FDA Approves Pembrolizumab/Chemo in Unresectable Pleural Mesothelioma

The regulatory agency approved pembrolizumab at a recommended dose of 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 2 years or until progressive disease or unacceptable toxicity.

A treatment regimen consisting of pembrolizumab (Keytruda) plus pemetrexed and platinum-based chemotherapy has earned FDA approval as a first-line therapy for patients with unresectable advanced or metastatic malignant pleural mesothelioma (MPM), according to a press release from the agency.¹

The regulatory agency approved pembrolizumab at a recommended dose of 200 mg every 3 weeks or 400 mg every 6 weeks for a maximum of 2 years or until progressive disease or unacceptable toxicity.

Supporting data for the pembrolizumab-based regimen in this indication came from the phase 2/3 KEYNOTE-483 trial (NCT02784171), in which investigators evaluated this combination among patients who received no prior systemic therapy for metastatic or advanced disease.

Topline data showed that the median overall survival (OS) was 17.3 months (95% CI, 14.4-21.3) with pembrolizumab plus chemotherapy vs 16.1 months (95% CI, 13.1-18.2) in patients who were treated with chemotherapy alone (HR, 0.79; 95% CI, 0.64-0.98; P = .0162). Additionally, the median progression-free survival (PFS) was 7.1 months (95% CI, 6.9-8.1) and 7.1 months (95% CI, 6.8-7.7) in each respective arm (HR, 0.80; 95% CI, 0.65-0.99; P = .0194).

The confirmed objective response rate (ORR) per blinded independent central review (BICR) was 52% (95% CI, 45.5%-59.0%) with pembrolizumab-based treatment vs 29% (95% CI, 23.0%-35.4%) in the chemotherapy-alone arm. Data also indicated a median duration of response (DOR) of 6.9 months (95% CI, 5.8-8.3) vs 6.8 months (95% CI, 5.5-8.5) in each arm.

Toxicity among patients with MPM was comparable with prior reports of pembrolizumab in combination with pemetrexed and platinum-based chemotherapy.

In the open-label KEYNOTE-483 trial, patients were randomly assigned 1:1 to receive pembrolizumab for up to 2 years plus pemetrexed and platinum-containing chemotherapy for a maximum of 6 cycles (n = 222) or chemotherapy alone (n = 218). Regarding chemotherapy, investigators administered pemetrexed at 500 mg/m² intravenously every 3 weeks for 6 cycles and cisplatin at 75 mg/m² intravenously every 3 weeks for 6 cycles.²

The trial’s primary end point was PFS in the phase 2 portion and OS in the phase 3 portion. Secondary end points included ORR and DOR per BICR using modified RECIST v1.1 criteria, quality of life per EORTC QLQ-C30 assessments, and adverse effects.

Patients 18 years and older with histologically confirmed MPM eligible to receive standard chemotherapy with pemetrexed and cisplatin and unresectable advanced and/or metastatic disease unamenable to standard therapies were able to enroll on the trial. Other eligibility criteria included having availability of a cellular tumor block from their primary or metastatic tumor, presence of radiologically documented disease, and an ECOG performance status of 0 or 1.

Those who had a diagnosis of immunodeficiency, active autoimmune disease requiring systemic therapy within 3 years of entry, or a live vaccine within 30 days of beginning study treatment were ineligible for enrollment on the trial. Patients were also excluded from enrollment if they had active central nervous system metastases and/or carcinomatous meningitis, untreated and/or uncontrolled cardiovascular conditions, concurrent treatment with other investigational agents or anti-cancer therapy, evidence of interstitial lung disease, or severe or uncontrollable pain that needed to be managed with radiotherapy prior to beginning study treatment.

Of note, those with serious illnesses or medical conditions that would prohibit the patient from being treated according to protocol were also ineligible to enroll on the study. These conditions included a history of significant neurologic or psychiatric disorders that would impair the ability to obtain consent; active infection requiring systemic therapy; prior or active non-infectious pneumonitis; and serious or non-healing wounds, ulcers, or bone fractures.

References

1. History of significant neurologic or psychiatric disorder which would impair the ability to obtain consent. News release. FDA. September 17, 2024. Accessed September 17, 2024. https://tinyurl.com/mr8p7hxr
2. Pembrolizumab in patients with advanced malignant pleural mesothelioma. ClinicalTrials.gov. Updated January 16, 2024. Accessed September 17, 2024. https://tinyurl.com/yknw223r