Health Canada Approves Pembrolizumab/Chemotherapy for Unresectable, Advanced or Metastatic Pleural Mesothelioma

Pembrolizumab in Pleural Mesothelioma |

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Health Canada has approved pembrolizumab (Keytruda) plus pemetrexed and platinum-based chemotherapy for the first-line treatment of adult patients with unresectable advanced or metastatic malignant pleural mesothelioma.1

The regulatory decision was based on data from the pivotal phase 2/3 IND.227/KEYNOTE-483 trial (NCT02784171), which showed a statistically significant improvement in overall survival (OS), progression-free survival (PFS), and overall response rate (ORR) in patients who were randomly assigned to receive pembrolizumab plus chemotherapy vs those treated with chemotherapy alone.

At the prespecified final analysis, patients treated in the pembrolizumab arm experienced a statistically significant improvement in OS vs chemotherapy alone (HR, 0.79; 95% CI, 0.64%-0.98%; P = .0162). The median OS was 17.3 months (95% CI, 14.4-21.3) vs 16.1 months (95% CI, 13.1-18.2) in the pembrolizumab and chemotherapy arms, respectively. A statistically significant improvement in PFS was also seen in the pembrolizumab vs chemotherapy arms (HR, 0.80; 95% CI, 0.65-0.99; P = .0194). The median PFS was 7.1 months (95% CI, 6.9-8.1) vs 7.1 months (95% CI, 6.8-7.7) in the pembrolizumab vs chemotherapy arms, respectively. At the interim analysis, the ORR was significantly higher in the pembrolizumab arm vs the chemotherapy arm, at 52% (95% CI, 45.5-59.0) vs 29% (95% CI, 23.0-35.4; P = .00001), respectively.

“This approval marks the first combination treatment of [pembrolizumab] and chemotherapy in Canada for patients with malignant pleural mesothelioma,” Quincy Chu, MD, FRCP(C), a medical oncologist at the Cross Cancer Institute and associate professor at the University of Alberta, stated in a news release. “This combination provides a new therapeutic option for this patient group, which has limited options available and may help improve health outcomes."

The multicenter, randomized, open-label, active-controlled study evaluated the efficacy and safety of pembrolizumab plus pemetrexed and platinum-based chemotherapy vs pemetrexed plus platinum-based chemotherapy for the treatment of patients with unresectable advanced or metastatic pleural mesothelioma who did not previously receive systemic therapy for advanced or metastatic disease. The study enrolled 440 patients, including patients at least 18 years of age or older who were eligible to receive standard chemotherapy with pemetrexed and cisplatin and had no contraindications to standard chemotherapy, had unresectable advanced and/or metastatic disease that is incurable by standard therapies, a presence of radiologically documented disease with at least 1 site of disease that is unidimensionally measurable, and an ECOG performance status of 0 or 1.2 Patients were not eligible for the study if they had autoimmune disease that required systemic therapy within 3 years of treatment of a medical condition that required immunosuppression.1

Patients on the study were randomly assigned 1:1 to either the pembrolizumab arm or the chemotherapy alone arm. Those in the combination arm were treated with intravenous pembrolizumab at 200 mg with pemetrexed at 500 mg/m2 plus cisplatin 75 mg/m2 or carboplatin AUC at 5 to 6 mg/mL/min on day 1 of each 21-day cycle for up to 6 cycles. Patients then received subsequent pembrolizumab at 200 mg every 3 weeks. Of note, pembrolizumab was administered before chemotherapy on day 1. Patients in the chemotherapy arm were treated with pemetrexed at 500 mg/m2 and cisplatin at 75 mg/m2 or carboplatin AUC at 5 to 6 mg/mL/min on day 1 of each 21-day cycle for up to 6 cycles.

Notably, treatment with pembrolizumab was continued until patients experienced disease progression, determined by the investigator per modified RECIST 1.1 criteria for mesothelioma, unacceptable toxicity, or a maximum of 24 months. An assessment of tumor status was performed every 6 weeks for 18 weeks and every 12 weeks thereafter. The primary end point of the study was OS; secondary end points included PFS, ORR, and duration of response (DOR), assessed per blinded independent central review using modified RECIST 1.1 criteria.

The most common adverse effects observed in at least 20% of patients treated with the pembrolizumab combination included fatigue, nausea, diarrhea, vomiting, and stomatitis.

The combination was granted FDA approval in September 2024 for the respective patient population, for which the decision was based on the KEYNOTE-483 study.3

“We’re pleased to announce this first-line treatment option for adults with advanced or metastatic malignant pleural mesothelioma, a condition that often has a challenging prognosis,” André Galarneau, PhD, executive director and vice president, Oncology Business Unit at Merck Canada, added in the news release.1 “This is an important step for us within the mesothelioma space. It demonstrates the Canadian Cancer Trials Group’s leadership in advancing patient care and underscores our commitment to research for patients with difficult-to-treat cancers.”

References

1. Health Canada approves Keytruda plus pemetrexed and platinum chemotherapy as first-line treatment for adult patients with unresectable advanced or metastatic malignant pleural mesothelioma. News release. Merck. April 22, 2025. Accessed April 22, 2025. https://www.merck.ca/en/newsroom/health-canada-approves-kn483/
2. Pembrolizumab in patients with advanced malignant pleural mesothelioma. ClinicalTrials.gov. Updated December 10, 2024. Accessed April 22, 2025. https://clinicaltrials.gov/study/NCT02784171
3. FDA approves pembrolizumab with chemotherapy for unresectable advanced or metastatic malignant pleural mesothelioma. FDA. September 17, 2024. Accessed April 22, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-chemotherapy-unresectable-advanced-or-metastatic-malignant-pleural