Drug Combo Achieves 60% Response Rate

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 in the Netherlands, enrolled 20 patients with pleural mesothelioma that had advanced after treatment with nivolumab plus ipilimumab—the current standard first-line immunotherapy regimen.

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%).

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.