Tremelimumab–Durvalumab Dual Immunotherapy Receives FDA Approval for Lung Cancer

For metastatic (stage 4) non-small cell lung cancer (NSCLC) in adults without EGFR or ALK mutations, tremelimumab (Imjudo, AstraZeneca) and durvalumab (Imfinzi, AstraZeneca) with platinum-based chemotherapy form an immunotherapy combination approved by the FDA (US Food and Drug Administration) on 10 November 2022.

2nd FDA Approval for Tremelimumab Plus Durvalumab

This is the 2nd FDA approval for the anti-CTLA4 tremelimumab and anti-PD-L1 durvalumab immunotherapy combination. In October 2022, it previously received approval for advanced liver cancer.

5th Immunotherapy–Chemotherapy Approval for First-Line NSCLC

This is the 5th immunotherapy–chemotherapy combination to receive FDA approval for first-line advanced non-small cell lung cancer (NSCLC), irrespective of PD-L1. Pembrolizumab, atezolizumab, nivolumab–ipilimumab and cemiplimab immunotherapies had previously been approved with platinum-based chemotherapy for these patients.

FDA Approval Based on the POSEIDON Study

Tremelimumab–durvalumab with platinum-based chemotherapy was evaluated in POSEIDON, a randomised (1:1:1), multicentre, active-controlled, open-label study in previously systemically untreated metastatic NSCLC.

Patients were randomised to one of three treatment arms:

1. Tremelimumab, durvalumab and platinum-based chemotherapy for four cycles, followed by durvalumab every 4 weeks and maintenance chemotherapy. Patients received a fifth tremelimumab dose at week 16;
2. Durvalumab plus platinum-based chemotherapy for four cycles, followed by durvalumab and maintenance chemotherapy; or
3. Platinum-based chemotherapy for six cycles, followed by maintenance chemotherapy.

Treatment continued until disease progression or unacceptable adverse effects. Approval was based on comparison of arms 1 and 3 (675 patients).

The main efficacy outcome measures were progression-free survival and overall survival.

Results

Tremelimumab plus durvalumab and platinum-based chemotherapy significantly improved overall survival, statistically and clinically, compared with platinum-based chemotherapy alone: a 23% reduction in the risk of death (hazard ratio [HR] 0.77 [95% CI: 0.65, 0.92], 2-sided p-value = 0.00304).

Median overall survival was 14 months (95% CI: 11.7, 16.1) in the combined immunotherapy arm and 11.7 months (95% CI: 10.5, 13.1) in the chemotherapy-only arm.

Median progression-free survival in the respective treatment arms was 6.2 months (95% CI: 5.0, 6.5) and 4.8 months (95% CI: 4.6, 5.8) (HR 0.72 [95% CI: 0.60, 0.86], 2-sided p-value = 0.00031).

Overall response rates in arms 1 and 3, respectively, were 39% (95% CI: 34,44) and 24% (95% CI: 20, 29). Median response duration was 9.5 months (95% CI: 7.2, not reached) in the immunotherapy arm and 5.1 months (95% CI: 4.4, 6.0).

The most common adverse effects (occurring in ≥ 20% of patients) were nausea, fatigue, decreased appetite, musculoskeletal pain, rash and diarrhoea. Grade 3 or 4 laboratory abnormalities (≥ 10%) were neutropenia, anaemia, leukopenia, lymphocytopenia, increased lipase, hyponatraemia and thrombocytopenia.

For patients weighing 30 kg or more, the recommended doses are tremelimumab 75 mg, durvalumab 1500 mg IV and platinum-based chemotherapy every 3 weeks for the first 4 cycles, followed by durvalumab 1500 mg every 4 weeks with maintenance chemotherapy. A fifth tremelimumab dose of 75 mg should be given at week 16.

According to the schedule above, for patients weighing 30 kg or less, the recommended tremelimumab dose is 1 mg/kg and the durvalumab dose is 20 mg/kg.