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.

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.