In the first ever placebo-controlled phase 3 trial in patients with relapsed mesothelioma, immunotherapy with nivolumab (Opdivo) significantly improved both overall survival (OS) and progression-free survival (PFS).

The CONFIRM trial involved 330 previously treated patients with mesothelioma who were randomly assigned to nivolumab or placebo for 1 year or until progression or unacceptable toxicity.

Although recruitment to the study was stopped early because of the COVID-19 pandemic, enough data accrued to show that the immunotherapy improved overall survival by 28% over placebo, and increased PFS by 39%.

"Nivolumab was deemed a safe and effective treatment and should be considered a new treatment option for patients with relapsed mesothelioma," said principal investigator Dean A. Fennell, MD, PhD, professor and consultant in Thoracic Medical Oncology, University of Leicester, United Kingdom.

He presented the results at the World Conference on Lung Cancer, which was held virtually because of the ongoing pandemic.

Rina Hui, MD, PhD, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, Australia, who was not involved in the study, told journalists that these results had been a "long time coming."

CONFIRM has added "important, encouraging data on immunotherapy in the salvage setting, particularly that patients were heavily pretreated," Hui said, with two thirds having received two or more lines of therapy.

Fennel noted that "a significant clinical benefit was observed in the epithelioid subtype" of the disease, but not in patients with non-epithelioid disease.

However, there was "no evidence" to support tumor programmed death ligand 1 (PD-L1) expression as predictive of outcomes, he added, which does appear to be the case in some trials on lung cancer and other tumors.

Commenting on these observations, Hui said that PD-L1 as a predictive biomarker in mesothelioma has been "controversial", and emphasized that the results from CONFIRM indicate "no evidence of PD-L1 being predictive".

However, she questioned the other observation that clinical benefit appeared to be seen only in the epithelioid subtype.

Hui emphasized that non-epithelioid disease is known to be a "more aggressive, chemo-resistant subtypewith a steep decline in the survival curves."

"Therefore a lot of patients would not have made it to a subsequent line clinical trial, explaining why there were only 12% in the CONFIRM study," and so the sample size may be "too small to detect a difference in outcome."

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

She argued that there was "no clear predictive biomarker for patient selection" emerging from the CONFIRM data.

She agreed that, in patients with mesothelioma who have progressed following platinum/pemetrexed-based chemotherapy as in the first line, "monotherapy nivolumab now can be considered as a treatment option in the secondor third-line setting, after second-line chemotherapy".

However, outstanding questions remain, including whether nivolumab "provides better outcomes than second-line single agent chemotherapy or second-line gemcitabine with the VGFR inhibitor ramucirumab (Cyramza)."

It may also be that nivolumab plus ipilimumab (Yervoy) might be superior to nivolumab alone in the salvage setting.

But a more fundamental question is what should be considered for salvage therapy "if nivolumab and ipilimumab have already been used in the first-line setting?"

Results of first-line immunotherapy combination trials are "eagerly awaitedto determine and develop other salvage treatments," she commented.

Responding on Twitter, Riyaz Shah, MD, PhD, consultant medical oncologist, Maidstone and Tunbridge Wells NHS Trust, UK, echoed these comments, saying that the results were "very exciting" but he also "cant wait to see the first-line chemoimmunotherapy data."

Stephen V. Liu, MD, director of thoracic oncology at Georgetown University, Washington, DC, commented on Twitter that there was "not a lot of safety data" in the presentation and awaits their eventual publication.

He added that it is "good to have a positive trial" in relapsed mesothelioma, "though the first-line studies will decrease the eventual impact as immunotherapy becomes involved earlier in treatment."

Relapsed mesothelioma is an "unmet need," and until now "there have been no phase 3 trials which have demonstrated improved overall survival," Fennell said in his presentation.

However, three phase 2 trials have shown that immune checkpoint targeting via PD-1 has shown useful clinical activity as a monotherapy in the relapsed setting, and one of these trials has led to approval of nivolumab in Japan for this indication.

CONFIRM was an investigator-initiated phase 3 trial in patients with relapsed mesothelioma who had received more than one prior line of therapy and had a good performance status.

Recruitment began in April 2017, and the "target sample size was 336 patients," Fennell said, but was "halted at 332 patients (in March 2020) due to the peaking of the COVID-19 pandemic in the UK."

"However, at the time it was felt there were sufficient events" to justify the current analysis of the co-primary endpoints of PFS and OS, despite the latter being 59 events short of the target of 291.

Fennell said that baseline characteristics were "generally well balanced" between the nivolumab (n = 221) and placebo (n = 111) arms.

However, there were more patients with a PD-L1 Tumor Proportion Score (TPS) 1% among the patients given nivolumab, at 37% vs 29% in the placebo arm.

After a median follow-up of 17.1 months in the nivolumab arm and 14.2 months in the placebo group, overall survival was significantly longer with the active treatment, at 9.2 months vs 6.6 months with placebo, or a hazard ratio of 0.72 (P = .018).

The proportion of patients alive at 12 months was 39.5% in the nivolumab group, and 26.9% in patients given placebo.

Investigator-assessed PFS was also significant longer with nivolumab, at 3.0 months vs 1.8 months with placebo, or a hazard ratio of 0.61 (P < .001).

The proportion of patients disease-free at 12 months was 14.5% with active treatment vs 4.9% months with the placebo.

"The role for PD-L1 as a potential biomarker was assessed," Fennell said, using the Dako 22C3 antibody, with 150 nivolumab and 84 placebo patients divided into those with a TPS <1% or 1%.

He noted that PD-L1 expression in the tumor "did not predict survival for patients in the CONFIRM trial", with neither PD-L1 positive nor PD-L1 negative patients demonstrating a significant improvement in overall survival with nivolumab vs placebo.

"For histology, epithelioid mesothelioma patients benefited from nivolumab," Fennell continued, at a hazard ratio for death of 0.71 vs placebo (P =.021). "However, for the non-epithelioid subgroup, in this immature survival analysisthe P value was not significant," he said, but this was a small subgroup of patients (12% in both nivolumab and placebo groups).

The safety analysis revealed that the proportion of patients with any serious adverse events, of any grade or grade 3, was almost identical between the active and placebo arms, Fennel reported. There were five deaths (3.6%) related to a serious adverse event in the nivolumab arm and four (5.3%) in the placebo group.

This research was funded by the Stand Up to Cancer campaign for Cancer Research UK, supported by Cancer Research UK core funding at the Southampton Clinical Trials Unit, and investigator-initiated support from Bristol-Myers Squibb for free drug labeling and distribution and funding for RECIST reporting.

Fennell reports relationships with Astex Therapeutics, AstraZeneca, Atara Biotherapeutics, Bayer, Boehringer Ingelheim, BMS, Clovis Oncology, Eli Lilly, Inventiva, Lab 21, MSD, and Roche. Hui reports relationships with AstraZeneca, BMS, Eli Lilly, MSD, Novartis, Pfizer, Roche, and Seagen.

2020 World Conference on Lung Cancer Singapore: Abstract PS01.11. Presented January 30, 2021.

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Nivolumab Improves Survival in Relapsed Mesothelioma - Medscape