First-line Zolbetuximab Plus CAPOX Prolongs Survival in CLDN18.2+/HER2– Unresectable Locally Advanced or Metastatic Gastric/GEJ Adenocarcinoma

The addition of zolbetuximab (IMAB362) to CAPOX led to a statistically significant improvement in progression-free survival (PFS) and overall survival (OS) compared with placebo plus CAPOX as first-line treatment for patients with Claudin-18.2 (CLDN18.2)–positive/HER2-negative, unresectable, locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, according to data from the primary analysis of the phase 3 GLOW trial (NCT03653507).¹

Findings presented at the 2023 March ASCO Plenary Series showed that at a median follow-up of 12.62 months for the experimental arm and 12.09 months for the placebo arm, patients treated with zolbetuximab plus CAPOX (n = 254) achieved a median PFS of 8.21 months (95% CI, 7.46-8.84), compared with 6.8 months (95% CI, 6.14-8.08) for those given placebo plus CAPOX (n = 253; HR, 0.687; 95% CI, 0.544-0.866; P = .0007). Additionally, the median OS was 14.39 months (95% CI, 12.29-16.49) in the experimental arm vs 12.16 months (95% CI, 10.28-13.67) in the control arm (HR, 0.771; 95% CI, 0.615-0.965; P = .0118).

“Across multiple prespecified subgroups, we see that the addition of zolbetuximab was favored [for PFS]. This is true with regard to the number of sites [of metastases], prior gastrectomy, Lauren classification, gender, and age,” presenting study author Manish A. Shah, MD, said in a presentation of the data. Shah is director of the Gastrointestinal Oncology Program at Weill Cornell Medicine, as well as chief of Solid Tumor Service and co-director of the Center for Advanced Digestive Disease at NewYork-Presbyterian in New York, New York.

In previously reported data from the phase 3 SPOTLIGHT trial (NCT03504397), the combination of zolbetuximab and mFOLFOX6 generated an improvement in PFS and OS vs placebo plus mFOLFOX6 in patients with CLDN18.2-positive/HER2-negative unresectable, locally advanced or metastatic gastric/GEJ adenocarcinoma.2 The median PFS was 10.61 months for zolbetuximab plus mFOLFOX6, compared with 8.67 months for placebo plus mFOLFOX6 (HR, 0.751; 95% CI, 0.589-0.942; P = .0066). The median OS was 18.23 months vs 15.54 months for the experimental and control arms, respectively (HR, 0.750; 95% CI, 0.601-0.936; P = .0053).

The global, multi-center, double-blind, randomized GLOW study assessed the efficacy and safety of zolbetuximab plus CAPOX vs placebo plus CAPOX as a first-line treatment for patients with CLDN18.2-positive/HER2-negative, unresectable, locally advanced or metastatic gastric or GEJ cancer.

Patients needed to be CLDN18.2 positive, defined as at least 75% of tumor cells with moderate-to-strong membranous CLDN18.2 staining, and HER2 negative. An ECOG performance status of 0 or 1 was also required.

The study enrolled 507 patients who were randomly assigned 1:1 to 800 mg/m2 of intravenous (IV) zolbetuximab on day 1 of the first 21-day cycle, followed by 600 mg/m2 on day 1 of subsequent cycles, plus CAPOX, consisting of 1000 mg/m2 of oral capecitabine twice per day on days 1 to 14 of each cycle and 130 mg/m2 of IV oxaliplatin on day 1 of each cycle, or the same CAPOX regimen plus placebo. CAPOX was given for 8 cycles in both arms. Patients could continue beyond 8 cycles with zolbetuximab or placebo plus capecitabine at investigator’s decision, and treatment continued until progressive disease or discontinuation criteria were met.

Patients were stratified by region (Asia vs non-Asia), number of organs with metastases (0 to 2 vs 3 or more), and prior gastrectomy (yes vs no).

PFS served as the trial’s primary end point, and OS was a key secondary end point. Other secondary end points included overall response rate (ORR), duration of response (DOR), and safety.

If the primary end point of PFS was statistically significant, investigators were able to evaluate for OS at the primary analysis.

The median age of patients in the zolbetuximab arm and the placebo arm was 61.0 years (range, 22-82) and 59.0 years (range, 21-83), respectively. Shah noted that baseline characteristics were similar between the 2 arms, with the majority of patients being male, from Asia, having 0 to 2 organs with metastases, not having prior gastrectomy, having stomach as the primary tumor site, and having an ECOG performance status of 1.

