KEY TAKEAWAYS
- Zolbetuximab + mFOLFOX6 improved PFS and OS in previously untreated CLDN18.2+ (≥75% IHC staining)/HER2− LA unresectable or mG/GEJ adenocarcinoma patients, per SPOTLIGHT phase 3 trial (NCT03504397).
- The study enrolled 565 patients randomized 1:1 to zolbetuximab + mFOLFOX6 (N = 283) or placebo + mFOLFOX6 (N = 282), with the primary endpoint being PFS per RECIST v1.1 by IRC.
- OS was a secondary endpoint of the study and significantly improved with zolbetuximab + mFOLFOX6 (median 18.23 vs. 15.54 mo, HR 0.750, P=0.0053, < 0.0135 as a boundary).
- Zolbetuximab + mFOLFOX6 caused typical TEAEs like nausea, vomiting, and appetite loss, as seen before. Serious TEAE rates were comparable in both groups.
- Zolbetuximab + mFOLFOX6 offers a potential new option for CLDN18.2+ (≥75% IHC staining)/HER2− LA unresectable or mG/GEJ adenocarcinoma patients, meeting an unfulfilled need as chemotherapy and immunotherapy are standard first-line treatments.
Patients with HER2-, metastatic genitourinary (mG/GEJ) adenocarcinoma are routinely treated initially with chemotherapy and immunotherapy. However, this is not meeting their needs. Normal cells of the gastric mucosa express CLDN18.2, and this expression is maintained in mG/GEJ tumor cells. Patients with unresectable or metastatic gastrointestinal or endocrine ductal adenocarcinoma had their survival time increased when chemo was paired with zolbetuximab, an antibody that targets CLDN18.2. Patients with CLDN18.2+/HER2, LA unresectable, or mG/GEJ adenocarcinoma will be randomly assigned to receive either zolbetuximab + folinic acid, 5-FU, and oxaliplatin (mFOLFOX6) or placebo + mFOLFOX6 as 1L treatment in the SPOTLIGHT (NCT03504397) phase 3 global, double-blind study.
Patients who had never received any prior treatment for CLDN18.2+ (moderate-to-strong membrane staining in 75% tumor cells by IHC)/HER2 LA unresectable or mG/GEJ adenocarcinoma were randomly assigned to receive either zolbetuximab IV 800 mg/m2 (cycle [C] 1, day [D] 1) or zolbetuximab IV 600 mg/m2 (C1D22, According to IRC’s implementation of RECIST v1.1, progression-free survival (PFS) was the primary endpoint (EP). OS, ORR, and safety were secondary EPs. Stratified log-rank tests were used to examine whether or not there were statistically significant differences in effectiveness between treatment groups; if PFS was significant, overall survival was also evaluated.
From the initial 2735 patients, 565 were randomly assigned to receive either zolbetuximab plus mFOLFOX6 (N = 283) or placebo plus mFOLFOX6 (N = 282). The combination of zolbetuximab and mFOLFOX6 significantly increased PFS (median 10.61 vs 8.67 months, HR 0.751, P=0.0066; Table). As can be seen in the table, the median OS increased from 15.54 months to 18.23 months (HR 0.750, P=0.0053, 0.0135 as border). Similar ORR was seen in both treatment groups. Nausea (82.4% versus 60.8% in zolbetuximab versus placebo arms), vomiting (67.4% versus 35.6%), and decreased appetite (47.0% against 33.5%) were the most common TEAEs with zolbetuximab + mFOLFOX6; the frequencies of significant TEAEs were similar between both arms (44.8% versus 43.5%).
Treatment of patients with CLDN18.2+/HER2, LA, unresectable, or mG/GEJ adenocarcinoma with 1L zolbetuximab in combination with mFOLFOX6 dramatically improved PFS and OS. The TEAEs matched those found in the literature. A potential novel treatment for these patients is zolbetuximab with mFOLFOX6.
Source: https://meetings.asco.org/abstracts-presentations/217453
Clinical Trial: https://clinicaltrials.gov/ct2/show/NCT03504397
Shitara, K., Lordick, F., Bang, Y.-J., Enzinger, P.C., Ilson, D.H., Shah, M.A., Van Cutsem, E., Xu, R., Aprile, G., Xu, J., Chao, J., Pazo-Cid, R., Kang, Y.-K., Yang, J., Moran, D.M., Bhattacharya, P.P., Arozullah, A., Wook Park, J. and Ajani, J.A. (2023). 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. Journal of Clinical Oncology, 41(4_suppl), pp.LBA292–LBA292. doi:https://doi.org/10.1200/jco.2023.41.4_suppl.lba292.
