286 Background: In a phase 2 study, tislelizumab (TIS), an anti-PD-1 monoclonal antibody, plus chemotherapy demonstrated durable antitumor activity as 1L in Chinese GC/GEJC patients (Xu et al, 2020). RATIONALE 305 (NCT03777657) was a global, double-blind, phase 3 study comparing 1L TIS plus investigator-chosen chemotherapy (TIS+ICC) vs placebo plus ICC (P+ICC) in GC/GEJC patients. Results from the interim analysis (IA) in the PD-L1+ population are presented; ITT population outcomes will be presented after final analysis. Methods: Adults with previously untreated, unresectable locally advanced or metastatic GC/GEJC, regardless of PD-L1 expression, were randomized (1:1) to receive TIS (200 mg IV Q3W) plus ICC (oxaliplatin [130 mg/m² IV Q3W] and oral capecitabine [1,000 mg/m² BID, Days 1-14 Q3W] or cisplatin [80 mg/m² IV Q3W] and 5-fluorouracil [800 mg/m²/day IV, Days 1-5 Q3W]) or P+ICC. Randomization was stratified by region, PD-L1 expression, peritoneal metastasis, and ICC. Patients with known HER2-positive status were excluded. RATIONALE 305 had dual primary endpoints of OS in the PD-L1+ and ITT analysis set; PD-L1+ was defined as PD-L1 TAP score ≥5% (VENTANA SP263 assay) assessed by blinded independent central laboratory. Secondary endpoints include PFS, ORR and DoR per RECIST 1.1, HRQoL, and safety profile. The prespecified IA was conducted after ~70% of total OS events had occurred. Results: Of 546 PD-L1+ patients enrolled from 13 counties/regions (73.8 % Asia; 26.2% Europe/ North America), 274 were randomized to receive TIS+ICC and 272 to receive P+ICC. As of 8 Oct 2021, median follow-up was 11.8 (TIS+ICC) and 11.7 mo (P+ICC). TIS+ICC showed statistically significant and clinically meaningful OS improvement vs P+ICC (HR 0.74 [95% CI: 0.59-0.94], mOS 17.2 vs 12.6 mo; 1-sided P= .0056). Compared with P+ICC, TIS+ICC also had longer PFS (mPFS 7.2 vs 5.9 mo; HR 0.67 [95% CI: 0.55-0.83]), higher ORR (50.4% vs 43.0%), and more durable response (mDoR 9.0 vs 7.1 mo). Patients treated with TIS+ICC reported better HRQoL than patients treated with P+ICC, as indicated by EORTC-QLQ-C30 global health status and physical functioning scores as well as the QLQST022 index score. No new safety signals were observed with TIS+ICC or P+ICC. While TEAEs leading to discontinuation of any treatment were higher with TIS+ICC than P+ICC (22.4% vs 12.1%), incidence rates of grade ≥3 TEAEs (64.7% vs 62.9%), serious TEAEs (42.3% vs 36.8%), and TEAEs leading to death (8.8% vs 7.7%) were comparable between both arms. Conclusions: In RATIONALE 305, TIS+ICC provided significant and clinically meaningful improvement in OS vs P+ICC with well acceptable safety as 1L in PD-L1+ patients with advanced GC/GEJC. These data suggest this combination is a new 1L option for this patient population. Clinical trial information: NCT03777657 .

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TPS4167 Background: Recent data from the KEYNOTE-590 study demonstrated the superiority of pembrolizumab plus chemotherapy compared with chemotherapy as first-line treatment for unresectable locally advanced recurrent or metastatic adenocarcinoma or squamous cell carcinoma of the esophagus, or advanced/metastatic Siewert type 1 adenocarcinoma of the gastroesophageal junction. Prior data also suggest promising antitumor activity of lenvatinib plus pembrolizumab in advanced solid tumors. LEAP-014 (NCT04949256) is a randomized, 2-part, open-label, phase 3 study that will evaluate the efficacy and safety of first-line lenvatinib plus pembrolizumab plus chemotherapy versus pembrolizumab plus chemotherapy in patients with metastatic esophageal squamous cell carcinoma (ESCC). Methods: Key eligibility criteria include histologically or cytologically confirmed metastatic ESCC, measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and Eastern Cooperative Oncology Group performance status 0 to 1. In part 1 (safety run-in), ̃6 patients will be treated for induction with intravenous (IV) pembrolizumab 400 mg every 6 weeks (Q6W) for 2 cycles plus oral lenvatinib 8 mg daily (QD) plus IV 5-fluorouracil (FU; 4000 mg/m2 on days 1-5) plus IV cisplatin (80 mg/m2) (FP) for 4 cycles and treated for consolidation with pembrolizumab 400 mg Q6W for ≤16 doses plus lenvatinib 20 mg QD; patients will be closely monitored for 21 days after the first dose of study intervention for dose-limiting toxicities. In part 2 (main study), approximately 850 patients will be randomly assigned 1:1 to induction with pembrolizumab plus lenvatinib plus chemotherapy (FP or mFOLFOX6 [Q2W for 6 cycles {IV oxaliplatin 85 mg/m2 plus bolus IV 5-FU 400 mg/m2 plus continuous IV 5-FU 2400 mg/m2 plus IV leucovorin 400 mg/m2 or IV levoleucovorin 200 mg/m2}]) followed by consolidation with pembrolizumab plus lenvatinib (arm 1) or pembrolizumab plus chemotherapy (FP or mFOLFOX6; arm 2). Randomization will be stratified by PD-L1 combined positive score (CPS; ≥10 vs < 10), region (East Asia vs North America and Western Europe vs rest of world), and chemotherapy backbone (FP vs mFOLFOX6). Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. Tumor imaging assessment will be performed Q6W for ≤1 year and Q9W thereafter. In part 1, the primary end point is safety and tolerability. In part 2, the dual primary end points are overall survival and progression-free survival (per RECIST v1.1 assessed by blinded independent central review [BICR]); secondary end points include objective response rate and duration of response (per RECIST v1.1 assessed by BICR) and safety and tolerability. Enrollment in this trial is ongoing. Clinical trial information: NCT04949256.

