Nivo/Ipi Combo Now 'Standard of Care' in Mesothelioma

Liam Davenport

September 17, 2021

The immunotherapy combination of nivolumab (Opdivo) and ipilimumab (Yervoy) offers a durable, long-term survival benefit over chemotherapy for patients with unresectable malignant pleural mesothelioma (MPM), confirms a 3-year updated analysis of the CheckMate 743 trial.

After 3 years, 23% of patients who received combination immunotherapy were still alive, in comparison with 15% of patients in the chemotherapy arm.

Combination immunotherapy continued to provide a "durable and long-term benefit" compared with chemotherapy, commented Solange Peters, MD, from the Oncology Department, Center Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

The new data from the additional 12 months of follow-up "confirm nivolumab plus ipilimumab as a standard of care for unresectable MPM, regardless of histology," she commented.

She presented the update on September 17 at the annual meeting of the European Society of Medical Oncology (ESMO). She is the current president of the organization.

Previously, 2-year data from this study showed that the combination yielded a median overall survival of 18.1 months, compared to 14.1 months with standard-of-care chemotherapy.

As reported by Medscape Medical News, this translated into a 26% improvement in overall survival; 41% of patients in the immunotherapy arm were still alive at 2 years, vs 27% in the chemotherapy group.

On the basis of these data, the combination was subsequently approved in the United States, the European Union, and elsewhere for the first-line treatment of adults with unresectable MPM.

The new data come from a 3-year update, as well as an exploratory biomarker analysis. The new data show significantly improved overall survival with the combination immunotherapy. Among those who responded to immunotherapy, response was ongoing for 28% of patients at 3 years.

Benefit was seen even for patients who discontinued the treatment because of treatment-related adverse events, indicating that discontinuance does not appear to have a negative impact on the long-term benefits, Peters commented.

In addition, the new analysis suggested that patients with a high score on a four-gene inflammatory signature did particularly well with nivolumab plus ipilimumab, whereas chemotherapy patients did worse if they had nonepithelioid disease, a finding not seen with immunotherapy.

The discussant for this abstract, Pilar Garrido, MD, PhD, associate professor of medicine at the Universidad de Alcalá, Madrid, Spain, said that despite the impressive findings, there is a "critical need" to establish predictive biomarkers in MPM.

This is particularly pressing in cases involving early progression, inasmuch as median progression-free survival (PFS) in CheckMate 743 was similar overall, and chemotherapy performed better than immunotherapy in the first 8 months.

There is also a need to be able to identify patients who will have an ongoing response at 3 years, as well as to clarify the impact of toxicity, given that the median duration of response was 20 months following discontinuation of treatment after just 4 months.

Garrido cautioned that the exploratory analyses were of "limited value," because RNA data for the gene signature analysis were available for only 54% of patients, and the study was not powered to detect differences on the basis of programmed cell death–ligand-1 (PD-L1) expression.

Summarizing, Garrido said that although the current results showed that combination immunotherapy "continued to provide" a survival benefit in "a subgroup of patients," the "better characterization of predictive biomarkers" will be "crucial" to improving these results.

Study Details

Peters reminded the audience that the CheckMate 743 trial involved patients with unresectable MPM who had not previously received any systemic therapy and who had a good performance status.

A total of 605 patients were enrolled. They were randomly assigned in a 1:1 ratio to receive either nivolumab plus ipilimumab for up to 2 years or six cycles of pemetrexed plus cisplatin or carboplatin.

The median age of the patients was 69 years, and 77% were men.The baseline characteristics were well balanced between the two treatment groups; 75% to 76% had epithelioid disease, and for 74% to 80% of patients, baseline PD-L1 expression was ≥1%.

Subgroup analysis indicated that combination immunotherapy was beneficial regardless of patient age, sex, performance status, and smoking status.

However, the new analysis suggested that the improvement in overall survival depended on PD-L1 expression, at a hazard ratio for combination immunotherapy vs chemotherapy of 0.71 in patients with expression of ≥1%, compared with 0.99 for patients with expression of <1%.

Peters explained that the performance of nivolumab plus ipilimumab was identical in both PD-L1 expression groups, but it was the chemotherapy arm that performed markedly better for patients with expression of <1%.

An inverse finding was observed when patients were stratified by tumor histology.

In those with epithelioid disease, the median overall survival with combination immunotherapy was 18.2 months, vs 16.7 with chemotherapy, at a hazard ratio of 0.85.

At 36 months, 24% of immunotherapy patients were still alive, as were 19% of those given standard-of-care chemotherapy.

Among patients with nonepithelioid disease, however, median overall survival was 18.1 months with nivolumab plus ipilimumab, vs just 8.8 months with chemotherapy, at a hazard ratio of 0.48. At 3 years, 22% of patients who received combination immunotherapy patients were still alive, compared with 4% of those who received chemotherapy.

Other results showed that (PFS was only slightly longer with combination immunotherapy, at 6.8 months vs 7.2 months, for a hazard ratio of 0.92.

Yet at 36 months, 14% of patients who received nivolumab plus ipilimumab had not experienced disease progression, vs just 1% of those in the chemotherapy arm.

This difference was even more pronounced when the researchers assessed objective response rates: 28% of patients who received combination immunotherapy were still responding at 36 months, vs 0% among patients given chemotherapy.

This translated into a median duration of response of 11.6 months for nivolumab plus ipilimumab, vs 6.7 months with chemotherapy.

The safety assessment showed that rates of treatment-related adverse events of any grade and of grade 3–4 were similar between the combination immunotherapy and chemotherapy arms.

However, rates of treatment-related adverse events that led to discontinuation of all components of the regimen were higher with immunotherapy, at 17% for events of any grade and 13% for events of grade 3–4, compared with 8% and 5%, respectively, with chemotherapy.

Serious treatment-related adverse events were more common with nivolumab plus ipilimumab. Events of grade 3–4 occurred in 13% of patients with nivolumab plus ipilimumab, vs 5% with chemotherapy.

Peters showed that this did not severely affect overall survival, however. Among patients who discontinued combination immunotherapy, the median duration of response was 20.0 months.

Median overall survival in these patients was 25.4 months, and the 3-year overall survival rate was 37%.

The study was funded by Bristol-Myers Squibb. Peters has relationships with AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Bio Invent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, e-cancer, Eli Lilly, Elsevier, F. Hoffmann–La Roche/Genentech, Foundation Medicine, Illumina, Incyte, IQVIA, Janssen, Medscape, Merck Sharp and Dohme, Merck Serono, Merrimack, Mirati, Novartis, Pharma Mar, PER, Phosplatin Therapeutics, Pfizer, Regeneron, Sanofi, Seattle Genetics, Takeda, and Vaccibody. Garrido has relationships with Abbvie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Gebro GlaxoSmithKline, Janssen, Lilly, MSD, Nordic, Novartis, Pfizer, Roche, and Takeda.

European Society for Medical Oncology (ESMO) Annual Meeting 2021: Abstract LBA65. Presented September 17, 2021.

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