Until the CONFIRM results, no phase 3 trial had demonstrated improvement survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy.
In patients with malignant mesothelioma who have progressed on first-line therapy, nivolumab (Opdivo) may be a beneficial treatment option, according to results from the phase 3 CONFIRM trial published recently in The Lancet Oncology.1
Until the CONFIRM results, no phase 3 trial had demonstrated improvement survival for patients with pleural or peritoneal malignant mesothelioma who have progressed following platinum-based chemotherapy. Considering that some malignant mesothelioma tumors express PD-L1, it was hypothesized that the use of an immune checkpoint inhibitor would improve survival outcomes as previously signaled in the phase 2 MERIT clinical trial conducted in Japan (JapicCTI-163247).
“The CONFIRM trial showed longer progression-free survival [PFS] and overall survival [OS] with nivolumab compared with placebo in patients with relapsed mesothelioma. To our knowledge, CONFIRM is the first randomized phase 3 trial to show significantly improved overall survival for patients with relapsed mesothelioma following platinum-based doublet chemotherapy,” wrote the study authors led by Dean A Fennell, MD.
CONFIRM (NCT03063450) is an ongoing multicenter, double-blind, placebo-controlled, parallel-group randomized study. Patients enrolled were 18 years of age or older with histologically confirmed disease of any subtype who were previously treated with at least 1 course of platinum-based chemotherapy but subsequently developed progressive disease. Patients enrolled were required to have an ECOG performance status of 0 or 1, measurable disease, archival tumor biopsy for biomarker analyses, and adequate laboratory values.
At 25 centers in the United Kingdom, a total of 535 patients were assessed for eligibility, but 200 were excluded for various reasons. 322 patients were enrolled and randomized 2:1 to receive either nivolumab 240 mg as a 30-minute intravenous infusion on day 1 of every 14-day treatment cycle or a matching placebo consisting of sterile 0.9% chloride.1,2
To determine the safety and efficacy of nivolumab in patients with malignant mesothelioma who have progressed on frontline, Fennell et al explored the coprimary end points of PFS and OS. The secondary study end points included overall response rate, 12-month PFS and OS, and safety. Efficacy was also evaluated based on patients’ PD-L1 tumor proportion score.
The study was 80% powered to detect an improvement in OS with 6 months of follow-up at a hazard ratio (HR) of 0.70. All patients who were enrolled were included in the efficacy and safety analyses.
At a median follow-up of 11.6 months (interquartile range [IQR], 7.2-26.8), the median PFS was 3.0 months (95% CI, 2.8-4.1) with nivolumab compared with 1.8 months (95% CI, 1.4-2.6) with placebo (adjusted HR, 0.67; 95% CI, 0.53-0.85; P =.0012). The median OS observed with nivolumab was 10.2 months (95% CI, 8.5-12.1) compared with 6.9 months (95% CI, 5.0-8.0) with placebo (adjusted HR, 0.69; 95% CI, 0.52-0.91; P =.0090).
Across the prespecified subgroups of patients with epithelioid histology or non-epithelial histology and PD-L1-positive or negative tumors, the median OS was 10.2 months (95% CI, 8.5-12.1) in the nivolumab arm versus 6.9 months (95% CI, 5.0-8.0) in the placebo arm (HR, 0.69; 95% CI, 0.52-0.91; P =.0090). At 1 year, the OS rate was 43.4% (95% CI 36.3%-50.4%) in the nivolumab arm versus 30.1% (21.0%-39.6%) in the placebo group.
“The cellular and molecular determinants of response to PD-1 checkpoint inhibition in mesothelioma remain elusive. Accordingly, extensive translational research studies have been initiated in CONFIRM to explore the genomic and tumor microenvironmental interactions with outcome and to understand the molecular determinants of sensitivity in mesothelioma. We will continue to follow-up participants in the CONFIRM trial for overall survival and progression-free survival, until the original planned study end,” wrote Fennell et al.
Treatment with nivolumab also led to a significantly higher rate of objective responses in patients with malignant mesothelioma in the CONFIRM study. The ORR was 11% with nivolumab versus only 1% with placebo (Odds ratio 14.0; 95% CI, 2.4 to not estimable; P =.00086). Responses to nivolumab in the study did not appear to be impacted by positive PD-L1 expression.
The safety analysis showed 14% of patients who received nivolumab discontinued treatment due to an adverse event (AE) compared with 3% of the placebo group. The most common AEs that led to treatment discontinuation were infusion-related reactions (13%] and diarrhea (10%).
Serious AEs were observed in 41% of patients in the nivolumab arm compared with 44% in the placebo arm. Of the serious AEs that occurred, most frequently in the nivolumab arm was dyspnea.
Treatment-related AEs (TRAEs) occurred in 74% of the nivolumab arm compared with 56% of the placebo arm. Diarrhea occurring in 2% of the nivolumab arm compared with 1% of the placebo was the most observed TRAE.
1. Fennell DA, Ewings S, Ottensmeier C, et al. Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial. Lancet Oncol. 2021;22(11):1530-1540. doi: 10.1016/S1470-2045(21)00471-X
2. Checkpoint blockade for inhibition of relapsed mesothelioma (CONFIRM). Clinicaltrials.gov. Accessed November 3, 2021. https://bit.ly/3nTWbgN