Ramaswamy Govindan, MD
IN A PHASE III trial reported by Ramaswamy Govindan, MD, of Washington University School of Medicine, and colleagues in the Journal of Clinical Oncology, the addition of first-line ipilimumab (Yervoy) to paclitaxel/carboplatin did not improve overall survival in patients with advanced squamous non–small cell lung cancer (NSCLC).1
In the double-blind trial, 956 patients with stage IV or recurrent chemotherapy-naive disease from 233 sites in 34 countries were randomized between August 2011 and June 2015 to receive paclitaxel and carboplatin with ipilimumab (n = 479) or placebo (n = 477). Treatment consisted of paclitaxel at 175 mg/m2 plus carboplatin AUC = 6 every 3 weeks for six 3-week cycles plus either ipilimumab at 10 mg/kg or intravenous placebo given every 3 weeks for up to four doses starting at cycle six. Patients with a complete response, partial response, or stable disease after induction were eligible for maintenance treatment beginning 9 weeks after induction, with maintenance treatment consisting of blinded ipilimumab at 10 mg/kg or placebo every 12 weeks until disease progression (modified World Health Organization criteria) or unacceptable toxicity, for ≤ 3 years.
The primary endpoint was overall survival in patients receiving at least one dose of blinded study therapy (modified intent-to-treat population). In total, 91 patients in the ipilimumab group and 116 patients in the control group did not receive any treatment or discontinued treatment before receiving the blinded study drug (usually due to disease progression). Thus, the modified intent-to-treat population consisted of 388 patients in the ipilimumab group and 361 patients in the control group.
For the modified intent-to-treat ipilimumab vs control groups: median age was 64 in both (49% in both ≥ 65 years); 84% vs 85% were male; 71% vs 67% were white and 27% vs 30% were Asian; the Eastern Cooperative Oncology Group performance status was 0 or 1 in virtually all patients; 95% vs 92% had stage IV disease and 5% vs 8% had recurrent disease; and 87% vs 88% were heavy smokers.
MEDIAN FOLLOW-UP for survival was 12.5 months in the ipilimumab group and 11.8 months in the control group. All four blinded induction doses were received by 52% of patients in the ipilimumab group vs 76% of the control group. Median doses of chemotherapy were five in the ipilimumab group and six in the control group. Maintenance treatment was started by 28% vs 34% of patients.
Median overall survival was 13.4 months in the ipilimumab group vs 12.4 months in the control group (hazard ratio [HR] = 0.91, P = .25). Subgroup analysis indicated no particular survival advantage of either treatment in any subgroup. Median progression-free survival was 5.6 months in both groups (HR = 0.87, 95% confidence interval [CI] = 0.75–1.01). Subsequent systemic therapy, consisting of chemotherapy in the vast majority of cases, was received by 47% vs 57% of patients in the ipilimumab vs control group, respectively. Objective response was observed in 44% vs 47% of patients, with median response durations of 5.7 vs 4.7 months. In the entire randomized population, median overall survival was 10.9 vs 10.7 months (HR = 0.92, P = .24).
Kaplan-Meier analysis of survival in the modified intent-to-treat population indicated that the survival curves crossed at approximately 10 months, with survival being better in the ipilimumab group after this point. Exploratory analysis indicated that hazard ratios were 1.44 (95% CI = 1.08–1.92) before 8 months, 0.67 (95% CI = 0.52–0.86) between 8 and 16 months, and 0.84 (95% CI = 0.57–1.23) after 16 months. In the ipilimumab vs control group, respectively, overall survival was 54% vs 53% at 1 year and 24% vs 18% at 2 years.
GRADE 3 OR 4 treatment-related adverse events occurred in 51% of patients in the ipilimumab group vs 35% in the control group, with the most common in the ipilimumab group being neutropenia (14% vs 14%) and anemia (12% vs 7%). Serious treatment-related adverse events occurred in 33% vs 10%. Treatment-related adverse events led to treatment discontinuation in 28% vs 7% of patients, with the most common reasons in the ipilimumab group being diarrhea (6%), colitis (3%), peripheral sensory neuropathy (2%), and anemia (2%).
The most common immune-related adverse events in the ipilimumab group were dermatologic (36%), gastrointestinal (28%), and neurologic (27%); the most common individual adverse events were diarrhea (27% in the ipilimumab group vs 11% in the control group), rash (17% vs 4%), and pruritus (14% vs 2%). Endocrine immune-related adverse events occurred in 9% of the ipilimumab group. Seven treatment-related deaths occurred in the ipilimumab group, due to acute hepatic failure, acute kidney insufficiency, anemia, intestinal perforation, ischemic colitis, multiorgan failure, and pneumonia (n = 1 for each). One patient in the control group died of treatment-related toxicity (sepsis with septic shock).
The investigators concluded: “The addition of ipilimumab to first-line chemotherapy did not prolong [overall survival] compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population.” They noted: “[T]he reduced chemotherapy exposure [in the ipilimumab group], triggered by the toxicity and higher discontinuation rates in the chemotherapy plus ipilimumab arm, potentially contributed to the failure of the study.” ■
DISCLOSURE: The study was supported by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.jco.ascopubs.org.