Abstract CT080: Tremelimumab (T) + durvalumab (D) + chemotherapy (CT) in 1L metastatic NSCLC: Outcomes by blood tumor mutational burden (bTMB) in POSEIDON
Authors: Peters Solange , Madison Hisani , Oliner Kelly , L’Hernault Anne , Ratcliffe Marianne , Barrett Karen , Shi Xiaojin , Garon Edward B. , Mok Tony , Johnson Melissa L. 
Published: April 2023

Background: In the Phase 3 POSEIDON study (NCT03164616), 1L T plus D and platinum-based CT demonstrated statistically significant improvements in both PFS (HR, 0.72; 95% CI, 0.60-0.86; p=0.0003; data cutoff [DCO] July 24, 2019) and OS (HR, 0.77; 95% CI, 0.65-0.92; p=0.0030; DCO March 12, 2021) vs CT in patients (pts) with EGFR/ALK wild-type metastatic (m) NSCLC. On the basis of these results, T+D+CT was approved by the FDA in November 2022 for use in this setting. Here we report outcomes in POSEIDON pt subgroups defined by a range of bTMB values, including a pre-specified cutoff of 20 mutations/megabase (mut/Mb).

Methods: Pts were randomized 1:1:1 to 1L T+D+CT (platinum-based), D+CT or CT, with stratification by tumor cell (TC) PD-L1 expression (TC ≥50% vs &lt;50%; VENTANA PD-L1 [SP263] assay), disease stage (IVA vs IVB) and histology (squamous vs non-squamous). bTMB was assessed using the GuardantOMNI platform. OS, PFS and ORR with T+D+CT vs CT were determined for pts with bTMB ≥ vs &lt;20 mut/Mb. Outcomes across additional bTMB cutoffs (10, 12 and 16 mut/Mb) were also explored.

Results: Plasma samples were available for 958/1013 pts from the intention-to-treat (ITT) population. Of those with available plasma samples, 81.8% (784/958) were evaluable for bTMB, including 277 in the T+D+CT arm and 241 in the CT arm. Similar demographic characteristics and OS were observed in the bTMB evaluable vs ITT populations. Consistent with previous reports, the proportion of never smokers was higher in the bTMB &lt;20 mut/Mb subgroup than in the bTMB ≥20 mut/Mb subgroup. Across all bTMB cutoffs analyzed, OS and PFS benefit for T+D+CT vs CT were generally consistent with the ITT population in both bTMB high and bTMB low subgroups. However, at each bTMB cutoff, OS and PFS benefit appeared more prominent among pts in the bTMB high subgroups. Median OS (mOS) was longer with T+D+CT vs CT in both the bTMB ≥20 mut/Mb and &lt;20 mut/Mb subgroups and HRs suggested more pronounced benefit in the bTMB high group. mOS was 13.5 months with T+D+CT vs 10.3 months with CT (unstratified HR, 0.61; 95% CI, 0.42-0.88) for pts with bTMB ≥20 mut/Mb and 12.6 months vs 10.9 months (unstratified HR, 0.79; 95% CI, 0.63-0.99) for pts with bTMB &lt;20 mut/Mb. PFS and ORR showed similar trends to OS (data will be presented). In both subgroups with PD-L1 TC ≥1% or &lt;1%, HRs suggested more pronounced OS/PFS benefit in pts with bTMB ≥20 (vs &lt;20) mut/Mb (data will be presented).

Conclusions: In pts with mNSCLC, treatment with a limited course of T plus D (until progression) and four cycles of CT consistently improved clinical outcomes vs CT alone in both bTMB high and low subgroups, supporting the use of this regimen as a 1L treatment option for pts with mNSCLC. The clinical benefit vs CT appeared to be greater in pts with higher bTMB over a range of cutoffs, consistent with expectations based on mechanistic biology and previous clinical data.

Citation Format: Solange Peters, Hisani Madison, Kelly Oliner, Anne L’Hernault, Marianne Ratcliffe, Karen Barrett, Xiaojin Shi, Edward B. Garon, Tony Mok, Melissa L. Johnson. Tremelimumab (T) + durvalumab (D) + chemotherapy (CT) in 1L metastatic NSCLC: Outcomes by blood tumor mutational burden (bTMB) in POSEIDON [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT080.