FDA Approves Pembrolizumab Plus Chemo for Unresectable Advanced or Metastatic Malignant Pleural Mesothelioma

FDA

The FDA has approved pembrolizumab (Keytruda) plus pemetrexed and platinum chemotherapy in the frontline treatment of patients with unresectable advanced or metastatic malignant pleural mesothelioma.¹

Data from the phase 2/3 KEYNOTE-483 study (NCT02784171) showed that pembrolizumab plus chemotherapy (n = 222) significantly improved overall survival (OS) vs chemotherapy alone (n = 218), with a median OS of 17.3 months (95% CI, 14.4-21.3) and 16.1 months (95% CI, 13.1-18.2), respectively (HR, 0.79; 95% CI, 0.64-0.98; P =.0162).

Moreover, the median progression-free survival was 7.1 months in both the investigative (95% CI, 6.9-8.1) and control (95% CI, 6.8-7.7) arms, respectively (HR, 0.80; 95% CI, 0.65-0.99; P =.0194); this translated to a 20% reduction in the risk of disease progression or death. The confirmed objective response rate was also higher with the addition of pembrolizumab to chemotherapy vs chemotherapy alone, at 52% (95% CI, 45.5%-59.0%) and 29% (95% CI, 23.0%-35.4%), respectively. The median duration of response in the respective arms was 6.9 months (95% CI, 5.8-8.3) and 6.8 months (95% CI, 5.5-8.5).

Keeping Up With KEYNOTE-483: Design, Treatment, Objectives

The study enrolled patients with unresectable advanced or metastatic malignant pleural mesothelioma. Patients needed to have measurable disease by modified RECIST 1.1 criteria, an ECOG performance status of 0 or 1, and acceptable hematological, liver, and renal function.² They could not have previously received systemic therapy in the advanced setting, a contraindication to immunotherapy, no other active malignancy, and no known central nervous system metastases unless treated and stable.

Study participants were randomly assigned 1:1 to receive pembrolizumab every 3 weeks for up to 2 years plus pemetrexed and platinum-based chemotherapy for up to 6 cycles or pemetrexed and platinum-based chemotherapy for up to 6 cycles.^1,2 Chemotherapy consisted of cisplatin at 75 mg/m² or carboplatin at area under the curve 5 or 6 and pemetrexed at 500 mg/m². Patients were stratified by histology.

The main efficacy outcome measure was OS and additional efficacy measures included PFS, ORR, and DOR per blinded independent central review and according to modified RECIST 1.1 criteria for mesothelioma.

Additional Efficacy Insights

Data from exploratory OS analyses showed that in those with epithelioid disease (n = 345), the median OS in the pembrolizumab/chemotherapy and chemotherapy arms were 19.8 months (95% CI, 16.0-22.2) and 18.2 months (95% CI, 16.0-20.4), respectively (HR, 0.89; 95% CI, 0.70-1.13).² The estimated 3-year OS rates were 26% (19%-34%) and 20% (14%-28%). The median PFS was 7.13 months (95% CI, 6.9-8.1) in the pembrolizumab arm vs 7.39 months (95% CI, 7.0-8.4) in the chemotherapy arm (HR, 0.93; 95% CI, 0.1-1.2).

In those with non-epithelioid disease (n = 95), the median OS with pembrolizumab plus chemotherapy was 12.3 months (95% CI, 8.67-21.2) vs 8.2 months (95% CI, 5.85-10.8) with chemotherapy alone (HR, 0.57; 95% CI, 0.36-0.89). The respective 3-year OS rates were 23% (13%-40%) and 7% (2%-21%). The median PFS was 6.9 months (95% CI, 4.5-9.7) in the pembrolizumab arm vs 4.5 months (95% CI, 4.0-6.4) in the chemotherapy arm (HR, 0.48; 95% CI, 0.3-0.8).

Shining a Light on Safety

At least 1 toxicity was experienced by 98% of those in the pembrolizumab arm (n = 222) and 95% of those in the chemotherapy arm (n = 211); these effects were grade 3 or 4 for 27% and 15% of patients, respectively. Fatigue and nausea were the most common adverse effects (AEs) reported in both arms.

Other grade 1/2 adverse effects reported in the pembrolizumab arm included oral mucositis (19%), vomiting (18%), anorexia (17%), constipation (16%), pruritus (15%), maculopapular rash (13%), dysgeusia (12%), watering eyes (12%), and peripheral sensory neuropathy (11%). The most common grade 3 effects were fatigue (7%), nausea (5%), febrile neutropenia (4%), anemia (2%), diarrhea (1%), maculopapular rash (1%), and vomiting (1%). Grade 4 effects were febrile neutropenia (1%) and anemia (<1%).

In the chemotherapy arm, 20% of patients discontinued any protocol therapy because of an AE, and 7% discontinued any treatment due to an AE excluding platinum; in the pembrolizumab arm, these respective rates were 37% and 28%. In the chemotherapy arm, deaths due to all-cause AEs, related AEs, and within 24 hours of onset of a related AE occurred in 5%, 1%, and <1%, respectively; in the pembrolizumab arm, these rates were 6%, 3%, and 1%.

References

1. FDA approves pembrolizumab with chemotherapy for unresectable advanced or metastatic malignant pleural mesothelioma. FDA. September 17, 2024. Accessed September 17, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-unresectable-advanced-or-metastatic-malignant-pleural
2. Chu QS, Perrone F, Greillier L, et al. Pembrolizumab plus chemotherapy versus chemotherapy in untreated advanced pleural mesothelioma in Canada, Italy, and France: a phase 3, open-label, randomised controlled trial. Lancet. 2023;402(10419):2295-2306. doi:10.1016/S0140-6736(23)01613-6