CheckMate-743: Immunotherapy Beats Chemo

Trial Results Show Significant Survival Benefit

The CheckMate-743 trial has demonstrated that combining two immunotherapy drugs, nivolumab (Opdivo) and ipilimumab (Yervoy), significantly extends survival for patients with unresectable malignant pleural mesothelioma compared to standard chemotherapy.

This Phase 3, multicenter, randomized trial represents the first immunotherapy regimen to show superior survival over chemotherapy in mesothelioma, potentially changing the standard of care for the first time in nearly two decades.

Key Survival Data

The trial showed a hazard ratio of 0.74 (p=0.002), representing a 26% reduction in the risk of death with the immunotherapy combination.

What This Means for Patients

The results are particularly significant because:

Doubled long-term survival: 3-year survival rates were nearly double (23% vs 15%), meaning more patients are living longer with immunotherapy.

First advance in 20 years: Pemetrexed plus platinum chemotherapy has been the standard since 2004. CheckMate-743 is the first regimen to demonstrate superior survival.

Durable responses: 38% of patients achieved partial tumor shrinkage, with some responses lasting over a year.

How the Treatment Works

The combination targets two different immune checkpoints:

Nivolumab blocks PD-1, a protein that cancer cells use to hide from the immune system. By blocking PD-1, T-cells can recognize and attack mesothelioma cells.

Ipilimumab blocks CTLA-4, which normally limits T-cell activation. Blocking CTLA-4 allows more T-cells to be primed and expanded to target cancer cells.

Together, the drugs produce a stronger immune response than either alone.

Treatment Schedule

• Nivolumab: 360 mg every 3 weeks
• Ipilimumab: 1 mg/kg every 6 weeks
• Duration: Up to 2 years or until disease progression

Who Was Studied

The trial enrolled 605 patients with:

• Previously untreated unresectable malignant pleural mesothelioma
• All histological subtypes (epithelioid, sarcomatoid, biphasic)
• Good performance status (ECOG 0-1)

Patients were randomized to receive either nivolumab plus ipilimumab or standard chemotherapy (pemetrexed plus cisplatin or carboplatin).

Benefit Across Subtypes

The immunotherapy combination showed benefit regardless of histological subtype:

The benefit was particularly striking in non-epithelioid (sarcomatoid/biphasic) disease, where chemotherapy historically performs poorly. These patients more than doubled their median survival with immunotherapy.

Side Effects

Immune-related adverse events occurred in approximately 30% of patients receiving immunotherapy. The most common included:

• Rash
• Diarrhea/colitis
• Thyroid dysfunction
• Hepatitis
• Pneumonitis

Most immune-related side effects were manageable with steroids or other immunosuppressive treatments. Treatment-related deaths occurred in 1.5% of immunotherapy patients vs 0.3% with chemotherapy.

Path to FDA Approval

Based on these results, the FDA granted approval to nivolumab plus ipilimumab as first-line treatment for unresectable malignant pleural mesothelioma on October 2, 2020.

This makes it the first immunotherapy approved specifically for mesothelioma.

What Patients Should Know

• The combination is approved for unresectable (cannot be surgically removed) pleural mesothelioma
• It is a first-line treatment, meaning it can be used before trying chemotherapy
• Not all patients respond, discuss with your oncologist whether immunotherapy is right for you
• Treatment is given intravenously at a cancer center
• Side effects differ from chemotherapy and require specialized management

Clinical Significance

Dr. Paul Baas, lead investigator, noted that this trial “provides a new first-line treatment option for patients with malignant pleural mesothelioma.” The results confirm that immunotherapy can fundamentally change outcomes in this historically difficult-to-treat cancer.