Zolbetuximab Plus Chemotherapy Offers Survival Benefits in Treatment-Naive HER2– Gastric/GEJ Cancer

The Claudin 18.2 (CLDN18.2)-targeted IgG1 monoclonal antibody zolbetuximab (Vyloy) in combination with frontline chemotherapy extended progression-free survival (PFS) and overall survival (OS) vs placebo plus chemotherapy in patients with HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma whose disease was positive for CLDN18.2, according to data from a combined analysis of the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials. These data were published in the New England Journal of Medicine. Findings from the studies supported the October 2024 FDA approval of zolbetuximab plus fluoropyrimidine- and platinum- containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic, HER2-negative gastric or GEJ adenocarcinoma whose tumors are CLDN18.2 positive, as determined by an FDA-approved test.^1,2

Across the 2 studies, patients who received zolbetuximab (n = 537) achieved a median PFS of 9.2 months (95% CI, 8.4-10.4) compared with 8.2 months (95% CI, 7.6-8.4) among patients in the placebo arm (n = 535; HR, 0.71; 95% CI, 0.61-0.83). The median OS was 16.4 months (95% CI, 15.0-17.9) vs 13.7 months (95% CI, 12.3-15.3), respectively (HR, 0.77; 95% CI, 0.67-0.89).

“There were some differences in patient characteristics and country distribution, as well as the chemotherapy backbone, [between SPOTLIGHT and GLOW], so we wanted to perform a pooled analysis,” Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology at the National Cancer Center Hospital East in Japan and first author of the pooled analysis, said in an interview with OncologyLive. “[We observed] a 29% reduction in the risk of progression or death [with zolbetuximab vs placebo]. Looking at the survival curves, there’s a nice separation between the 2 arms. An updated analysis of survival may change the shape of the Kaplan- Meier curves, but this study showed a very nice separation between the 2 arms.”

The baseline characteristics in the pooled analysis were well balanced between the zolbetuximab/chemotherapy and placebo/chemotherapy arms; the median age was 61.0 years (range, 22.0-83.0) vs 60.0 years (range, 20.0- 86.0). Most patients in both arms were men (62.4% vs 61.9%), were not from Asia (54.4% vs 53.8%), had 0 to 2 organs with metastases (76.0% vs 76.1%), did not undergo a prior gastrectomy (70.4% vs 70.7%), had the stomach as their primary disease site (81.6% vs 78.3%), and had an ECOG performance status of at least 1 (56.2% vs 57.8%).

In the safety population of the zolbetuximab arm (n = 533), any-grade treatment-emergent adverse effects (TEAEs) occurred in 99.2% of patients, including events of at least grade 3 severity (80.7%) and serious TEAEs (48.0%). Treatment-related adverse effects (TRAEs) leading to dose interruption of any study drug (72.2%), dose interruption of zolbetuximab (53.7%), discontinuation of any study drug (30.8%), discontinuation of zolbetuximab (10.5%), and death (2.1%) were also reported.

The most common any-grade TEAEs in the zolbetuximab arm included nausea (76.0%), vomiting (66.8%), and decreased appetite (45.2%). Grade 3 or higher TEAEs included neutropenia (18.2%), decreased neutrophil count (17.8%), and vomiting (14.3%).

“There were no new safety concerns [with zolbetuximab] at this updated follow-up,” Shitara said. “Gastrointestinal toxicity, such as nausea and vomiting, is more frequently observed with zolbetuximab [compared with] placebo. But, as previously described, these events mostly happen at first infusion and clearly decrease over subsequent cycles.”

Comparatively, in the safety population of the placebo arm (n = 527), any-grade TEAEs, grade 3 or higher TEAEs, and serious TEAEs were reported at rates of 98.9%, 74.8%, and 48.4%, respectively. TRAEs leading to dose interruption of any study drug (45.2%), dose interruption of placebo (19.0%), discontinuation of any study drug (23.3%), discontinuation of placebo (3.4%), and death (2.3%) also occurred.

In the placebo arm, the most common any-grade TEAEs included nausea (56.2%), diarrhea (40.2%), and anemia (37.8%). Grade 3 or higher TEAEs included decreased neutrophil count (17.6%), neutropenia (13.7%), and anemia (10.2%).

Additional efficacy findings from the pooled analysis demonstrated that the objective response rate (ORR) in the zolbetuximab group was 45.4% (95% CI, 41.2%-49.8%) with a 6.0% complete response (CR) rate vs 43.6% (95% CI, 39.3%-47.9%) with a 3.2% CR rate in the placebo arm. The median duration of response (DOR) was 8.1 months (95% CI, 6.4-9.0) vs 6.5 months (95% CI, 6.2-7.7).

Data from a subgroup analysis showed that patients in every subgroup experienced a PFS benefit with zolbetuximab vs placebo except for those with GEJ cancer (HR, 1.12; 95% CI, 0.80-1.57; Table).¹ Similarly, every subgroup experienced an OS benefit with zolbetuximab vs placebo except for patients with GEJ cancer (HR, 1.02; 95% CI, 0.76-1.39).

