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

Author(s): Melissa L. Johnson, MD¹; Byoung Chul Cho, MD, PhD²; Alexander Luft, MD³; Jorge Alatorre-Alexander, MD⁴; Sarayut Lucien Geater, MD⁵; Konstantin Laktionov, MD⁶; Sang-We Kim, MD, PhD⁷; Grygorii Ursol, MD⁸; Maen Hussein, MD⁹; Farah Louise Lim, MBBS, MRCP¹⁰; Cheng-Ta Yang, MD¹¹; Luiz Henrique Araujo, MD, PhD¹²; Haruhiro Saito, MD, PhD¹³; Niels Reinmuth, MD, PhD¹⁴; Xiaojin Shi, MD¹⁵; Lynne Poole, MSc¹⁶; Solange Peters, MD, PhD¹⁷; Edward B. Garon, MD¹⁸; and Tony Mok, MD¹⁹for the POSEIDON investigators

Source: DOI: 10.1200/JCO.22.00975 Journal of Clinical Oncology 41, no. 6 (February 20, 2023) 1213-1227.

Dr. Maen Hussein's Thoughts

Another option for combination chemo immunotherapy; we have a clinical trial in FCS now with another combination of chemotherapy + PD-L1 and TIGIT inhibitors, PLEASE CONSIDER IT FOR UNRESECTABLE NSCLC patients.

PURPOSE

The open-label, phase III POSEIDON study evaluated tremelimumab plus durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D + CT) versus chemotherapy alone (CT) in first-line metastatic non–small-cell lung cancer (mNSCLC).

METHODS

Patients (n = 1,013) with EGFR/ALK wild-type mNSCLC 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; all arms). Primary end points were progression-free survival (PFS) and overall survival (OS) for D + CT versus CT. Key alpha-controlled secondary end points were PFS and OS for T + D + CT versus CT.

RESULTS

PFS was significantly improved with D + CT versus CT (hazard ratio [HR], 0.74; 95% CI, 0.62 to 0.89; P = .0009; median, 5.5 v 4.8 months); a trend for improved OS did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.02; P = .0758; median, 13.3 v 11.7 months; 24-month OS, 29.6% v 22.1%). PFS (HR, 0.72; 95% CI, 0.60 to 0.86; P = .0003; median, 6.2 v 4.8 months) and OS (HR, 0.77; 95% CI, 0.65 to 0.92; P = .0030; median, 14.0 v 11.7 months; 24-month OS, 32.9% v 22.1%) were significantly improved with T + D + CT versus CT. Treatment-related adverse events were maximum grade 3/4 in 51.8%, 44.6%, and 44.4% of patients receiving T + D + CT, D + CT, and CT, respectively; 15.5%, 14.1%, and 9.9%, respectively, discontinued treatment because of treatment-related adverse events.

CONCLUSION

D + CT significantly improved PFS versus CT. A limited course of tremelimumab added to durvalumab and chemotherapy significantly improved OS and PFS versus CT, without meaningful additional tolerability burden, representing a potential new option in first-line mNSCLC.

Author Affiliations

¹Sarah Cannon Research Institute, Tennessee Oncology, PLLC, Nashville, TN²Yonsei Cancer Center, Seoul, South Korea³Leningrad Regional Clinical Hospital, St Petersburg, Russia⁴Health Pharma Professional Research, Mexico City, Mexico⁵Prince of Songkla University, Songkhla, Thailand⁶Federal State Budgetary Institution “N.N. Blokhin National Medical Research Center of Oncology” of the Ministry of Health of the Russian Federation (N.N. Blokhin NMRCO), Moscow, Russia⁷Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea⁸Acinus, Kropyvnytskyi, Ukraine⁹Florida Cancer Specialists—Sarah Cannon Research Institute, Leesburg, FL¹⁰Queen Mary University of London, London, United Kingdom¹¹Chang Gung Memorial Hospital, Taoyuan City, Taiwan¹²Instituto Nacional de Cancer-INCA, Rio de Janeiro, Brazil¹³Kanagawa Cancer Center, Yokohama, Japan¹⁴Asklepios Lung Clinic, member of the German Center for Lung Research (DZL), Munich-Gauting, Germany¹⁵AstraZeneca, Gaithersburg, MD¹⁶AstraZeneca, Cambridge, United Kingdom¹⁷Centre Hospitalier Universitaire Vaudois, Lausanne University, Lausanne, Switzerland¹⁸David Geffen School of Medicine at UCLA, Los Angeles, CA¹⁹State Key Laboratory of Translational Oncology, Department of Clinical Oncology, Chinese University of Hong Kong, Hong Kong, China

Amivantamab Plus Lazertinib in Atypical EGFR-Mutated Advanced Non–Small Cell Lung Cancer: Results From CHRYSALIS-2

The CHRYSALIS-2, the cohort C analysis of patients with atypical EGFR mutations showed meaningful and durable activity. Atypical mutations can be difficult to deal with as a clinician, and having concrete data on these (S768I, L861Q and G719ZX) mutations gives assurance that this doublet is active. Overall response rate (ORR) was 52% and median progression-free survival (PFS) was 11.1 months in refractory patients and 19.5 months in the treatment-naive population.

Survival with Osimertinib plus Chemotherapy in EGFR-Mutated Advanced NSCLC

The final overall survival (OS) analysis from the FLAURA2 confirms the well-published findings that Osi + chemo improves survival over Osi monotherapy. OS difference was about 10 months at 47 vs 37 months, with a predictable toxicity tradeoff.

Updated Overall Survival Analysis From the Phase II PHAROS Study of Encorafenib Plus Binimetinib in Patients With BRAF V600E-Mutant Metastatic Non–Small Cell Lung Cancer

This update demonstrated that encorafenib plus binimetinib was associated with the longest median overall survival (mOS) reported to date among targeted therapies in patients with treatment-naïve BRAF V600E–mutant metastatic NSCLC (mNSCLC). Median OS was 47.6 months in treatment-naïve patients. By the way check the authors there 😊.

Simultaneous Durvalumab and Platinum-Based Chemoradiotherapy in Unresectable Stage III Non–Small Cell Lung Cancer: The Phase III PACIFIC-2 Study

PACIFIC-2 was a phase III trial testing durva given concurrently with cCRT (and continued as consolidation) versus placebo + cCRT in unresectable stage III NSCLC, and it did not meet its primary endpoint. The overall response rate (ORR) was essentially identical (60.7% vs 60.6%), and pneumonitis rates were similar (any grade 28.8% vs 28.7%; grade ≥3: 4.6% vs 5.6%), but adverse events (AEs) leading to discontinuation and fatal AEs were higher with durva (25.6% vs 12.0%; 13.7% vs 10.2%), especially early on. Starting IO up front with cCRT didn’t improve outcomes and added early toxicity—consolidation durva after cCRT is still the way to go.

Sevabertinib in Advanced HER2-Mutant Non–Small-Cell Lung Cancer

Sevabertinib shows strong efficacy in HER2-mutant NSCLC, with an overall response rate (ORR) of 64% and median progression-free survival (PFS) of 8.3 months in previously treated, HER2-TKI–naive patients, and an overall response rate (ORR) of 71% with a duration of response (DOR) of 11.0 months in first-line therapy. Activity is highest in TKD mutations, especially Y772_A775dupYVMA, and intracranial responses are seen. Safety is manageable: diarrhea is common but mostly low grade, with grade ≥3 in 5–23% and rare discontinuations. Notably, interstitial lung disease (ILD) was not observed. These data position sevabertinib as a viable oral TKI alongside ADCs for HER2-mutant NSCLC, particularly for TKD/YVMA disease.