In the phase III CONFIRM trial reported in The Lancet Oncology, Dean A. Fennell, FRCP, PhD, and colleagues found that nivolumab improved progression-free and overall survival vs placebo in patients with relapsed malignant mesothelioma.

In October 2020, the combination of nivolumab and ipilimumab was approved for the first-line treatment of unresectable malignant pleural mesothelioma.

Dean A. Fennell, FRCP, PhD

As stated by the investigators, “No phase III trial has yet shown improved survival for patients with pleural or peritoneal malignant mesothelioma [that has] progressed following platinum-based chemotherapy.”

Study Details

In the double-blind multicenter trial, 332 patients with pleural or peritoneal mesothelioma who had received first-line platinum-based chemotherapy and had radiologic evidence of disease progression were randomly assigned 2:1 between May 2017 and March 2020. Patients received either nivolumab at 240 mg (n = 221) or placebo (n = 111) every 2 weeks until disease progression, unacceptable toxicity, or for a maximum of 12 months.

Overall, 95% of patients in each group had pleural mesothelioma; 88% in each group had epithelioid histology. The co-primary endpoints were investigator-assessed progression-free survival and overall survival, with analysis adjusted for epithelioid type.  

Progression-Free and Overall Survival

Median follow-up was 11.6 months (interquartile range [IQR] = 7.2–16.8 months). Median progression-free survival was 3.0 months (95% CI = 2.8–4.1 months) in the nivolumab group vs 1.8 months (95% CI = 1.4–2.6 months) in the placebo group (adjusted hazard ratio [HR] = 0.67, 95% CI = 0.53–0.85, P = .0012). Rates at 1 year were 14.2% (95% CI = 9.9%–19.3%) vs 7.2% (95% CI = 3.1%–13.8%).

Subsequent systemic treatment was received by 35% of patients in the nivolumab group and 35% of the placebo group, with 11% of the placebo group receiving nivolumab.

Median overall survival was 10.2 months (95% CI = 8.5–12.1 months) in the nivolumab group vs 6.9 months (95% CI = 5.0–8.0 months) in the placebo group (adjusted HR = 0.69, 95% CI = 0.52–0.91, P = .0090). Overall survival at 1 year was 43.4% (95% CI = 36.3%–50.4%) vs 30.1% (95% CI = 21.0%–39.6%).

Among 252 patients with quantifiable PD-L1 expression, there was no evidence of an association of PD-L1 status with progression-free survival (HR for interaction = 1.55, P = .16) or overall survival (HR for interaction = 1.16, P = .70).

Objective responses (all partial) were observed in 25 patients (11%) in the nivolumab group vs 1 (1%) in the placebo group (odds ratio = 14.0, P = .00086). Among responders in the nivolumab group, median time to response was 84 days (95% CI = 81–145 days) and median duration of response was 143 days (95% CI = 92–211 days).

Adverse Events

Treatment-related adverse events of any grade occurred in 74% of patient in the nivolumab group vs 56% of the placebo group. The most common grade ≥ 3 treatment-related adverse events in the nivolumab group were diarrhea (3% vs 2% in the placebo group) and infusion-related reaction (3% vs 0%).

Serious adverse events occurred in 41% vs 44% of patients, most commonly dyspnea (8% vs 9%) and pneumonia (6% vs 5%). Adverse events led to treatment discontinuation in 14% vs 3%, most commonly due to infusion-related reaction (1.8%) and diarrhea (1.3%) in the nivolumab group. No treatment-related deaths occurred in either group.

The investigators concluded, “Nivolumab represents a treatment that might be beneficial to patients with malignant mesothelioma who have [had disease progression] on first-line therapy.”

Dr. Fennell, of the Mesothelioma Research Programme, Leicester Cancer Research Centre, University of Leicester, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Stand up to Cancer–Cancer Research UK and Bristol Myers Squibb. For full disclosures of the study authors, visit thelancet.com.