in the arm receiving ipilimumab every 12 weeks and 13% when ipilimumab was dosed every 6 weeks. These rates were similar to those of patients receiving nivolumab monotherapy, noted Dr Hellmann.
The confirmed ORRs were 47% when ipilimumab was dosed every 12 weeks and 39% when the dosing was every 6 weeks. The median duration of response was not yet reached in either group at a median length of follow-up of 12.9 months and 11.8 months, respectively. The median PFS times were 8.1 months and 3.9 months, respectively.
Twelve of the 15 (80%) responders to ipilimumab every 6 weeks and 14 of the 18 (78%) responders to ipilimumab every 12 weeks achieved a response by the time of the first restaging CT scan.
Efficacy was observed across all levels of tumor PD-L1 expression, but efficacy with the combination was “enhanced with increasing PD-L1 expression,” Dr Hellmann said. With ≥50% tumor PD-L1 expression, the ORR was 92% compared with 57% when PD-L1 expression was ≥1%.
Nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks is being evaluated in the phase 3 CheckMate 227 trial.