Phase III Trial Finds No Survival Benefit of Adding Ipilimumab to Etoposide/Platinum in Extensive-Stage SCLC
The addition of the anti–CTLA-4 (cytotoxic T-lymphocyte–associated protein 4) checkpoint inhibitor ipilimumab (Yervoy) to etoposide/platinum did not improve overall survival in the first-line treatment of patients with extensive-stage small cell lung cancer (SCLC), according to a phase III trial reported in the Journal of Clinical Oncology by Reck et al.
Study Details
In the double-blind CA184-156 trial, 1,132 patients from 224 sites in 34 countries were randomized between January 2012 and September 2014 to receive ipilimumab (n = 566) or placebo (n = 566) combined with etoposide and investigator’s choice of cisplatin or carboplatin. Treatment consisted of four 3-week induction cycles of etoposide at 100 mg/m2 on days 1, 2, and 3 and cisplatin at 75 mg/m2 or carboplatin AUC (area under the curve) = 5 on day 1 of each cycle, with ipilimumab at 10 mg/kg or placebo given during cycles 3 to 6.
Patients with complete or partial response during induction could undergo prophylactic cranial irradiation at investigator discretion before the maintenance phase. Maintenance treatment with ipilimumab at 10 mg/kg or placebo was given every 12 weeks starting at 9 to 12 weeks after induction until disease progression or unacceptable toxicity for a maximum of 3 years. A total of 954 patients received at least one dose of blinded study therapy—ie, chemotherapy plus ipilimumab (n = 478) or chemotherapy plus placebo (n = 476). The primary endpoint was overall survival among patients receiving at least one dose of blinded study therapy.
For the ipilimumab and placebo groups: median age was 62 and 63 years (37% and 42% ≥ 65 years); 66% and 68% were male; 76% and 75% were white and 23% and 22% were Asian; 39% and 41% were from North America or Western Europe; all but 1 patient in each group had Eastern Cooperative Oncology Group performance status of 0 [29% and 31%] or 1; 12% and 10% had central nervous system [CNS] metastases; 56% and 57% were heavy smokers and 36% and 35% were nonsmokers or light smokers; lactate dehydrogenase level was > the upper limit of normal in 48% in both; 14% and 15% had prior surgery; 3% and 2% had prior radiotherapy; and median time from diagnosis to first study dose was 0.6 months (range = 0–109 months) and 0.5 months (range = 0–1,082 months).
During induction, cisplatin was used in 34% and 33%, and carboplatin was used in 66% and 67%. Prophylactic cranial irradiation was performed prior to maintenance treatment in 11% and 14% of patients.
Overall Survival
Median follow-up for overall survival was 10.5 months in the ipilimumab group and 10.2 months in the placebo group. Median overall survival was 11.0 months (95% confidence interval [CI], 10.45–11.33 months) in the ipilimumab group vs 10.9 months (95% CI = 10.02–11.50 months) in the placebo group (hazard ratio [HR] = 0.94, P = .3775).
Subgroup analyses showed that hazard ratios for overall survival at 1 year did not appear to favor one group over another. The only significant hazard ratio was among the 100 patients with CNS metastases (1.58, 95% CI = 1.02–2.44). Hazard ratios were 1.14 among patients receiving carboplatin and 0.93 among those receiving cisplatin, with neither being significant.
Progression-Free Survival and Response Rates
Median progression-free survival was 4.6 months vs 4.4 months (HR = 0.85, 95% CI = 0.75– 0.97, P = .0161). Subsequent chemotherapy was received by 48% and 52% of patients, respectively. Objective response occurred in 62% of patients in both groups (1 complete response in ipilimumab patient), and 26% vs 27% had stable disease. Median duration of response was 4.01 vs 3.45 months.
Adverse Events
The most common treatment-related adverse events of any grade in the ipilimumab group were diarrhea (25% vs 10%), neutropenia (24% vs 33%), anemia (24% vs 29%), and nausea (23% vs 16%). Grade ≥ 3 treatment-related adverse events occurred in 48% vs 45%, with the most common in the ipilimumab group being neutropenia (14% vs 24%) and anemia (8% vs 11%). Treatment was discontinued due to treatment-related adverse events in 18% vs 2%, with the most common reasons in the ipilimumab group being diarrhea (5%) and colitis (4%). Treatment-related death occurred in five patients in the ipilimumab group and two patients in the placebo group.
The investigators concluded: “Addition of ipilimumab to chemotherapy did not prolong [overall survival] versus chemotherapy alone in patients with newly diagnosed extensive-stage SCLC. No new or unexpected adverse events were observed with chemotherapy plus ipilimumab. Several ongoing studies are evaluating ipilimumab in combination with programmed death-1 inhibitors in SCLC.”
The study was supported by Bristol-Myers Squibb.
Martin Reck, MD, PhD, of LungenClinic Grosshansdorf, Germany, is the corresponding author of the Journal of Clinical Oncology article.
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