Abstract 632P
Background
First-line TIS + chemo improved PFS vs chemo in patients (pts) with metastatic NSQ NSCLC without sensitizing EGFR/ALK alterations in the RATIONALE-304 study (NCT03663205). Here, we reported updated results with around 4-year follow-up and outcomes of pts with long-term exposure (LTE) to TIS.
Methods
Pts were randomized 2:1 to received 4-6 cycles of TIS + carboplatin/cisplatin and pemetrexed or chemo alone every 3 weeks, followed by maintenance TIS + pemetrexed or pemetrexed only, until PD/unacceptable toxicity. The primary endpoint was PFS assessed by IRC; secondary points included OS and safety. Crossover from the chemo arm to TIS monotherapy was permitted after PD, OS was adjusted by two-stage method. LTE was defined as ≥35 cycles of TIS treatment. PD-L1 expression, TMB, gene expression profiling, and genetic alterations were assessed on baseline tumor samples.
Results
Among 334 randomized pts (TIS + chemo, n = 223; chemo, n = 111) in the ITT population, median time from randomization to data cutoff (Apr 26, 2023) was 49.4 mo (range, 44.9-57.1). 37.8% (42/111) of pts crossed over to receive TIS monotherapy. Median PFS was 9.8 vs 7.6 mo with TIS + chemo vs chemo (HR, 0.61, 95% CI 0.46-0.82). Median OS was 21.4 vs 20.1 mo (stratified HR, 0.87; 95% CI 0.65‒1.17), with 4-y OS rates of 32.8% vs 29.7%, respectively. After adjusting for the in-study crossover effect, the stratified OS HR was 0.67 (95% CI 0.48-0.95). 38 pts (17.0%) with LTE were observed in TIS + chemo arm, with median treatment cycles of 52.5 (range, 36-77), ORR of 100% (CR, n=10; PR, n=28), and 4-y OS rate of 89.3%. The profile of imAEs in LTE pts was generally similar to the overall population of TIS + chemo arm. Higher PD-L1 expression, TMB, tumor inflammation signature levels (TISL), and a notable enrichment of LRP1B mutations (LTE vs non-LTE, 61.9% [13/21] vs 14.0% [13/93]) were observed in LTE pts.
Conclusions
The OS benefit trend was well maintained, with a clinically promising 4-y OS rate of 32.8% in TIS + chemo arm. Among pts in the TIS+chemo arm, LTE pts showed higher ORR and long-term survival, with higher baseline PD-L1 expression, TMB, and TISL; the presence of LRP1B mutation may be an indicator for potential LTE of TIS treatment.
Clinical trial identification
NCT03663205.
Editorial acknowledgement
Legal entity responsible for the study
BeiGene. Ltd.
Funding
BeiGene. Ltd.
Disclosure
N. Zhao, L. Liang, M. Song: Financial Interests, Personal, Full or part-time Employment: BeiGene. Ltd. All other authors have declared no conflicts of interest.