In POSEIDON, first-line durvalumab plus chemotherapy significantly improved progression-free survival (PFS) versus chemotherapy in patients with metastatic non-small cell lung cancer (NSCLC), with a positive trend for overall survival (OS) improvement that did not reach statistical significance. Adding a limited course of tremelimumab to durvalumab and four cycles of chemotherapy in first-line treatment demonstrated statistically significant and clinically meaningful improvements in both PFS and OS versus chemotherapy, alongside early disease control and a manageable tolerability profile. The study findings are published by Dr. Melissa L. Johnson of the Sarah Cannon Research Institute-Tennessee Oncology in Nashville, TN, US and POSEIDON investigators on 3 November 2022 in the Journal of Clinical Oncology.
POSEIDON is a phase III, global, randomised, open-label study with a three-arm design, which evaluated the efficacy of tremelimumab plus durvalumab plus chemotherapy and durvalumab plus chemotherapy versus chemotherapy alone in first-line metastatic NSCLC. The addition of a limited course of anti–CTLA4 to anti–PD-L1 and chemotherapy provides insights into both long-term efficacy and tolerability in the context of common treatment strategies used in the first-line EGFR/ALK wild-type metastatic NSCLC setting. In the article published in the JCO, the study team reports results from the primary and secondary analyses.
In total, 1013 patients with EGFR/ALK wild-type metastatic NSCLC were randomly assigned (1:1:1) to tremelimumab 75 mg plus durvalumab 1,500 mg and platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression and one additional tremelimumab dose; durvalumab plus chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression; or chemotherapy for up to six 21-day cycles with or without maintenance pemetrexed in all arms. Primary endpoints were PFS and OS for durvalumab plus chemotherapy versus chemotherapy. Key alpha-controlled secondary endpoints were PFS and OS for tremelimumab plus durvalumab plus chemotherapy versus chemotherapy.
PFS was significantly improved with durvalumab plus chemotherapy versus chemotherapy (hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.62 to 0.89; p = 0.0009; median, 5.5 versus 4.8 months), but a trend for improved OS did not reach statistical significance (HR 0.86; 95% CI 0.72 to 1.02; p = 0.0758; median, 13.3 versus 11.7 months; 24-month OS, 29.6% versus 22.1%). However, both PFS (HR 0.72; 95% CI 0.60 to 0.86; p = 0.0003; median, 6.2 versus 4.8 months) and OS (HR 0.77; 95% CI 0.65 to 0.92; p = 0.0030; median, 14.0 versus 11.7 months; 24-month OS, 32.9% versus 22.1%) were significantly improved with tremelimumab plus durvalumab plus chemotherapy versus chemotherapy.
Treatment-related adverse events (TRAEs) were maximum grade 3/4 in 51.8%, 44.6%, and 44.4% of patients receiving tremelimumab plus durvalumab plus chemotherapy, durvalumab plus chenotherapy, and chemotherapy, respectively. A total, 15.5%, 14.1%, and 9.9% in three arms discontinued treatment because of TRAEs.
The authors commented that although not formally assessed in the statistical analysis plan, the addition of tremelimumab to durvalumab and chemotherapy led to more durable responses than were observed with durvalumab plus chemotherapy, and a notable separation of the survival curves, particularly at later landmarks. The addition of anti–CTLA4 extended clinical benefit to patients with PD-L1 < 1% which is a subgroup with hard-to-treat disease and outcomes that can be suboptimal in clinical practice with currently available treatments. Tremelimumab plus durvalumab plus chemotherapy may represent a new first-line treatment option in metastatic NSCLC.
In an accompanied editorial, Dr. Jordi Remon of the Department of Cancer Medicine, Gustave Roussy in Villejuif, France and colleagues wrote that POSEIDON endorses that dual immune checkpoint inhibitors (ICIs) plus chemotherapy is safe and feasible in the first-line setting for patients with advanced NSCLC without a targetable oncogenic driver and suggests that the addition of anti-CTLA4 extends clinical benefit to PD-L1 < 1% tumours, a hard-to-treat population.
However, the role of dual ICIs versus monotherapy when combined with chemotherapy or the optimal population for a more intensive regimen is not answered in this study. Just adding new drugs in the current available strategies in an unselected population may not be the most promising avenue to pursue according to the editorialists, who also wrote that despite progress made since the introduction of ICI to the clinic, given the current redundancy of ICI strategies in advanced NSCLC, there is a strong need for innovations in the coming clinical trials.
POSEIDON study was supported by AstraZeneca.
References
Johnson ML, Chul Cho B, Luft A, et al. 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. JCO; Published 3 November 2022. DOI: 10.1200/JCO.22.00975
Remon J, Hendriks LEL, Reck M. The POSEIDON Trial: Will Secondary End Points Change Our Clinical Practice? JCO; Published online 3 November 2022. DOI: 10.1200/JCO.22.01737