5 Background: Blood-based genomic profiling by ctDNA analysis has a promise to potentially identify actionable genomic alterations. However, utility of clinical sequencing with ctDNA compared with that with tumor tissue for enrolling cancer pts to matched clinical trials remains unclear. Herein we investigated the utility of ctDNA clinical sequencing by the SCRUM-Japan GI-SCREEN and GOZILA Combined Analysis. Methods: In the GI-SCREEN, tumor tissue samples of pts with advanced GI cancer were analyzed by a next generation sequencing (NGS)-based assay, Oncomine Comprehensive Assay since Feb 2015. In the GOZILA, plasma samples of pts with advanced GI cancer were analyzed by an NGS-based ctDNA assay, Guardant360 since Feb 2018. Tests were performed centrally by CLIA-certified and CAP-accredited laboratories. Pts with actionable alterations were enrolled to matched company-sponsored or investigator-initiated clinical trials. Results: As of Apr 2019, test results were generated in 5,029 out of 5,743 pts (88%) in GI-SCREEN and 1,089 out of 1,103 pts (99%) in GOZILA ( P < 0.0001).Median turnaround time (TAT) was 35 days in GI-SCREEN and 12 days in GOZILA ( P < 0.0001). There were no differences in other baseline characteristics between GI-SCREEN and GOZILA. Proportion of enrolling matched clinical trials in GOZILA was significantly higher than that in GI-SCREEN (126 pts [2.2%] in GI-SCREEN vs. 60 pts [5.4%] in GOZILA, P < 0.0001). Median time from GI-SCREEN or GOZILA enrollment to clinical trial enrollment was 5.9 and 1.0 months (mo), respectively ( P < 0.0001). The objective response rate (ORR) and progression-free survival (PFS) were not significantly different (ORR: 17.5 vs. 16.7%, P = 1.00; median PFS: 2.8 vs. 2.0 mo, P = 0.24). Conclusions: Clinical sequencing with ctDNA having the advantage of the shorter TAT enrolled more pts with advanced GI cancer to matched clinical trials than those with tumor tissue, without compromising the efficacy. Clinical trial information: UMIN000029315.

90 Background: Nivolumab (NIVO) monotherapy demonstrated a survival benefit and durable responses in pts with CTx-R adv G/GEJ cancer (Boku N et al ESMO 2017; Janjigian Y et al ASCO 2017). Here we describe the safety profile of NIVO in Asian (A) and Western (W) pts with CTx-R adv G/GEJ who had received ≥ 2 prior CTx in the ATTRACTION-2 and CheckMate-032 trials, respectively. Methods: The safety population included pts who received ≥ 1 dose of study drug at the data cutoff of August 2016 for ATTRACTION-2 and March 2016 for CheckMate-032. TRAEs, serious TRAEs, and select TRAEs (sTRAE; with a potential immune-related etiology) were assessed. sTRAEs were managed using protocol-specified algorithms, which included corticosteroids as immune-modulating treatment (tx). Time to onset and resolution of sTRAEs were also assessed. Results: Median duration of NIVO tx was 1.9 mo in A and 2.3 mo in W pts. TRAEs (any grade) were reported in 43% of A and 64% of W pts; grade 3–4 TRAEs (A pts:10%; W pts:14%), serious TRAEs (A pts:10%; W pts:7%) and TRAEs leading to discontinuation (≤ 3% of pts in both groups) were infrequent. Most sTRAEs were grade 1–2 (Table) and occurred within the first 3 mo of NIVO tx. In A and W pts, median time to resolution of sTRAEs ranged from 3–19 wk. For those sTRAEs that required tx with immune-modulating agents, the median time to resolution of most sTRAEs ranged from 3–35 wk. Conclusions: NIVO demonstrated an acceptable safety profile in both A and W pts with CTx-R adv G/GEJ cancers with no clinically meaningful racial differences. Most sTRAEs were grade 1–2 in both cohorts and manageable using the recommended tx algorithms. Clinical trial information: NCT02267343 ATTRACTION-2 and NCT01928394 CheckMate 032. [Table: see text]