FDA Approves Keytruda Combo for Mesothelioma

The FDA approved pembrolizumab (Keytruda) in combination with pemetrexed and platinum-based chemotherapy as a first-line treatment for adults with unresectable advanced or metastatic malignant pleural mesothelioma on September 17, 2024. The approval is based on the phase 2/3 KEYNOTE-483 trial, which demonstrated a statistically significant improvement in overall survival compared to chemotherapy alone.

What the Trial Showed

The KEYNOTE-483 trial (NCT02784171) enrolled 440 patients with previously untreated advanced pleural mesothelioma and randomized them 1:1 to receive either pembrolizumab plus pemetrexed and platinum chemotherapy or chemotherapy alone.

Patients in the combination arm received pembrolizumab for up to 24 months alongside up to six cycles of chemotherapy. The primary endpoints were overall survival and progression-free survival.

The results showed:

• Overall survival: 17.3 months median with the combination versus 16.1 months with chemotherapy alone (hazard ratio 0.79, 95% CI 0.64-0.98, p=0.016)
• Objective response rate: 52% with the combination versus 29% with chemotherapy alone
• Progression-free survival: Hazard ratio 0.80 (95% CI 0.65-0.99, p=0.019)

The 21% reduction in death risk was statistically significant and consistent across patient subgroups.

How the Treatment Works

Pembrolizumab is a PD-1 inhibitor, a type of immunotherapy that blocks a protein cancer cells use to hide from the immune system. By removing this shield, the drug allows the body’s immune cells to recognize and attack mesothelioma cells.

The approved regimen combines pembrolizumab with pemetrexed and either cisplatin or carboplatin. Patients receive chemotherapy for up to six cycles and continue pembrolizumab for up to 24 months or until disease progression.

What This Means for Patients

The approval gives oncologists a new first-line option for people diagnosed with pleural mesothelioma who are not candidates for surgery. Previously, the standard first-line chemotherapy regimen of pemetrexed plus cisplatin had been the primary option for two decades, with the nivolumab-ipilimumab combination available since 2020.

The addition of pembrolizumab to chemotherapy offers a different mechanism of action than the nivolumab-ipilimumab approach, potentially benefiting patients whose tumors respond differently to various immunotherapy strategies.

People diagnosed with mesothelioma should discuss treatment options with their oncology team. Access to pembrolizumab may also be available through other clinical trials testing combinations and sequencing strategies.

The Regulatory Path

The FDA granted Priority Review for the application and conducted the review under Project Orbis, a collaborative initiative with the Australian Therapeutic Goods Administration and Health Canada. Priority Review is designated for treatments that address serious conditions and offer a significant improvement over available therapies.

Merck, the manufacturer of Keytruda, reported that the drug generated $25 billion in global sales in 2023, making it the world’s top-selling prescription drug. The mesothelioma indication expands its approved uses to more than 30 cancer types.

Treatment Centers

People with mesothelioma seeking access to immunotherapy-chemotherapy combinations may benefit from evaluation at an NCI-designated cancer center with experience treating the disease. Mesothelioma requires specialized oncological expertise, and treatment decisions are typically made by multidisciplinary teams.