Additional data showed that the 12- and 24-month PFS rates were 35% and 14%, respectively, for the zolbetuximab arm, vs 19% and 7%, respectively, for the placebo arm. In the experimental arm, the 12- and 24-month OS rates were 58% and 29%, respectively, compared with 51% and 17%, respectively, in the placebo arm.

Patients treated with zolbetuximab plus CAPOX evaluable for response (n = 195) experienced an ORR of 53.8% (95% CI, 46.58%-60.99%), compared with 48.8% (95% CI, 41.76%-55.84%) for those given placebo plus CAPOX (n = 205). In the experimental arm, 3.1% of patients had a complete response (CR), 50.8% had a partial response (PR), 23.6% had stable disease (SD), and 5.1% had progressive disease (PD). The CR, PR, SD, and PD rates in the control arm were 1.5%, 47.3%, 27.8%, and 12.2%, respectively.

The median DOR was 6.28 months (95% CI, 5.39-8.28) in the zolbetuximab arm, compared with 6.18 months (95% CI, 4.53-6.41) in the placebo arm.

Regarding safety, any-grade treatment-emergent adverse effects (TEAEs) were reported in 98.8% of patients in the zolbetuximab group (n = 254), compared with 98.0% in the placebo group (n = 249). Grade 3 or higher TEAEs occurred in 72.8% and 69.9% of patients in the experimental and control arms, respectively. Additionally, 47.2% of patients treated with zolbetuximab plus CAPOX had serious TEAEs, compared with 49.8% for those given CAPOX plus placebo.

The most common any-grade TEAEs included nausea (68.5% and 50.2% in the experimental arm and control arm, respectively), vomiting (66.1% and 30.9%), and decreased appetite (41.3% and 33.7%).

“Most of that nausea/vomiting was experienced in cycle 1, and then by cycle 2, any nausea/vomiting...was less than 10% and equal on both arms. So, this was [generally a] grade 1 toxicity, and once we get through [cycle 1], we’re able to manage it better,” Shah said.

Treatment-related AEs (TRAEs) leading to discontinuation of any study drug occurred in 21.7% of patients in the zolbetuximab arm and 15.7% of patients in the placebo arm. Additionally, 7.1% of patients in the experimental arm discontinued zolbetuximab due to TRAEs, and 4.4% of patients in the control arm discontinued placebo due to TRAEs. TRAEs leading to death occurred in 2.4% of patients in the experimental vs 2.8% of patients in the control arm.

In a discussion of the presentation, Yelena Y. Janjigian, MD, a medical oncologist and chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center in New York, New York, reiterated that given the heterogeneity of gastric cancer and the lack of a single driver of disease in most patients, treatment selection and biomarker identification remains critical for the management of these patients.

“We need to reflexively test all of our patients in all tumors, and if we do that successfully, we find that there is some overlap [in biomarkers],” Janjigian said. “However, in terms of the overlap between patients with a PD-L1 combined positive score of 5 and greater and high CLDN18.2, the prospective data suggest that it is approximately 20% of the population. So [this is] not a very high percentage of patients.”

Editor’s note: Dr Shah reported receiving study funding to the participating institution from Astellas Pharma Inc., Merck, Bristol Myers Squibb, and Oncolys BioPharma, and reported serving in a leadership or fiduciary role on the ASCO Leadership Council.

Dr Janjigian reported stock ownership in Rgenix, serving in a consulting or advisory role with Pfizer, Merck, Bristol Myers Squibb, Merck Serono, Daiichi Sankyo, Rgenix, Bayer, Imugene, AstraZeneca, Eli Lilly, Zymeworks, Basilea Pharmaceutical, MJH Associates, Paradigm Medical Communications, Seagen, AmerisourceBergen, Arcus Biosciences, Geneos Therapeutics, GlaxoSmithKline, Imedex, Lynx Health, PeerView, Silverback Therapeutics, Mersana Therapeutics, and Research to Practice; receiving institutional research funding from Bayer, Rgenix, Bristol Myers Squibb, Merck, Eli Lilly, NCI, Department of Defense, Cycle for Survival, Fred’s Team, and Genentech/Roche; and other relationships with Clinical Care Options, Axis Medical Education, and Research to Practice.

References

1. Xu R, Shitara K, Ajani JA, et al. 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. J Clin Oncol. 2023;41(suppl 36):405736. doi:10.1200/JCO.2023.41.36_suppl.405736
2. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary results from phase 3 SPOTLIGHT study. J Clin Oncol. 2023;41(suppl 4):LBA292. doi:10.1200/JCO.2023.41.4_suppl.LBA292