Immunotherapy is taking on yet another highly aggressive cancer and yielding strong results, according to data presented during the 2020 International Association for the Study of Lung Cancer’s World Conference on Lung Cancer Virtual Presidential Symposium.¹

A prespecified interim analysis of the phase III CheckMate 743 study of patients with previously untreated, unresectable malignant pleural mesothelioma showed a 26% reduction in the risk of death with nivolumab plus ipilimumab vs chemotherapy (hazard ratio [HR] = 0.74, P = .002). At 2 years, 41% of patients treated with dual checkpoint inhibition were alive compared with 27% who received chemotherapy.

Paul Baas, MD, PhD

Dean A. Fennell, FRCP, PhD

“This is the first positive randomized trial of dual immunotherapy in the first-line treatment of patients with unresectable malignant pleural mesothelioma,” said lead study author Paul Baas, MD, PhD, Professor of Thoracic Oncology at the Netherlands Cancer Institute and the University of Leiden, Amsterdam. “Nivolumab plus ipilimumab should be considered the new standard of care.”

Of note, the survival benefit with nivolumab plus ipilimumab vs chemotherapy was observed regardless of histology, leading to a “transformative improvement” in patients with nonepithelioid mesothelioma, said invited study discussant Dean A. Fennell, FRCP, PhD.

Study Background and Methods

As Dr. Baas commented, malignant pleural mesothelioma is a rare and highly aggressive type of cancer. The median survival for previously untreated patients with advanced or metastatic malignant pleural mesothelioma is less than 1 year, and the 5-year survival rate is less than 10%.²

Platinum doublet chemotherapy has been the approved standard of care for first-line unresectable malignant pleural mesothelioma since 2004, said Dr. Baas. However, epithelioid histology has been associated with significantly better outcomes than nonepithelioid mesothelioma.

Although randomized trials of single-agent immune checkpoint inhibitors have not demonstrated significant benefits in the second-line setting and beyond in malignant pleural mesothelioma, clinical activity has been observed in single-arm studies with nivolumab plus ipilimumab, Dr. Baas reported. “Nivolumab (an anti–PD-1 inhibitor) and ipilimumab (an anti–CTLA-4 inhibitor) have distinct but complementary mechanisms of action,” said Dr. Baas. “Nivolumab restores antitumor T-cell function, whereas ipilimumab induces de novo antitumor T-cell responses.”

For the phase III CheckMate 743 study, Dr. Baas and colleagues randomly assigned patients to receive either nivolu­mab plus ipilimumab (for up to 24 months or until disease progression [n = 303]) or pemetrexed with cisplatin or carboplatin (maximum of 6 courses [n = 302]) as first-line therapy. Patients were required to have unresectable pleural mesothelioma, no prior systemic therapy, and a good performance status (Eastern Cooperative Oncology Group grade 0 or 1) and were stratified by histology (epithelioid vs nonepithelioid) and gender.

The primary endpoint of the study was overall survival. Secondary endpoints included objective response rate, disease control rate, and progression-free survival. A prespecified interim analysis was scheduled to be performed by an external, independent data monitoring committee when 85% of total deaths had occurred.

Improvement in Nonepithelioid Histology

As Dr. Baas reported, the data monitoring committee confirmed the primary endpoint of improved overall survival for nivolumab plus ipilimumab vs chemotherapy at the prespecified interim analysis. At the time of analysis, 89% of total deaths had occurred, with a median follow-up of 29 months.

Median overall survival was 18.1 months with the immunotherapy combination and 14.1 months with standard chemotherapy (HR = 0.74; P = .002). The 2-year overall survival rates were 41% and 27% in the experimental and chemotherapy arms, respectively.

Subgroup analysis showed that the majority of subgroups experienced benefit from nivolumab plus ipilimumab, said Dr. Baas, and no subgroups were harmed with the experimental treatment vs control.

Histologic analysis also showed improved overall survival in both epithelioid and nonepithelioid histologies with nivolumab plus ipilimumab vs chemotherapy. Moreover, although dual immunotherapy performed similarly in both histologies, Dr. Baas noted, chemotherapy performed better in epithelioid mesothelioma, as expected.

Patients with nonepithelioid mesothelioma who received chemotherapy had a median overall survival of 8.8 months vs 18.1 months with nivolumab plus ipilimumab (HR = 0.46).

Analysis of PD-L1 expression showed similar rates of overall survival between study arms in the absence of PD-L1 expression. Conversely, with the presence of PD-L1 expression, the performance of nivolumab plus ipilimumab was improved vs chemotherapy, with a median overall survival of 18.0 vs 13.3 months, respectively (HR = 0.69). According to Dr. Baas, however, PD-L1 data were descriptive in nature, precluding firm conclusions.

The safety profile of nivolumab plus ipilimumab was consistent with previously reported studies, with no new signals were observed, Dr. Baas reported. 

DISCLOSURE: Dr. Baas has served on the advisory board for BMS, MSD, AstraZeneca, and Takeda.

REFERENCES

1. Baas P, Scherpereel A, Nowak AK, et al: First-line nivolumab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. 2020 World Conference on Lung Cancer. Presidential Symposium. Abstract 3.

2. Milano MT, Zhang H: Malignant pleural mesothelioma: A population-based study of survival. J Thorac Oncol 5:1841-1848, 2010.