KEYNOTE-483: Keytruda Combo Approved

FDA Approves Pembrolizumab Combination for Mesothelioma

On September 18, 2024, the FDA approved pembrolizumab (Keytruda) in combination with pemetrexed and platinum chemotherapy as first-line treatment for unresectable advanced or metastatic malignant pleural mesothelioma.

The approval was based on the Phase 3 KEYNOTE-483 trial, which demonstrated improved survival compared to chemotherapy alone.

Trial Results

The hazard ratio of 0.78 (p=0.002) represents a 22% reduction in the risk of death with the pembrolizumab combination.

How It Differs from CheckMate-743

Mesothelioma patients now have two FDA-approved immunotherapy options for first-line treatment:

KEYNOTE-483 offers an alternative for patients who may benefit from receiving chemotherapy alongside immunotherapy, or who may not be candidates for the dual checkpoint inhibitor approach.

Study Design

KEYNOTE-483 enrolled 440 adults with:

• Previously untreated unresectable advanced or metastatic malignant pleural mesothelioma
• All histological subtypes (epithelioid, sarcomatoid, biphasic)
• No prior systemic therapy

Patients were randomized to receive:

• Treatment arm: Pembrolizumab 200 mg every 3 weeks plus pemetrexed and platinum (cisplatin or carboplatin) for up to 4 cycles, followed by pembrolizumab maintenance
• Control arm: Chemotherapy alone

Treatment Schedule

Initial Phase (4 cycles):

• Pembrolizumab 200 mg IV every 3 weeks
• Pemetrexed 500 mg/m² IV every 3 weeks
• Cisplatin 75 mg/m² or Carboplatin AUC 5 IV every 3 weeks

Maintenance Phase:

• Pembrolizumab 200 mg IV every 3 weeks
• Continue until progression, unacceptable toxicity, or up to 35 cycles (~2 years)

Response Across Histologies

The combination showed benefit across all mesothelioma subtypes. Unlike some treatments that work better for epithelioid disease, pembrolizumab plus chemotherapy provided responses in sarcomatoid and biphasic cases as well.

No reliable biomarkers (such as PD-L1 expression) currently predict who will respond best, meaning the treatment benefits patients regardless of PD-L1 status.

Side Effects

The most common adverse events with pembrolizumab plus chemotherapy included:

From Chemotherapy:

• Anemia
• Fatigue
• Nausea
• Neutropenia

From Pembrolizumab (immune-related):

• Rash
• Thyroid dysfunction
• Pneumonitis
• Colitis
• Hepatitis

Immune-related adverse events occurred in approximately 25% of patients and were generally manageable with dose delays or corticosteroids.

What This Means for Patients

More options for first-line treatment: Patients and oncologists can now choose between:

1. Nivolumab + ipilimumab (immunotherapy only)
2. Pembrolizumab + chemotherapy (combination approach)
3. Chemotherapy alone

Factors that may favor pembrolizumab + chemotherapy:

• Desire to include chemotherapy as part of initial treatment
• Concerns about dual checkpoint inhibitor toxicity
• Oncologist recommendation based on individual factors

Clinical Significance

The KEYNOTE-483 approval expands treatment options for mesothelioma patients. As Dr. Evan Alley, mesothelioma specialist, noted: “Having multiple immunotherapy options allows us to tailor treatment to individual patients based on their specific circumstances and preferences.”