Drug Combo Achieves 60% Response Rate
A Dutch trial found two drugs achieved a 60% response rate in mesothelioma patients whose cancer returned after immunotherapy.
A Dutch phase II clinical trial found that combining pembrolizumab (Keytruda) with lenvatinib achieved a 60% objective response rate in patients with pleural mesothelioma whose disease progressed after first-line immunotherapy. The results offer a potential new option for patients with limited second-line choices.
The PEMMELA study, a single-center trial conducted at the Netherlands Cancer Institute in Amsterdam, enrolled 20 patients with pleural mesothelioma that had advanced after treatment with nivolumab plus ipilimumab. The current standard first-line immunotherapy regimen. The Netherlands Cancer Institute is a comprehensive cancer center that runs clinical and translational thoracic oncology research, including studies of immunotherapy and targeted agents in pleural mesothelioma.
Key Response Data
At a median follow-up of 11.9 months (as of September 2024), the combination showed the following results:
- 60% objective response rate (12 of 20 patients), including one complete response
- 90% disease control rate at three months
- 52.6% disease control rate at six months
- 8.6 months median duration of response
- 6.9 months median progression-free survival
The investigators concluded that the combination “met its primary endpoint, showing high clinical activity” and identified it as “promising for future studies in pleural mesothelioma.”
How the Combination Works
Pembrolizumab is a PD-1 checkpoint inhibitor. A drug that helps the immune system recognize and attack cancer cells. Lenvatinib is a multi-kinase inhibitor that blocks tumor blood vessel growth and may also enhance the immune response against tumors.
The rationale for combining these agents is that anti-angiogenic drugs can potentially improve checkpoint inhibitor effectiveness. By normalizing the tumor’s blood vessel environment, they may reduce immune suppression within tumors.
Safety Considerations
The combination showed substantial toxicity that clinicians would need to weigh against its benefits. Of the 20 patients enrolled:
- 85% experienced grade 3-4 adverse events
- 35% experienced serious treatment-related events
- 45% required dose reductions
- 10% discontinued treatment due to toxicity
No treatment-related deaths occurred. The most common toxicities were hypertension (25%), fatigue (20%), and musculoskeletal pain (10%).
About 85% of patients experienced grade 3-4 adverse events and 45% required dose reductions. While no treatment-related deaths occurred, careful patient selection is essential. Discuss risks and benefits thoroughly with your oncology team.
Context for Second-Line Treatment
Second-line treatment options for mesothelioma remain limited. Patients who progress after first-line immunotherapy with nivolumab plus ipilimumab often have few evidence-based options. Common approaches include chemotherapy (pemetrexed or gemcitabine-based regimens), clinical trials, and supportive care focused on symptom management.
The PEMMELA results suggest pembrolizumab plus lenvatinib could be a viable option for some patients. However, the toxicity profile means careful patient selection would be important, and patients should discuss the risks and benefits with their treatment team.
Limitations and Next Steps
The PEMMELA trial was a small, single-center study without a control group. Larger, randomized trials would be needed to confirm these findings and better characterize the risk-benefit profile.
The combination of checkpoint inhibitors with anti-angiogenic agents is being explored in several ongoing mesothelioma trials. Patients interested in second-line treatment options should discuss clinical trial opportunities with their oncologist.
References
ASCO Post. Second-Line Pembrolizumab Plus Lenvatinib in Pleural Mesothelioma.
https://ascopost.com/news/december-2025/second-line-pembrolizumab-plus-lenvatinib-in-pleural-mesothelioma/
Reader Q&A
Frequently Asked Questions
What is the PEMMELA trial?
PEMMELA was a Dutch phase II clinical trial testing pembrolizumab (Keytruda) plus lenvatinib in patients with pleural mesothelioma whose disease progressed after first-line nivolumab plus ipilimumab immunotherapy. It enrolled 20 patients at a single center.
How effective was the combination?
The combination achieved a 60% objective response rate (12 of 20 patients), including one complete response, with 90% disease control at 3 months. Median progression-free survival was 6.9 months, and median duration of response was 8.6 months.
What are the side effects?
Toxicity was substantial: 85% experienced grade 3-4 adverse events, 35% had serious treatment-related events, 45% required dose reductions, and 10% discontinued due to toxicity. Common side effects included hypertension (25%), fatigue (20%), and musculoskeletal pain (10%).
Is this treatment available now?
This was a small, single-center study without a control group. Larger randomized trials are needed to confirm findings. Patients interested in second-line options should discuss clinical trial opportunities with their oncologist.
What is the life expectancy of someone with immunotherapy for mesothelioma?
People with mesothelioma treated with immunotherapy, such as Opdivo plus Yervoy, have a median survival of 18.1 months, compared to 14.1 months with chemotherapy alone, per the CheckMate 743 trial. Keytruda combined with chemotherapy yields a median survival of 17.3-19.8 months. The DREAM trial reported 20.4 months median overall survival with durvalumab plus chemotherapy, rising to 24.3 months for epithelioid pleural mesothelioma. Overall, 3-year survival rates reach 23-25% with these treatments.
Is lenvatinib considered immunotherapy?
No, lenvatinib is a targeted multi-kinase inhibitor that blocks receptors such as VEGFR1-3, FGFR1-4, RET, KIT, and PDGFR to inhibit tumor growth and angiogenesis, not an immunotherapy. Immunotherapies boost the immune system to target cancer cells, whereas lenvatinib directly inhibits kinase activities. It is FDA-approved for first-line treatment of unresectable hepatocellular carcinoma based on the REFLECT trial, which showed non-inferior overall survival to sorafenib (13.6 months), and is often combined with immunotherapies like pembrolizumab for other cancers.
Is there a cure for cancer caused by asbestos?
No cure exists for mesothelioma, the cancer caused by asbestos exposure. Evidence shows 1-year survival rates of 79.6% for people with pleural mesothelioma receiving multimodal treatment, with 11% of surveyed individuals achieving remission through chemotherapy, surgery, or immunotherapy. The NERO trial demonstrated niraparib, a PARP inhibitor, reduced progression or death risk by 27% and delayed worsening by 1.5 months on average in recurrent cases. Ongoing research explores preventive agents like sulforaphane and therapies such as tumor treating fields, which extend survival by 4-6 months with chemotherapy. Standard options include surgery, radiation, chemotherapy, immunotherapy (nivolumab plus ipilimumab), and targeted therapy.
Does immunotherapy work for pleural mesothelioma?
Immunotherapy works for unresectable pleural mesothelioma, with FDA-approved options including nivolumab plus ipilimumab (Opdivo and Yervoy) as first-line treatment based on the CheckMate 743 trial, which showed median overall survival of 18.1 months versus 14.1 months with chemotherapy alone. Pembrolizumab (Keytruda) combined with pemetrexed and platinum chemotherapy is also FDA-approved following the KEYNOTE-483 trial, improving overall survival to 17.3 months from 16.1 months with chemotherapy. These immune checkpoint inhibitors demonstrate particular effectiveness in non-epithelioid subtypes, extending survival and controlling disease in people with pleural mesothelioma. Ongoing trials like BEAT-meso explore further combinations.