FDA Approves Nivolumab/Ipilimumab for Frontline Unresectable Malignant Pleural Mesothelioma

The FDA has approved nivolumab (Opdivo) at 360 mg every 3 weeks plus ipilimumab (Yervoy) at 1 mg/kg every 6 weeks for the frontline treatment of adult patients with unresectable malignant pleural mesothelioma.¹

The approval is based on findings from a prespecified interim analysis of the phase 3 CheckMate-743 trial, in which the combination demonstrated an improvement in overall survival (OS) versus platinum-based standard chemotherapy (HR, 0.74; 95% CI, 0.61-0.89; P = .002). At 22.1 months of follow-up, the median OS was 18.1 months with the combination (95% CI, 16.8- 21.5) versus 14.1 months with chemotherapy (95% CI, 12.5 -16.2). The 2-year OS rates were 41% and 27%, respectively.

“Malignant pleural mesothelioma is a rare cancer with limited treatment options. When it is diagnosed in advanced stages, the five-year survival rate is approximately 10 percent,” said study investigator Anne S. Tsao, MD, professor and Section Chief Thoracic Medical Oncology and Director of the Mesothelioma Program at The University of Texas MD Anderson Cancer Center, in a press release. “The survival results from the CheckMate-743 trial show that the combination of nivolumab and ipilimumab could become a new front-line standard of care option. This is exciting news, instilling hope for patients with this devastating disease and for the healthcare providers who care for them."

A total of 605 patients with unresectable pleural mesothelioma were enrolled on the randomized, open-label phase 3 trial. Participants had not received prior systemic therapy and they had an ECOG performance status ranging from 0 to 1. Patients were stratified based on histology, either epithelial or non-epithelial disease, as well as gender.

In the trial, patients were randomized in a 1:1 fashion to receive either nivolumab at 3 mg/kg once every 2 weeks in combination with ipilimumab at 1 mg/kg once every 6 weeks for up to 2 years or chemotherapy comprised of cisplatin or carboplatin plus pemetrexed every 3 weeks. Participants continued to receive treatment until either disease progression, intolerable toxicities, or up to 2 years for those on the immunotherapy arm.

The primary end point of the trial was OS, while secondary end points included objective response rate (ORR), disease control rate, and progression-free survival (PFS) as assessed by blinded independent central review (BICR), and PD-L1 expression as a predictive biomarker.

The analysis plan was to identify a HR of 0.72 with a power of 90% and a 5% type-I error, with a planned total of 600 randomized participants and 473 deaths. Notably, the primary end point of OS was met at the time of the prespecified interim analysis.3

Additional results demonstrated that those in the immunotherapy arm experienced a shorter median PFS versus those on the chemotherapy arm, at 6.8 months versus 7.2 months, respectively (HR, 1.00; 95% CI, 0.82-1.21). However, the combination did have a higher PFS rate at both 12 months and 24 months versus the chemotherapy arm, at 30% versus 16%, respectively, and 24% and 7%, respectively.

Moreover, the ORR per BICR was 40% with nivolumab/ipilimumab compared with 43% with chemotherapy. The partial response (PR) rate in the immunotherapy arm was 38%, while the complete response (CR) rate was 2%. In the chemotherapy arm, the PR rate was 43% and the CR rate was 0%. The median duration of response (DOR) was 5.6 months in the investigational arm versus 3.5 months in the control arm.

At 12 months, results presented during the 2020 International Association for the Study of Lung Cancer’s World Conference on Lung Cancer Virtual Presidential Symposium showed that the OS rates in the experimental and control arms were 68% and 58%, respectively; these rates were 41% and 27%, respectively, at 24 months.²

Notably, the significant OS benefit observed with nivolumab/ipilimumab also extended to key patient subgroups analyzed in the trial, such as those with epithelioid or non-epithelioid disease and those with PD-L1 expression of less than 1% or 1% or higher.

With regard to safety, treatment-related adverse effects (TRAEs) of any grade were reported in 80% of participants who received the immunotherapy combination and 30% of patients had toxicities that were grade 3 or 4. Eighty-two percent of patients in the chemotherapy arm experienced TRAEs; 32% reported grade 3 or 4 toxicities. Serious TRAEs were experienced by 21% of those on the immunotherapy arm versus 8% of those on the chemotherapy arm.

The most commonly experienced TRAEs in the nivolumab/ipilimumab arm were diarrhea and pruritus. In the chemotherapy arm, participants reported nausea, anemia, neutropenia, fatigue, decreased appetite, and asthenia.

References

1. U.S. Food and Drug Administration approves Opdivo (nivolumab) + Yervoy (ipilimumab) as the first and only immunotherapy treatment for previously untreated unresectable malignant pleural mesothelioma. Bristol Myers Squibb. October 2, 2020. Accessed October 2, 2020. https://bit.ly/2Sn2t9e

2. Baas P, Scherpereel A, Nowak A, et al. First-line nivolumab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. Presented at: International Association for the Study of Lung Cancer 2020 Presidential Symposium; August 8, 2020; Virtual. Abstract 3.