Addition of ipilimumab to chemotherapy did not prolong [overall survival] versus chemotherapy alone in patients with newly diagnosed extensive-stage disease SCLC.— Martin Reck, MD, PhD, and colleagues
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In a phase III trial (CA184-156) reported in the Journal of Clinical Oncology by Martin Reck, MD, PhD, of LungenClinic Grosshansdorf, Germany, and colleagues, 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 extensive-stage small cell lung cancer (SCLC).1
In this double-blind 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 one patient in each group had an Eastern Cooperative Oncology Group performance status of 0 [29% and 31%] or one; 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.
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. 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.
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 disease 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.” ■
Disclosure: The study was supported by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.jco.ascopubs.org.
1. Reck M, Luft A, Szczesna A, et al: Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol. July 25, 2016 (early release online).
For now, initial management of small cell lung cancer continues to be driven by chemotherapy with platinum and etoposide. Meanwhile, management of small cell lung cancer post chemotherapy is undergoing a rapid and much-needed revolution.!-->!-->— Jeffrey Crawford, MD