Phase III Randomized Trial of Ipilimumab Plus Etoposide and Platinum Versus Placebo Plus Etoposide and Platinum in Extensive-Stage Small-Cell Lung Cancer

Abstract

Purpose Patients with extensive-stage disease small-cell lung cancer (SCLC) have poor survival outcomes despite first-line chemotherapy with etoposide and platinum. This randomized, double-blind phase III study evaluated the efficacy and safety of ipilimumab or placebo plus etoposide and platinum in patients with newly diagnosed extensive-stage disease SCLC. Patients and Methods Patients were randomly assigned at a ratio of one to one to receive chemotherapy with etoposide and platinum (cisplatin or carboplatin) plus ipilimumab 10 mg/kg or placebo every 3 weeks for a total of four doses each in a phased induction schedule (chemotherapy in cycles one to four; ipilimumab or placebo beginning in cycle three up to cycle six), followed by ipilimumab or placebo maintenance every 12 weeks. Primary end point was overall survival (OS) among patients receiving at least one dose of blinded study therapy. Results Of 1,132 patients randomly assigned, 954 received at least one dose of study therapy (chemotherapy plus ipilimumab, n = 478; chemotherapy plus placebo, n = 476). Median OS was 11.0 months for chemotherapy plus ipilimumab versus 10.9 months for chemotherapy plus placebo (hazard ratio, 0.94; 95% CI, 0.81 to 1.09; P = .3775). Median progression-free survival was 4.6 months for chemotherapy plus ipilimumab versus 4.4 months for chemotherapy plus placebo (hazard ratio, 0.85; 95% CI, 0.75 to 0.97). Rates and severity of treatment-related adverse events were similar between arms, except for diarrhea, rash, and colitis, which were more frequent with chemotherapy plus ipilimumab. Rate of treatment-related discontinuation was higher with chemotherapy plus ipilimumab (18% v 2% with chemotherapy plus placebo). Five treatment-related deaths occurred with chemotherapy plus ipilimumab and two with chemotherapy plus placebo. Conclusion Addition of ipilimumab to chemotherapy did not prolong OS 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.

Current standards for clinical management of small cell lung cancer

“…However, despite over 30 years of clinical trials designed to improve therapies for SCLC, the vast majority of SCLCs remain incurable. The median overall survival (mOS) for patients with metastatic SCLC receiving standard chemotherapy has remained in range of 9-11 months over the past 20+ years, even in the most recent large randomized clinical trials (2)(3)(4)(5)(6). While there is tremendous hope for therapeutic breakthroughs to come from improved preclinical models, promising new therapeutic strategies, and innovative clinical trials, it is instructive to review the current clinical management strategies for patients diagnosed with SCLC today.…”

Immunotherapy in the Treatment of Lung Cancer

“…Ipilimumab (10 mg/ kg, q3w) byl srovnáván s placebem, hlavním cílem sledování bylo OS. Výsledky neprokázaly prodloužení PFS (4,6 vs. 4,4 měsíce, HR 0,85) ani OS (11,0 vs. 10,9 měsíce, HR 0,94; p = 0,3775) u pa cientů léčených kombinací s ipilimumabem [57]. V léčbě pa cientů s pokročilým stadiem NSCLC se úspěšně etablovaly zatím dva anti-PD-1 checkpoint inhibitory, nivolumab a pembrolizumab.…”

Perspectives in small cell lung cancer: is something moving?

“…Among 954 patients evaluable, median PFS and OS were 4.6 and 11 months in the chemotherapy plus ipilimumab arm and 4.4 and 10.9 in the control arm, respectively. These disappointing results have been worsened by the fact that, even if the rates and severity of adverse events have been similar in the two arms, the treatment-related discontinuation rate was higher in the experimental arm (18% vs. 2% in the control arm), with 5 treatment-related deaths in the chemotherapy plus ipilimumab arm and 2 in the chemotherapy plus placebo group (17).…”