FDA OKs Opdivo+Yervoy for Mesothelioma

Key Facts

• First immunotherapy approved for mesothelioma treatment
• First new FDA-approved treatment in 16 years (since pemetrexed in 2004)
• Median survival: 18.1 months vs 14.1 months with chemotherapy
• Approved for first-line treatment of unresectable malignant pleural mesothelioma

On October 2, 2020, the U.S. Food and Drug Administration approved the combination of nivolumab (Opdivo) plus ipilimumab (Yervoy) for adult patients with unresectable malignant pleural mesothelioma who have not received prior treatment. The approval marked a watershed moment for mesothelioma patients, bringing the first immunotherapy option and the first new systemic treatment in over 16 years.

A 16-Year Wait for New Treatment

Before this approval, the standard first-line treatment for mesothelioma had remained unchanged since 2004, when the FDA approved pemetrexed (Alimta) combined with cisplatin. While this chemotherapy regimen extended survival compared to cisplatin alone, outcomes remained poor, with median survival typically around 12 months.

The approval of Opdivo + Yervoy represented a fundamental shift in treatment approach, from killing cancer cells directly with chemotherapy to harnessing the patient’s own immune system to fight the disease.

CheckMate-743 Trial Results

The FDA approval was based on results from the CheckMate-743 clinical trial, a randomized Phase 3 study comparing the immunotherapy combination to standard chemotherapy.

Key Efficacy Results

The trial enrolled 605 patients with previously untreated, unresectable malignant pleural mesothelioma. Patients were randomized to receive either:

• Immunotherapy arm: Nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks for up to 2 years
• Chemotherapy arm: Pemetrexed plus cisplatin or carboplatin for up to 6 cycles

How the Drugs Work

Opdivo (nivolumab) and Yervoy (ipilimumab) are both immune checkpoint inhibitors, but they work through different mechanisms:

Nivolumab (Opdivo) blocks the PD-1 checkpoint on T cells, preventing cancer cells from using the PD-L1 “off switch” to evade immune detection.

Ipilimumab (Yervoy) blocks the CTLA-4 checkpoint, which normally acts as a brake on T cell activation. Blocking CTLA-4 allows for stronger, more sustained immune responses.

The combination approach attacks cancer’s immune evasion from two angles, potentially producing more durable responses than either drug alone.

Benefits by Cell Type

Notably, the immunotherapy combination showed particular benefit for patients with non-epithelioid mesothelioma (sarcomatoid and biphasic types), who historically have worse outcomes with chemotherapy:

For patients with sarcomatoid or biphasic mesothelioma, the immunotherapy combination more than doubled median survival compared to chemotherapy.

Safety Profile

The most common side effects reported in the CheckMate-743 trial included:

• Fatigue
• Musculoskeletal pain
• Rash
• Diarrhea
• Shortness of breath
• Nausea
• Decreased appetite
• Cough
• Itching

Immune-related adverse events occurred in some patients, requiring careful monitoring. Approximately 23% of patients discontinued treatment due to adverse reactions, compared to 16% in the chemotherapy arm.

Global Regulatory Coordination

The FDA review was conducted under Project Orbis, an initiative allowing concurrent review by multiple international regulatory agencies. The FDA collaborated with:

• Australian Therapeutic Goods Administration
• Brazilian Health Regulatory Agency (ANVISA)
• Health Canada
• Swissmedic (Switzerland)

This coordination helped ensure faster global access to the new treatment option.

What This Means for Patients

The approval of Opdivo + Yervoy gave mesothelioma patients a meaningful new option, particularly for:

1. Patients with non-epithelioid cell types who historically responded poorly to chemotherapy
2. Patients seeking alternatives to the toxicity profile of platinum-based chemotherapy
3. Those hoping for durable responses: some immunotherapy responders maintain disease control for years

However, not all patients respond to immunotherapy. Ongoing research aims to identify biomarkers that can predict which patients are most likely to benefit.

Subsequent Developments

Since the 2020 approval, additional immunotherapy options have emerged for mesothelioma:

• 2024: KEYNOTE-483 trial showed pembrolizumab plus chemotherapy improved survival
• Ongoing: Multiple clinical trials testing new immunotherapy combinations and sequences

The Opdivo + Yervoy approval opened the door to the immunotherapy era for mesothelioma, fundamentally changing how the disease is treated and offering hope for continued progress.