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First-Ever Survival Bump in Relapsed Mesothelioma

— OS, PFS improved with nivolumab, but questions remain about alternatives, biomarkers

Last Updated February 1, 2021
MedpageToday

Patients with progressive mesothelioma obtained a first-ever survival improvement with nivolumab (Opdivo) as second-line therapy, a randomized trial showed.

Median overall survival (OS) increased by almost 40%, and the progression-free interval also improved significantly with the immune checkpoint inhibitor as compared with placebo. In particular, a significant clinical benefit was evidence in patients with epithelioid subtype, the predominant mesothelioma histology.

PD-L1 expression status did not influence response to treatment, although only a third of patients tested positive for the biomarker, reported Dean Fennell, MD, of the University of Leicester in England, at the virtual World Conference on Lung Cancer.

"The was the first-ever phase III in the relapse setting to meet a primary endpoint of improved survival," Fennell said during a press briefing that followed his presentation. "There was no evidence to support the use of PD-L1, at least with the Dako 22C3 tumor proportion score as a test. Finally, nivolumab is safe, and for that reason, along with the efficacy, should be considered a standard treatment for patients with relapsed mesothelioma."

Thoracic oncologists and their patients have waited decades for an effective treatment for relapsed mesothelioma, said invited discussant Rina Hui, MD, PhD, of Crown Princess Mary Cancer Center and the University of Sydney in Australia. The only other phase III trial in relapsed mesothelioma (PROMISE1) showed no improvement in survival with pembrolizumab (Keytruda) as compared with standard chemotherapy.

"This has been a long time coming," said Hui. "Some phase II studies showed improved outcomes in patients with PD-L1-positive disease, while some did not."

She acknowledged the low proportion of PD-L1-positive tumors in the study, due in large part to the fact that PD-L1 status could be assessed in only 70% of tumors. Hui also noted that nivolumab did not improve OS in patients with non-epithelioid tumors, which has a more aggressive phenotype.

"A lot of patients [with non-epithelioid tumors] would not have made it to a subsequent-line clinical trial after chemotherapy, explaining why this subtype was only 12% of the CONFIRM study," she said. "A first-line trial showed an increased benefit with nivolumab plus ipilimumab (Yervoy) in non-epithelioid subtype, likely due to association with a high level of PD-L1."

"I would not deny patients with non-epithelioid histology from considering nivolumab in the salvage setting," she added.

Despite a lack of high-quality evidence in the second-line setting, single-agent nivolumab demonstrated activity in patients with relapsed mesothelioma and has been licensed for that indication in Japan, Fennell noted. Investigators in the CONFIRM trial sought to provide level 1 evidence of activity in the relapse setting.

The study included 332 patients who had received more than one prior line of therapy for mesothelioma. They were randomized 2:1 to nivolumab or placebo, and treatment continued until disease progression, toxicity, or withdrawal. The trial had coprimary endpoints of OS and investigator-assessed progression-free survival (PFS).

The patients had a median age of 70, and men accounted for three-fourths of the study population. All but 5% of patients had pleural involvement, and a total of 80 patients had PD-L1 expression ≥1%.

The trial ended after an interim analysis showed a significant difference in median OS (9.2 vs 6.6 months, hazard ratio 0.72, 95% CI 0.55-0.94, P=0.018). The 12-month survival was 39.5% versus 26.9%. Median PFS was 3.0 months with nivolumab and 1.8 months with placebo, representing a 39% reduction in the hazard for disease progression or death (95% CI 0.48-0.77, P<0.001). The 12-month PFS was 14.5% with nivolumab and 4.9% with placebo.

An analysis of the coprimary endpoints by PD-L1 expression showed a median OS of 8.0 months with nivolumab and 8.7 months with placebo (P=0.864). Median OS in the PD-L1-negative subgroup was 9.0 months with nivolumab and 6.4 months with placebo (P=0.115).

Patients with epithelioid histology had significant improvement in OS with nivolumab (9.4 vs 6.6 months, HR 0.71, 95% CI 0.53-0.95, P=0.021) but those with non-epithelioid did not (5.9 vs 6.7 months, P=0.572).

Grade ≥3 adverse events (AEs) occurred in a similar proportion of patients treated with nivolumab (45%) or placebo (42%), as did serious AEs (36% vs 39%).

Hui said future studies should address key unanswered questions: whether nivolumab would be superior to chemotherapy or to gemcitabine plus the VEGF inhibitor ramucirumab (Cyramza) in the second-line setting; the most appropriate second-line therapy for patients who received nivolumab and ipilimumab as initial treatment; and identification of predictive biomarkers.

Disclosures

The CONFIRM trial was supported by Stand Up to Cancer and Cancer Research UK in collaboration with Bristol-Myers Squibb (BMS).

Fennell disclosed relevant relationships with AstraZeneca, Astex Therapeutics, Bayer, BMS, Atara Biotherapeutics, Boehringer Ingelheim, Clovis Oncology, Eli Lilly, Lab 21, Merck Sharp & Dohme, Inventiva, and Roche.

Primary Source

World Conference on Lung Cancer

Fennell D, et al "Nivolumab versus placebo in relapsed malignant mesothelioma: Preliminary results from the CONFIRM phase III trial" WCLC 2020;Abstract PS01-11.