GLOW Examines Zolbetuximab Plus CAPOX

GLOW was a global, double-blind study that enrolled adult patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Eligibility criteria included moderate to strong CLDN18 membranous staining on at least 75% of tumor cells per immunohistochemistry, an ECOG performance status of 1 or less, radiologically evaluable disease by RECIST 1.1, and adequate organ function. CLDN18.2 positivity was determined using the investigational VENTANA CLDN18 (43-14A) RxDx Assay.³

Patients were randomly assigned 1:1 to receive intravenous (IV) zolbetuximab 800 mg/m² on day 1 of cycle 1, followed by 600 mg/m² on day 1 of subsequent cycles or placebo. Both arms also received oral capecitabine (Xeloda) 1000 mg/m² twice daily on days 1 through 14 of each cycle and IV oxaliplatin 130 mg/m² on day 1 of each cycle for eight 21-day cycles. Treatment in both arms, with the exception of oxaliplatin, continued until disease progression, unacceptable toxicity, start of another anticancer therapy, or occurrence of other discontinuation criteria.

The primary end point was PFS per RECIST 1.1 by independent review committee (IRC). OS and time to confirmed deterioration were the key secondary end points, with additional secondary end points including ORR, DOR, and safety.

SPOTLIGHT Evaluates Zolbetuximab/mFOLFOX6 Combination

SPOTLIGHT was global, placebo-controlled, double-blind trial that enrolled adult patients with CLDN18.2-positive, HER2-negative, treatment- naive locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. Key inclusion criteria included having radiologically evaluable disease per RECIST 1.1, an ECOG performance status of 1 or less, and adequate organ function.⁴

Eligible patients were randomly assigned 1:1 to receive IV zolbetuximab 800 mg/m2 on day 1 of cycle 1, followed by 600 mg/m² on day 22 of cycle 1 and days 1 and 22 of subsequent cycles or placebo. Patients in both arms also received IV folinic acid 400 mg/m² or, optionally in Japan, levofolinate 200 mg/m², fluorouracil 400 mg/m² bolus followed by 2400 mg/m² in a 46-hour to 48-hour infusion, and oxaliplatin 85 mg/m² on days 1, 15, and 29. Treatment in both arms occurred over four 42-day cycles, and patients who did not experience disease progression continued treatment with zolbetuximab or placebo plus chemotherapy at the investigator’s discretion. Therapy continued until disease progression, unacceptable toxicity, start of another anticancer treatment, or occurrence of other discontinuation criteria.

The primary end point was PFS per IRC. OS and time to confirmed deterioration were the key secondary end points. Other secondary end points included ORR, DOR, and safety.

Zolbetuximab Wins Approval in Japan and Europe

In March 2024, zolbetuximab became the world’s first approved CLDN18.2-targeted therapy, earning an indication for patients with CLDN18.2-positive, unresectable, advanced or recurrent gastric cancer in Japan. Then, in September 2024, the European Commission approved the agent in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adult patients with locally advanced unresectable or metastatic CLDN18.2-positive, HER2-negative gastric or GEJ adenocarcinoma.^5,6

“We are waiting for approval in other regions outside of Japan [and Europe],” Shitara said. “This is a significant achievement in gastric cancer [because] we have very limited treatment options, but the magnitude of survival benefit was still modest and not enough. We need additional, better treatment [options. Next, we want] to combine [zolbetuximab] with the current available treatments, such as checkpoint inhibitors, and this is supported by clinical and preclinical studies.”

References

1. Shitara K, Shah MA, Lordick F, et al. Zolbetuximab in gastric or gastroesophageal junction adenocarcinoma. N Engl J Med. 2024;391(12):1159-1162. doi:10.1056/NEJMc2409512
2. FDA approves zolbetuximab-clzb with chemotherapy for gastric or gastroesophageal junction adenocarcinoma. FDA. October 18, 2024. Accessed October 21, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zolbetuximab-clzb-chemotherapy-gastric-or-gastroesophageal-junction-adenocarcinoma
3. Shah MA, Shitara K, Ajani JA, et al. Zolbetuximab plus CAPOX in CLDN18.2-positive gastric or gastroesophageal junction adenocarcinoma: the randomized, phase 3 GLOW trial. Nat Med. 2023;29(8):2133-2141. doi:10.1038/s41591-023-02465-7
4. Shitara K, Lordick F, Bang YJ, et al. Zolbetuximab plus mFOLFOX6 in patients with CLDN18.2-positive, HER2-negative, untreated, locally advanced unresectable or metastatic gastric or gastro-oesophageal junction adenocarcinoma (SPOTLIGHT): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2023;401(10389):1655-1668. doi:10.1016/S0140- 6736(23)00620-7
5. Astellas’ Vyloy (zolbetuximab) approved in Japan for treatment of gastric cancer. News release. Astellas Pharma Inc. March 26, 2024. Accessed October 7, 2024. https://www.astellas.com/en/news/29026
6. Astellas receives approval from the European Commission for Vyloy (zolbetuximab) in combination with chemotherapy for advanced gastric and gastroesophageal junction cancer. News release. Astellas Pharma Inc; September 20, 2024. Accessed October 7, 2024. https://www.astellas.com/en/news/29401