Final overall survival results from phase 3 SPOTLIGHT study evaluating zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin 18 isoform 2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma.

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4036 Background: The phase 3 SPOTLIGHT study showed statistically significant improvements in progression-free survival (PFS) and overall survival (OS) with 1L zolbetuximab + modified folinic acid, 5-FU, and oxaliplatin regimen (mFOLFOX6) vs placebo (PBO) + mFOLFOX6 in pts with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma at prespecified interim and later updated analyses. We present the prespecified final OS analysis. Methods: Pts were randomly assigned 1:1 to zolbetuximab IV 800 mg/m2 (cycle 1, day [D] 1) followed by 600 mg/m2 (every 3 weeks) + mFOLFOX6 IV (D1, D15, D29) for four 42-day cycles or to PBO + mFOLFOX6; pts without PD continued with zolbetuximab or PBO, + folinic acid and 5-FU at investigator’s discretion, until PD or discontinuation criteria were met. The primary endpoint was PFS per RECIST v1.1 by IRC. OS was a key secondary endpoint; additional secondary endpoints were objective response rate (ORR) and safety. Ad hoc analyses examined PFS and OS in per-protocol set population (PPS; pts adherent to protocol) and time to progression (TTP) by best overall response (BOR). Results: At data cutoff (September 8, 2023), 565 pts were assigned to zolbetuximab arm (n = 283) or PBO arm (n = 282). In zolbetuximab vs PBO arms, median follow-up was 18.04 vs 17.91 mo for PFS and 33.28 vs 31.38 mo for OS, respectively. Efficacy results are summarized in Table. Median PFS and OS were significantly longer in zolbetuximab vs PBO arms. Separation of PFS and OS curves occurred earlier in the PPS population analysis (excluded majority of early withdrawals) compared with the ITT population. ORR was similar between treatment arms in ITT and pts with measurable lesions – despite this, TTP for patients with BOR of CR/PR was numerically longer in zolbetuximab vs PBO arms. Safety and tolerability were maintained with no new findings. Conclusions: Zolbetuximab + mFOLFOX6 continued to demonstrate statistically significant and clinically meaningful improvement in PFS and OS vs PBO + mFOLFOX6, with no new safety signals—supporting zolbetuximab + mFOLFOX6 as a new standard of care option for 1L treatment of pts with CLDN18.2+, HER2–, LA unresectable or mG/GEJ adenocarcinoma. Clinical trial information: NCT03504397 . [Table: see text]

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