The FDA has approved tremelimumab (Imjudo®, AstraZeneca) in combination with durvalumab (Imfinzi®, AstraZeneca) and platinum-based chemotherapy for patients with metastatic non–small cell lung cancer (NSCLC) who have no sensitizing epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) genomic tumor aberrations. Tremelimumab is a fully human immune checkpoint inhibitor against CTLA-4.
"Although some patient subsets, such as those with higher levels of tumor programmed death ligand 1 (PD-L1) expression, derive favorable long-term outcomes with anti–PD-L1 therapy, the unmet needs of others are becoming better understood with clinical experience," wrote Melissa Johnson, MD, Program Director of Lung Cancer Research at Sarah Cannon Research Institute, and colleagues, in their published results of the POSEIDON trial (NCT03164616), on which the approval was based. "For example, patients with PD-L1–low or PD-L1–negative tumors are less likely to respond to anti–PD-L1 therapy, underlying the need for new therapeutic strategies with immunotherapy combinations in this setting."
The multicenter, active-controlled, open-label, phase 3 trial enrolled 1,013 patients with metastatic NSCLC who had not received prior systemic therapy. Patients were randomized 1:1:1 to receive 75 mg tremelimumab plus 1,500 mg durvalumab and platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab once every four weeks until disease progression, with a fifth dose of tremelimumab at Week 16 (Arm 1); durvalumab with platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab and maintenance chemotherapy (Arm 2); or platinum-based chemotherapy for up to six 21-day cycles, followed by maintenance chemotherapy (Arm 3). The trial's primary end points were progression-free survival and overall survival, with prespecified secondary end points of overall response rate and duration of response. A comparison of Arms 1 and 3, consisting of a total of 675 patients, served as the basis for the approval.
Tremelimumab in combination with durvalumab and platinum-based chemotherapy produced a statistically significant, clinically meaningful improvement in median overall survival compared with chemotherapy alone (14.0 vs 11.7 months). The tremelimumab combination group also saw improvements in median progression-free survival (6.2 vs 4.8 months), overall response rate (39% vs 24%), and median duration of response (9.5 vs 5.1 months) compared with chemotherapy alone.
The most common adverse events occurring in ≥20% of patients were nausea, fatigue, decreased appetite, musculoskeletal pain, rash, and diarrhea. Grade 3 or 4 laboratory abnormalities occurring in ≥10% of patients included neutropenia, anemia, leukopenia, lymphocytopenia, increased lipase, hyponatremia, and thrombocytopenia.
"Adding a limited course of tremelimumab to durvalumab and four cycles of chemotherapy provided long-term survival benefits for patients with metastatic NSCLC, alongside early disease control and a manageable tolerability profile, without compromising treatment exposure," concluded Dr. Johnson and colleagues in their results. "Tremelimumab plus durvalumab plus chemotherapy may represent a new first-line treatment option in metastatic NSCLC."
For patients weighing at least 30 kg, the recommended dosage is 75 mg tremelimumab administered intravenously (IV) every 3 weeks, in combination with 1,500 mg durvalumab IV and maintenance chemotherapy every four weeks. At Week 16, a fifth dose of 75 mg tremelimumab should be given. For patients weighing 30 kg or less, the recommended dose is 1 mg/kg tremelimumab and 20 mg/kg durvalumab, following the same schedule.
For More Information
Johnson ML, Cho BC, Luft A, et al (2022). Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non–small cell lung cancer: the phase III POSEIDON study. J Clin Oncol. [Epub ahead of print] DOI:10.1200/JCO.22.00975
Clinicaltrials.gov (2022). Study of durvalumab + tremelimumab with chemotherapy or durvalumab with chemotherapy or chemotherapy alone for patients with lung cancer (POSEIDON). NLM identifier: NCT03164616.
Imjudo® (tremelimumab) prescribing information (2022). AstraZeneca. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761270s000lbl.pdf
Imfinzi® (durvalumab) prescribing information (2022). AstraZeneca. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761069s033lbl.pdf
US Food & Drug Administration (2022). FDA approves tremelimumab in combination with durvalumab and platinum-based chemotherapy for metastatic non–small cell lung cancer. Available at: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tremelimumab-combination-durvalumab-and-platinum-based-chemotherapy-metastatic-non
Imagre credit: Yale Rosen. Licensed under CC BY-SA 2.0