1323P - RATIONALE-307 long-term outcomes: First-line tislelizumab (TIS) plus chemotherapy (chemo) vs chemo alone for advanced squamous (sq) NSCLC

Background

First-line TIS + chemo has improved PFS vs chemo alone for advanced sq-NSCLC in RATIONALE-307 (NCT03594747). Here, we reported the long-term outcomes in the ITT population and in patients (pts) with long-term exposure (LTE) to TIS.

Methods

Pts were randomized 1:1:1 to receive TIS + paclitaxel + carboplatin (T+PC arm), TIS + nab-paclitaxel + carboplatin (T+nPC arm), or paclitaxel + carboplatin (PC arm). The primary endpoint was PFS; OS was a secondary endpoint. Crossover from PC 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 the 360 randomized pts (T+PC arm, n=120; T+nPC arm, n=119; PC arm, n=121), median time from randomization to data cutoff (Apr 28, 2023) was 50.3 mo (range, 46.5-57.0). 58.7% (71/121) of pts crossed over to receive TIS monotherapy. The improvement in PFS with TIS + chemo vs chemo (mPFS, 5.5 mo) was maintained, with mPFS of 7.7 mo (HR, 0.45; 95% CI 0.33-0.62) for T+PC and 9.5 mo (HR, 0.45; 95% CI 0.33-0.62) for T+nPC. Median OS was 26.1 vs 19.4 mo with T+PC vs PC (HR, 0.67; 95% CI 0.49-0.92), and 23.3 vs 19.4 mo with T+nPC vs PC (HR, 0.82; 95% CI, 0.60-1.11). 4-y OS rates were 32.2% for T+PC, 26.0% for T+nPC, and 19.2% for PC. After adjusting for the in-study crossover effect, the stratified HRs were 0.53 (95% CI 0.34-0.84) and 0.65 (95% CI 0.39-1.07), respectively. 42 (17.6%) pts with LTE were observed in TIS+chemo arms, with median treatment cycles of 58 (range 37-71), 4-y OS rate of 97.5%, and ORR of 100% (CR, n=11; PR, n=31). The profile of imAEs in LTE pts was similar to the overall population of TIS + chemo arms. Higher PD-L1 expression, tumor inflammation signature levels (TISL), and enriched FAT1 mutations (LTE vs non-LTE, 34.6% [9/26] vs 15.4% [23/149]) were observed in LTE pts.

Conclusions

The OS benefit favoring TIS + chemo was well maintained, with clinically promising 4-y OS rates of 32.2% with T+PC and 26.0% withT+nPC. LTE pts achieved higher ORR and long-term survival, with higher baseline PD-L1 expression and TISL; the FAT1 mutation may play an indicative role for LTE, which needs to be further explored.

Clinical trial identification

NCT03594747.

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

BeiGene, Ltd.

Disclosure

N. Zhao: Other, Personal, Full or part-time Employment: BeiGene (Shanghai) Co., Ltd. L. Liang, J. Fan: Financial Interests, Personal, Full or part-time Employment: BeiGene (Beijing) Co., Ltd. All other authors have declared no conflicts of interest.