Pembrolizumab/Chemo sBLA Receives FDA Priority Review in Advanced Mesothelioma

• The FDA has granted priority review to a supplemental biologics license application (sBLA) of pembrolizumab (Keytruda) plus chemotherapy in unresectable or metastatic malignant pleural mesothelioma.

• Findings from the phase 2/3 IND.227/KEYNOTE-483 trial (NCT02784171) support this sBLA.

• A Prescription Drug User Fee Act target action date has been set for September 25, 2024.

The sBLA for pembrolizumab given in combination with chemotherapy for the frontline treatment of patients with unresectable or metastatic malignant pleural mesothelioma has been granted priority review by the FDA.¹

In the pivotal phase 2/3 IND.227/KEYNOTE-483 trial, the combination elicited a statistically significant improvement in overall survival (OS) vs chemotherapy alone (HR, 0.79; 95% CI, 0.64-0.98; 2-sided P =.0324), as well as progression-free survival (PFS; HR, 0.80; 95% CI, 0.65-0.99; 2-sided P = .0372) in this patient population.

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Data from the final analysis of the trial also demonstrated there to be an OS of 17.3 months with the addition of pembrolizumab to chemotherapy (95% CI, 14.4-21.3) compared with 16.1 months (95% CI, 13.1-18.2) among those treated with chemotherapy alone. At this time, the median PFS was 7.13 months (95% CI, 6.93-8.12) vs 7.16 months (95% CI, 6.83-7.69) among those given the combination vs chemotherapy alone.² These data support the FDA’s decision.

“Malignant pleural mesothelioma is typically diagnosed in advanced stages when curative surgery is not an option, and progresses quickly,” said Gregory Lubiniecki, MD, vice president, oncology clinical research, Merck Research Laboratories, in a press release.¹ “We continue to evaluate [pembrolizumab] in new and difficult-to-treat tumors and look forward to working with the FDA to help bring [pembrolizumab] as a potential treatment option to certain patients with advanced malignant pleural mesothelioma.”

The trial also showed that at 12 and 24 months, the estimated PFS rate was 26% and 9% with the combination vs 17% and 4% with chemotherapy alone. OS rates at 24 and 36 months were 39% and 25% with the combination vs 33% and 17% with chemotherapy alone, respectively.

A higher objective response rate (ORR) was seen among patients treated with the addition of pembrolizumab compared with those given chemotherapy alone, at 62% vs 38%, respectively (P <.0001). A total of 32% of patients had stable disease in the experimental arm compared with 47% of patients in the control arm. Another 4% and 5% of patients had disease progression, respectively.

Moreover, the median duration of response with the addition of pembrolizumab was 5.8 months (95% CI, 5.5-7.0) vs 5.5 months (95% CI, 4.2-6.0) with chemotherapy alone (P =.185).² For safety, the combination had a consistent safety profile compared with what has been previously seen in clinical studies of the agents.

A target action date of September 25, 2024, has been set by the FDA.¹

Background of the IND.227/KEYNOTE-483 Trial

The randomized, open-label, phase 2/3 IND.227/KEYNOTE-483 trial sought to investigate the combination of pembrolizumab with chemotherapy vs chemotherapy alone in patients with unresected advanced pleural mesothelioma.³

Enrollment in the study was open to patients with measurable disease, an ECOG performance status of 0 or 1, and adequate hematologic, liver, and renal function. Patients must have had no contraindications to standard chemotherapy, must have been eligible to receive standard chemotherapy with pemetrexed and cisplatin, and must have been incurable with use of standard therapies.

While patients were permitted to have had prior radiation at least 28 days prior to registration, radiation to the thorax was not allowed unless clear disease progression was seen. Previous major surgery was also permitted at least 28 days prior to registration.

A total of 440 patients were enrolled during the phase 3 portion and randomized to receive 200 mg of pembrolizumab given intravenously every 3 weeks for up to 35 cycles in combination with 500 mg/m² of pemetrexed every 3 weeks for 6 cycles and 75 mg/m² of cisplatin every 3 weeks for 6 cycles. Patients also could have been given pemetrexed plus cisplatin alone. Additionally, cisplatin could be substituted with carboplatin at an area under the curve of 5 or 6 every 3 weeks for 6 cycles in either arm.

The primary end point evaluated in the study was OS. PFS, ORR, safety, and quality of life served as the secondary end points of the study.

REFERENCES

1. FDA grants priority review to Merck’s application for KEYTRUDA (pembrolizumab) plus chemotherapy as first-line treatment of patients with unresectable advanced or metastatic malignant pleural mesothelioma. News release. Merck. May 29, 2024. Accessed May 29, 2024. https://tinyurl.com/wsh3hnkr

2. Chu QS, Piccirillo MC, Greillier L, et al. IND227 phase III (P3) study of cisplatin/pemetrexed (CP) with or without pembrolizumab (pembro) in patients (pts) with malignant pleural mesothelioma (PM): a CCTG, NCIN, and IFCT trial. J Clin Oncol. 2023;41(suppl 17):LBA8505. doi:10.1200/JCO.2023.41.17_suppl.LBA8505

3. Pembrolizumab in patients with advanced malignant pleural mesothelioma. ClinicalTrials.gov. Updated January 16, 2024. Accessed May 29, 2024. https://clinicaltrials.gov/ct2/show/NCT02784171