FDA Approves Frontline Nivolumab/Ipilimumab for Malignant Pleural Mesothelioma

The FDA has approved nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the frontline treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).¹ The indication is for 360 mg of nivolumab every 3 weeks plus 1 mg/kg of ipilimumab every 6 weeks injected for intravenous use.

This approval represents the first and only immunotherapy regimen indicated for the treatment of patients with previously untreated unresectable MPM.

“Malignant pleural mesothelioma is a rare cancer with limited treatment options. When it is diagnosed in advanced stages, the 5-year survival rate is approximately 10%,” said Anne S. Tsao, MD, in a statement.

Approval of the application was based on findings from a prespecified interim analysis of the phase 3 CheckMate 743 trial.

“The survival results from the CheckMate 743 trial show that the combination of nivolumab and ipilimumab could become a new frontline 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,” said Tsao, professor and Section Chief Thoracic Medical Oncology and Director of the Mesothelioma Program at The University of Texas MD Anderson Cancer Center, and CheckMate 743 study investigator.

According to findings presented during the 2020 World Conference on Lung Cancer Virtual Presidential Symposium, the median overall survival (OS) with nivolumab and ipilimumab was 18.1 months (95% CI, 16.8-21.5) compared with 14.1 months (95% CI, 12.5-16.2) with platinum-based chemotherapy (HR, 0.74; 96.6% CI, 0.60-0.91; P = .002).^2,3 At 2 years, 41% of patients in the immunotherapy arm were still alive compared with 27% in the chemotherapy arm.

CheckMate 743 is a randomized, open-label trial that investigated the combination of nivolumab plus ipilimumab versus standard-of-care chemotherapy of cisplatin or carboplatin and pemetrexed (Alimta) in the first-line setting for patients with unresectable MPM.

The study enrolled 605 patients, and administered treatment at 3 mg/kg every 2 weeks for nivolumab and 1 mg/kg every 6 weeks for ipilimumab in the experimental arm (n = 303) and for 6 cycles of cisplatin 75 mg/m2 or carboplatin AUC 5 plus pemetrexed 500 mg/m2 every 3 weeks in the control arm (n = 302).

The primary end point was OS and the secondary end points were objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) by blinded independent committee review (BICR). In addition, PD-L1 was explored as a predictive biomarker.

At baseline, both arms were 77% male. In terms of histology, the majority of the patient population had epithelioid tumors including 76% of the nivolumab/ipilimumab arm and 75% of the chemotherapy arm. The remaining patients had non-epithelioid tumors. The median age of patients in both arms was 69 years. At baseline, 80% of patients in the immunotherapy arm had positive PD-L1expression plus 74% in the chemotherapy arm.

The immunotherapy arm was favored across subgroup analyses. Patients with epithelioid tumors treated with the immunotherapy combination had a median OS of 18.7 months versus 16.5 months with chemotherapy (HR, 0.86; 95% CI, 0.69-1.08). For those with non-epithelioid tumors, the median OS was 18.1 months in the nivolumab-plus-ipilimumab arm compared with 8.8 months in the chemotherapy arm (HR, 0.46; 95% CI, 0.31-0.68). In patients with positive PD-L1 expression, the median OS was 18.0 months in the immunotherapy arm versus 13.3 months in the chemotherapy arm (HR, 0.69; 95% CI, 0.55-0.87). Whereas in the negative PD-L1 expression subgroup, the median OS was 17.3 months nivolumab plus ipilimumab compared with 16.5 months with chemotherapy (HR, 0.94; 95% CI, 0.62-1.40).

Median PFS by BICR was 6.8 months with the nivolumab/ipilimumab regimen versus 7.2 months with chemotherapy (HR, 1.00; 95% CI, 0.82-1.21). At 2 years, the PFS rate was 16% with nivolumab and ipilimumab versus 7% with chemotherapy.

ORR in the immunotherapy arm was 40% with complete responses seen in 2% versus an ORR of 43% in the chemotherapy arm, which consisted of all partial responses. The DCR was 76.6% and 85.1% for the immunotherapy and chemotherapy arms, respectively.

The median DOR was 11.0 months in the nivolumab/ipilimumab combination arm versus 6.7 months in the chemotherapy arm. At 2 years, the DOR rate was 32% with the immunotherapy regimen versus 8% with the chemotherapy regimen.

Treatment-related adverse events (TRAEs) of any grade were observed in 80% of patients in the nivolumab/ipilimumab arm compared with 82% in the chemotherapy arm. Events occurring in ≥15% of patients included diarrhea and pruritis in the immunotherapy arm and nausea, anemia, neutropenia, fatigue, decreased appetite, and asthenia in the chemotherapy arm.

TRAEs led to treatment discontinuation in 23 patients in the immunotherapy arm and 16 in the chemotherapy arms. Grade 3/4 TRAEs led to therapy discontinuation in 15 patients who received immunotherapy and 7 who received chemotherapy.

Serious TRAEs were more abundant in the nivolumab/ipilimumab arm with 21 any-grade serious TRAEs and 15 grade 3/4 events. In the chemotherapy arm, there were 8 serious TRAEs of any grade and 6 grade 3/4 events.

One treatment-related death occurred in the study, in the immunotherapy arm.

“Thoracic cancers can be complex and difficult to treat, and we are focused on developing immunotherapy options that may have the potential to extend patients’ lives,” said Adam Lenkowsky, general manager and head, US, Oncology, Immunology, Cardiovascular, Bristol Myers Squibb, in a statement.

Nivolumab and ipilimumab are also approved for the frontline treatment of other thoracic cancers, including for the first-line treatment of patients with metastatic non–small cell lung cancer (NSCLC) whose tumors express PD-L1 ≥1%, as determined by an FDA-approved test, and without EGFR or ALK genomic tumor aberrations, as well as in combination with limited chemotherapy for the treatment of previously untreated adult patients with metastatic or recurrent NSCLC with no EGFR or ALK genomic tumor aberrations regardless of PD-L1 expression.

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. News release. Bristol Myers Squibb. October 2, 2020. Accessed October 2, 2020. https://bwnews.pr/2GACgkT​
2. Baas P, Scherpereel A, Nowal AK, et al. First-line nivolumab + ipilimumab vs chemotherapy in unresectable malignant pleural mesothelioma: CheckMate 743. Presented at: 2020 World Conference on Lung Cancer Virtual Presidential Symposium. August 8, 2020.
3. Opdivo® (nivolumab) plus Yervoy® (ipilimumab) demonstrates durable survival benefit vs. chemotherapy in patients with previously untreated malignant pleural mesothelioma. News release. Bristol Myers Squibb. August 8, 2020. Accessed August 8, 2020. https://bit.ly/2Cf6OHj​