FDA Approves Keytruda Combo for Mesothelioma
The FDA approved pembrolizumab (Keytruda) with chemotherapy for advanced pleural mesothelioma, showing a 21% reduction in death risk in the KEYNOTE-483 trial.
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.
This is the second immunotherapy regimen approved for pleural mesothelioma following the 2020 approval of nivolumab plus ipilimumab (Opdivo + Yervoy). The Keytruda combination is the first to pair immunotherapy with chemotherapy as a first-line approach.
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.
References
U.S. Food and Drug Administration. (2024-09-17). FDA Approves Pembrolizumab with Pemetrexed and Platinum Chemotherapy for Mesothelioma.
https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-pemetrexed-and-platinum-chemotherapy-unresectable-advanced-or-metastatic
OncLive. (2024-09-17). FDA Approves Pembrolizumab Plus Chemo for Malignant Pleural Mesothelioma.
https://www.onclive.com/view/fda-approves-pembrolizumab-plus-chemo-for-unresectable-advanced-or-metastatic-malignant-pleural-mesothelioma
Reader Q&A
Frequently Asked Questions
Is Keytruda plus chemo better than Opdivo plus Yervoy for mesothelioma?
What are the side effects of Keytruda plus chemotherapy?
Who is eligible for this treatment?
How long does treatment last?
What is the success rate of immunotherapy for mesothelioma?
Immunotherapy combinations like nivolumab plus ipilimumab (Opdivo + Yervoy) show median overall survival of 18.1 months for people with mesothelioma, compared to 14.1 months with chemotherapy alone. One-year survival reaches 68%, two-year survival 41%, and three-year survival 23-25% in clinical trials. Five-year survival is 14% overall (14% epithelioid, 12% non-epithelioid), versus 6% with chemotherapy. Around 40% of people with epithelioid mesothelioma respond with tumor shrinkage or stabilization. These rates reflect FDA-approved first-line treatments from trials like CheckMate 743.
Who is not a good candidate for immunotherapy?
People with preexisting autoimmune diseases face higher risks of disease exacerbation (41%) and adverse events (75%) from immunotherapy. Solid organ transplant recipients are at substantial risk of graft rejection, with rates up to 40% in kidney transplants, often requiring immunosuppression and treatment discontinuation. Immunocompromised individuals, including those with HIV/AIDS or on chemotherapy, show limited benefit and increased complications due to altered T-cell function. Those with uncontrolled asthma, severe COPD, or interstitial lung disease also experience elevated risks of severe reactions or worsening pulmonary issues. Life-threatening autoimmune disorders or high-dose immunosuppressant use further contraindicate immunotherapy in many cases.
What is life expectancy after immunotherapy?
Life expectancy after stopping immunotherapy varies by cancer type, stage, patient health, and treatment details. Studies in advanced non-small cell lung cancer show median overall survival of 18.4 months with first-line immunotherapy , 22 months with immunotherapy plus chemotherapy , and 5-year survival rates of 15-30% depending on PD-L1 expression. Post-treatment progression-free survival rates reached 98% at 1 year, 91% at 2 years, and 84% at 3 years in one analysis , with 79% of patients alive 2 years after completing 2-year therapy. Evidence indicates benefits often persist after discontinuation.
What does immunotherapy do for mesothelioma?
Immunotherapy for mesothelioma uses checkpoint inhibitors like nivolumab (Opdivo) and ipilimumab (Yervoy) to block proteins that prevent T-cells from attacking cancer cells, enabling the immune system to recognize and destroy mesothelioma tumors. This approach strengthens immune responses against cancer cells that evade natural defenses, often extending survival compared to chemotherapy alone, with median overall survival of 18.1 months for Opdivo plus Yervoy in unresectable pleural mesothelioma. Combinations with chemotherapy, such as pembrolizumab (Keytruda) plus pemetrexed and platinum drugs, further improve progression-free and overall survival, as shown in the KEYNOTE-483 trial leading to FDA approval in 2024. It shows particular effectiveness in non-epithelioid subtypes like sarcomatoid or biphasic mesothelioma.