On 10 November 2022, the US Food and Drug Administration (FDA) approved tremelimumab (Imjudo, AstraZeneca Pharmaceuticals) in combination with durvalumab (Imfinzi, AstraZeneca Pharmaceuticals) and platinum-based chemotherapy for adult patients with metastatic non-small cell lung cancer (NSCLC) with no sensitising epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumour aberrations.
Efficacy was evaluated in POSEIDON (NCT03164616), a randomised (1:1:1), multicentre, active-controlled, open-label study in patients with metastatic NSCLC who had not received prior systemic treatment. Patients were randomised to one of three treatment arms: 1. tremelimumab, durvalumab, and platinum-based chemotherapy for 4 cycles, followed by durvalumab and maintenance chemotherapy every 4 weeks; patients were treated with a fifth tremelimumab dose at week 16; 2. durvalumab plus platinum-based chemotherapy for 4 cycles followed by durvalumab and maintenance chemotherapy; or 3. platinum-based chemotherapy for 6 cycles followed by maintenance chemotherapy.
Treatment was continued until disease progression or unacceptable toxicity. This approval is based on a comparison of treatment arm 1 and 3 (675 patients).
The major efficacy outcome measures were progression-free survival (PFS) assessed by using blinded independent central review according to RECIST v1.1. and overall survival (OS). Tremelimumab plus durvalumab and platinum-based chemotherapy demonstrated a statistically significant and clinically meaningful improvement in OS compared to platinum-based chemotherapy (hazard ratio [HR] of 0.77, 95% confidence interval [CI] 0.65, 0.92; 2-sided p-value = 0.00304); median OS was 14 months (95% CI 11.7, 16.1) and 11.7 months (95% CI 10.5, 13.1) in the treatment arm 1 and 3, respectively. Median PFS was 6.2 months (95% CI 5.0, 6.5) and 4.8 months (95% CI 4.6, 5.8) in the treatment arms, respectively (HR 0.72, 95% CI 0.60, 0.86; 2-sided p-value = 0.00031).
Overall response rate was 39% (95% CI 34,44) in and 24% (95% CI 20, 29) in the treatment arm 1 and 3, respectively. Median duration of response was 9.5 months (95% CI 7.2, not reached) and 5.1 months (95% CI 4.4, 6.0) in the two treatment arms.
The most common adverse reactions (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, lipase increased, hyponatraemia, and thrombocytopenia.
The recommended tremelimumab dose for patients weighing 30 kg or more is 75 mg i.v. every 3 weeks with durvalumab 1500 mg i.v. and platinum-based chemotherapy for 4 cycles, then durvalumab 1500 mg with maintenance chemotherapy every 4 weeks. A fifth tremelimumab dose (75 mg) should be given at week 16.
Using the above schedule, for patients weighing 30 kg or less, the recommended tremelimumab dose is 1 mg/kg and the durvalumab dose is 20 mg/kg.
This review used the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.
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