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

Abstract

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.

Trial registration: ClinicalTrials.gov NCT03164616.

Figures

FIG 1.

CONSORT diagram. Data cutoff date: March 12, 2021. aAmong these patients, one patient each randomly assigned to the T + D + CT arm and the D + CT arm did not receive immunotherapy and were included in the CT arm of the safety population; one patient randomly assigned to the T + D + CT arm received durvalumab and tremelimumab but not chemotherapy. bThe most common cause of treatment discontinuations classified as other was investigator's decision (39%). AE, adverse event; CT, chemotherapy; D, durvalumab; ITT, intention-to-treat; T, tremelimumab.

FIG 2.

(A) PFS and (B) OS (ITT) with D + CT versus CT. (C) PFS and (D) OS (ITT) with T + D + CT versus CT. Data cutoff date for PFS: July 24, 2019. Data cutoff date for OS: March 12, 2021. One patient died 1 day before random assignment and was censored at day 1. CT, chemotherapy; D, durvalumab; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; PFS, progression-free survival; T, tremelimumab.

FIG 3.

OS in patient subgroups with (A) D + CT versus CT or (B) T + D + CT versus CT. Data cutoff date: March 12, 2021. The size of circle in the forest plot is proportional to the number of events across both treatment groups. HRs and 95% CIs in the ITT population were estimated using a Cox proportional hazards model stratified by PD-L1 expression status, histology, and disease stage; HRs and 95% CIs in subgroups were estimated using an unstratified Cox proportional hazards model. AJCC, American Joint Committee on Cancer; CT, chemotherapy; D, durvalumab; ECOG, Eastern Cooperative Oncology Group; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; PD-L1, programmed cell death ligand-1; PFS, progression-free survival; T, tremelimumab; TC, tumor cell.

FIG 4.

(A) PFS and (B) OS in patients with nonsquamous histology. (C) PFS and (D) OS in patients with squamous histology. Data cutoff date for PFS: July 24, 2019. Data cutoff date for OS: March 12, 2021. HRs and 95% CIs were calculated using an unstratified Cox proportional hazards model. CT, chemotherapy; D, durvalumab; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; T, tremelimumab.

FIG 5.

Duration of response with (A) T + D + CT versus CT and (B) D + CT versus CT. Data cutoff date: July 24, 2019. Data included are for confirmed response (at least one visit response of complete response or partial response and a confirmatory scan no sooner than 4 weeks after the initial response) by BICR per RECIST v1.1; confirmation was not required per protocol (post hoc analysis). DoR was defined as the time from the first documentation of complete response/partial response until the date of progression, death in absence of progression, or the last evaluable RECIST assessment for patients who progressed or died after two or more missed visits. aN = patients with measurable disease at baseline. BICR, blinded independent central review; CT, chemotherapy; D, durvalumab; DoR, duration of response; NE, not estimable; T, tremelimumab.