Zolbetuximab + CAPOX in 1L claudin-18.2+ (CLDN18.2+)/HER2− locally advanced (LA) or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary phase 3 results from GLOW.

Abstract

405736 Background: There is an unmet need for novel targeted therapies that improve outcomes for pts with HER2− LA unresectable or mG/GEJ adenocarcinoma. CLDN18.2 is expressed in normal gastric mucosa cells and retained in most G/GEJ adenocarcinomas. In the phase 3 SPOTLIGHT study, zolbetuximab, a CLDN18.2-targeted chimeric monoclonal antibody, significantly prolonged PFS and OS in pts with CLDN18.2+/HER2− LA unresectable or mG/GEJ adenocarcinoma when combined with mFOLFOX6. GLOW (NCT03653507) is a phase 3 global, double-blind study comparing zolbetuximab or PBO with capecitabine and oxaliplatin (CAPOX) as 1L treatment for this pt population. Methods: Pts with CLDN18.2+ (moderate-to-strong membranous CLDN18 staining in ≥75% tumor cells by IHC)/HER2− LA unresectable or mG/GEJ adenocarcinoma were randomized 1:1 to zolbetuximab IV 800 mg/m2 (cycle 1, day [D] 1) followed by 600 mg/m2 (D1 in subsequent cycles) + CAPOX (oral capecitabine 1000 mg/m2 BID on D1−14 of each cycle; oxaliplatin IV 130 mg/m2 on D1 of each cycle) for eight 21-day cycles vs PBO + CAPOX; pts continued for >8 cycles with zolbetuximab or PBO, plus capecitabine (investigator decision), until PD or a discontinuation criterium was met. The primary endpoint (EP) was PFS per RECIST v1.1 by IRC. OS was a key secondary EP; other secondary EPs included ORR and safety. Differences between treatment arms in PFS and OS were tested by stratified log-rank tests; OS was tested if PFS was significant. Results: 507 pts were randomized 1:1 to zolbetuximab + CAPOX (N = 254) or PBO + CAPOX (N = 253). Both PFS (median 8.21 vs 6.80 mo, HR 0.687, P=0.0007) and OS (median 14.39 vs 12.16 mo, HR 0.771, P=0.0118) were significantly prolonged with zolbetuximab + CAPOX (Table); in pts with measurable disease, ORR (95% CI) was 53.8% (46.58−60.99) vs 48.8% (41.76−55.84) in zolbetuximab vs PBO arm. The most common TEAEs with zolbetuximab + CAPOX were nausea (68.5% vs 50.2% in zolbetuximab vs PBO arm), vomiting (66.1% vs 30.9%), and decreased appetite (41.3% vs 33.7%); serious TEAEs (47.2% vs 49.8%), grade ≥3 TEAEs (72.8% vs 69.9%), and drug-related TEAEs leading to death (2.4% vs 2.8%) were similar in both arms. Conclusions: Targeting CLDN18.2 with zolbetuximab combined with CAPOX significantly prolonged PFS and OS in 1L pts with CLDN18.2+/HER2− LA unresectable or mG/GEJ adenocarcinoma. These results align with those observed in SPOTLIGHT and establish zolbetuximab + chemotherapy as a potential new standard-of-care option for these pts. Clinical trial information: NCT03653507 . [Table: see text]

A narrative review of the evolving landscape of the management of metastatic gastric cancer: the role of targeted therapies

“…A survival benefit was also demonstrated in the investigational group with a significant reduction in the risk of death vs. placebo (HR: 0.75; 95% CI: 0.60–0.94; P=0.0053) ( 56 ). Similar results were replicated in the GLOW trial, a global, randomized, placebo-controlled, double-blind, phase 3 trial ( 57 ). Here, CAPOX was used instead of mFOLFOX6.…”

“…Here, CAPOX was used instead of mFOLFOX6. Both mOS (14.39 vs. 12.16 months; HR: 0.771; P=0.0118) and mPFS (8.21 vs. 6.80 months; HR: 0.687; P=0.0007) were found to be significantly prolonged with zolbetuximab compared to placebo ( 57 ). Of note, CLDN18.2-positivity was fairly common, seen in 40% of screened patients in both trials ( 56 , 57 ).…”

“…Both mOS (14.39 vs. 12.16 months; HR: 0.771; P=0.0118) and mPFS (8.21 vs. 6.80 months; HR: 0.687; P=0.0007) were found to be significantly prolonged with zolbetuximab compared to placebo ( 57 ). Of note, CLDN18.2-positivity was fairly common, seen in 40% of screened patients in both trials ( 56 , 57 ). Zolbetuximab remains investigational, but both the GLOW and SPOTLIGHT trials support its use in CLDN18.2-positive, HER2-negative, locally advanced unresectable or metastatic gastric cancer in the first-line setting.…”

The Present and Future of Neoadjuvant and Adjuvant Therapy for Locally Advanced Gastric Cancer

“…Preliminary results from the GLOW trial have validated the results of the SPOTLIGHT trial [111]. This trial found that zolbetuximab in combination with capecitabine and oxaliplatin (CAPOX) extended OS in patients with unresectable locally advanced or metastatic CLDN 18.2+ GC compared to placebo and CAPOX (14.4 versus 12.2 months, HR = 0.771, p = 0.0118) [111].…”

HER2-Positive Gastric Cancer: The Role of Immunotherapy and Novel Therapeutic Strategies

“…Zolbetuximab is a first-in-class monoclonal antibody that binds to the protein claudin 18.2. Targeting this protein has demonstrated promising results in HER2-negative patients, as observed in the clinical trials SPOTLIGHT (NCT03504397) [134] and GLOW (NCT03653507) [135], in which Zolbetuximab was tested in association with first-line chemotherapy. The ongoing ILUS-TRO trial will provide information in pre-treated HER2-positive gastric cancer patients, with results still pending.…”