At the 2023 ASCO Gastrointestinal Symposium, Kohei Shitara MD, National Cancer Center Hospital East, Chiba, Japan, presented the primary results from the phase 3 SPOTLIGHT trial, which compared zolbetuximab plus modified FOLFOX-6 chemotherapy (leucovorin calcium, fluorouracil, and oxaliplatin) to placebo plus FOLFOX-6 for patients with claudin-18.2-positive/HER2-negative gastric or gastroesophageal junction adenocarcinoma.

This global, randomized trial showed a statistically significant and clinically meaningful improvement of both progression-free survival and overall survival for patients treated with zolbetuximab plus modified FOLFOX-6 vs placebo plus FOLFOX-6.

Dr Shitara stated he believes these results “support zolbetuximab plus FOLFOX as the new potential standard of care for patients with claudin-18.2-positive, HER2-negative gastric/gastroesophageal junction adenocarcinoma” and this may be “the new beginning of precision therapy for gastric cancer.”

Transcript:

Hi. My name is Kohei Shitara. I'm an GI medical oncologist working at National Cancer Center Hospital East in Japan. At this ASCO GI meeting, we presented the primary results from the phase 3 SPOTLIGHT study to investigate zolbetuximab plus FOLFOX6 as a first-line therapy for patients with claudin-18.2-positive gastric and [gastroesophageal junction] GEJ adenocarcinomas.

Claudin-18.2 is a tight-junction protein, which is usually expressed throughout the region of normal gastric mucosa cells. During malignant transformation to gastric cancer, this claudin-18.2 is exposed on the tumor cell surface with the disruption of tight-junction and it becomes an attractive target for cancer treatment.

Zolbetuximab is a first-in-class [immunoglobulin G] IgG or monoclonal antibody against claudin-18.2 with ADCC and CDC activity. Zolbetuximab showed some single-agent activity, and the previous randomized phase 2 FAST study showed the efficacy of zolbetuximab in first-line therapy, especially in patients with high claudin-18.2 expression.

This SPOTLIGHT study is a global, randomized, double-blinded, placebo-controlled phase 3 trial. Eligible patients have unresectable, or metastatic first-line gastric or GEJ adenocarcinoma, with claudin-18.2 positive and HER2-negative expression. Claudin-18.2 was centrally assessed by immunohistochemistry, and “positive” was defined as moderate to strong expression in 75% or more tumor cells. Patients were randomized to either zolbetuximab plus FOLFOX, or placebo plus FOLFOX. The primary endpoint of this study was [progression-free survival] PFS by central assessment, and overall survival was one of the key secondary endpoint. During the past 4 years, more than 2700 patient were screened and 39% patient had claudin-18.2 positive tumors. Finally, 565 patients were randomized to this SPOTLIGHT study.

In result, this trial showed the statistically significant improvement of PFS as a primary endpoint. Median PFS was 10.6 months with zolbetuximab and 8.7 months with placebo. The hazard ratio was 0.75 with P-value of .0066, which was highly statistically significant. Actually, the Kaplan-Meier curve showed relatively early separation and this difference was maintained until the tail of the curves.

Since we showed statistically significant improvement of the PFS, then overall survival was also statistically tested. The Kaplan-Meier curve of overall survival was similar until around 8 months and then showed very nice separation. Median overall survival was 18.2 months with zolbetuximab and 15.5 months with placebo. I believe this 18-month median survival should be the longest median survival in a global phase 3 trial for gastric cancer. The hazard ratio was 0.75 with a P-value of .0053, which was lower than to the defined significant threshold. So again, this trial showed statistically significant of improvement of both PFS and overall survival.

The objective response rate was similar between 2 arms and looking into safety profiles, nausea and vomiting were more frequently observed with zolbetuximab by 20%. Grade 3 or higher nausea and vomiting was also 10% more common with zolbetuximab. Anorexia is also 10% more common with zolbetuximab, with no difference in grade 3 or higher event rate. The on-target GI toxicity of zolbetuximab are very similar to that observed in previous trial. Otherwise, there were no major difference of toxicities.

The nausea and vomiting usually occurred in very early cycles of treatment, at the first or second infusion of zolbetuximab, and were managed by infusion adjustment. The incidence clearly decreased at subsequent cycles.

In summary, this SPOTLIGHT study showed statistically significant and clinical meaningful improvement of both PFS and overall survival with zolbetuximab plus FOLFOX for claudin-18.2-positive gastric and GEJ adenocarcinoma. I believe this result supports zolbetuximab plus FOLFOX as a new potential standard of care for patients with claudin-18.2-positive and HER2-negative gastric and GEJ adenocarcinoma. And this may be also the new beginning of precision therapy for gastric cancer.

Source:

Shitara K, Lordick F, Bang Y-J, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) with claudin-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. Presented at 2023 ASCO Gastrointestinal Symposium; January 19 – 21, 2023; San Francisco, CA. Abstract LBA292