Keytruda + chemotherapy significantly improved overall survival v. chemotherapy alone as first-line treatment for unresectable advanced pleural mesothelioma

At the final analysis of the study, Keytruda plus chemotherapy significantly improved overall survival (OS), reducing the risk of death by 21% (HR=0.79 [95% CI, 0.64-0.98]; two-sided p value=0.0324), with a median OS of 17.3 months (95% CI, 14.4-21.3) versus 16.1 months (95% CI, 13.1-18.2) for chemotherapy alone. These late-breaking data are being presented during an oral abstract session at the 2023 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract #LBA8505) and are being discussed with regulatory authorities worldwide.

“Patients with pleural mesothelioma are usually diagnosed at an advanced stage, when the five year survival rate is only 12% and curative surgery is not an option,” said Dr. Lesley Seymour, Director of the Investigational New Drug program at CCTG, and Senior Investigator for IND.227. “The addition of pembrolizumab to platinum-pemetrexed in our study resulted in significantly improved overall survival, progression-free survival and objective response rates compared to platinum-pemetrexed alone, regardless of PD-L1 expression. This regimen represents a potential new treatment option for patients with advanced pleural mesothelioma.”

“These results support the potential of Keytruda plus chemotherapy as a new first-line option for patients with advanced pleural mesothelioma, who currently have limited treatment options,” said Dr. Gregory Lubiniecki, Vice President, Global Clinical Development, Merck Research Laboratories. “These data demonstrate our commitment to improving outcomes for patients with different types of thoracic cancer through our expansive clinical development program and research evaluating Keytruda in new, difficult-to-treat tumors.”

Study design and additional data from IND.227/KEYNOTE-483: .227/KEYNOTE-483 is a randomized, open-label Phase II/III trial (ClinicalTrials.gov, NCT02784171) sponsored and conducted by CCTG in collaboration with National Cancer Institute of Naples (NCIN) and Intergroupe Francophone de Cancérologie Thoracique (IFCT). Merck provided Keytruda and support for the trial. The trial evaluated Keytruda plus chemotherapy versus chemotherapy alone for the treatment of patients with unresected advanced pleural mesothelioma. The primary endpoint of the study is OS, and secondary endpoints include progression-free survival (PFS) and objective response rate (ORR) as assessed by blinded independent central review (BICR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) modified for mesothelioma, safety and quality of life.

The Phase III part of the trial enrolled 440 patients who were randomized to receive: Keytruda (200 mg intravenously [IV] every three weeks [Q3W] for up to 35 cycles) plus pemetrexed (500 mg/m2 Q3W for six cycles) and cisplatin (75 mg/m2 Q3W for six cycles; carboplatin substitution [AUC 5-6 Q3W for six cycles] was permitted), or pemetrexed and cisplatin (carboplatin substitution was permitted) alone.

PFS was also significantly improved for Keytruda plus chemotherapy compared to chemotherapy alone (HR=0.80 [95%CI, 0.65-0.99], two-sided p value = 0.0372; median PFS 7.13 months versus 7.16 months respectively). At 12 months, the estimated PFS rate was 26% for Keytruda plus chemotherapy versus 17% for chemotherapy alone. The ORR was significantly higher for Keytruda plus chemotherapy versus chemotherapy alone (62% versus 38%, p<0.0001).

The safety profile of Keytruda plus chemotherapy in this study was consistent with previously reported studies. Adverse events related to study treatment of grade 3 or 4 occurred in 27% of patients in the Keytruda plus chemotherapy arm, and 15% of patients on the chemotherapy-alone arm. The most common grade greater than 3 adverse events in the Keytruda arm were fatigue (7%), nausea (5%) and febrile neutropenia (5%); the corresponding values for the chemotherapy arm were 6%, 1% and 1%. Keytruda-related adverse events resulting in discontinuation of Keytruda occurred in 16% of patients receiving Keytruda plus chemotherapy.