CLDN18.2 positive + HER-2 negative

Zolbetuximab was launched in June 2024 as an anticancer drug useful for patients with CLDN18.2 positive and HER2 negative curatively unresectable advanced or recurrent gastric cancer. The mechanism and response to side effects such as hypoalbuminemia are still unclear, and more cases need to be accumulated.

Zolbetuximab is an anti-claudin18.2 (CLDN18.2) antibody, and the addition of zolbetuximab in combination with fluoropyrimidine and oxaliplatin as a first-line treatment for CLDN18.2-positive and HER2-negative gastric or gastroesophageal junction adenocarcinoma has been shown to improve survival. The secondary endpoints are the time to treatment failure, progression-free survival, overall survival, response rate, incidence of adverse events, and incidence of Grade 3 or higher adverse events. The results will be used to evaluate the feasibility of the treatment and are expected to be used to evaluate whether future trials can be conducted.

P2, N=100, Recruiting, AstraZeneca

P2, N=100, Recruiting, AstraZeneca

P1/2, N=17, Recruiting, AstraZeneca AB

From these clinically meaningful results, CLDN18.2-targeting therapy including zolbetuximab has attracted a lot of attention. In this review, we summarize the clinical implications of CLDN18.2-positive gastric or GEJ cancer, and CLDN18.2-targeting therapy, mainly for zolbetuximab.

In gastric or gastroesophageal junction (GEJ) cancers, trastuzumab combined with first-line chemotherapy in human epidermal growth factor receptor 2 (HER2)-positive patients and ramucirumab combined with second-line paclitaxel remarkably prolonged overall survival (OS) compared with chemotherapy alone, according to phase 3 trial results. Global phase Ⅲ trials revealed that the addition of zolbetuximab to first-line chemotherapy prolonged OS in CLDN18.2-positive and HER2-negative GC patients. This review summarizes recent clinical trials of CLDN18.2-targeted therapy.

Zolbetuximab, a first-in-class investigational monoclonal antibody (mAb) targeting tumor-associated antigen CLDN18.2 which is highly expressed on gastric cancer cells, was recently reported to meet the primary endpoint in Phase III trial as first-line treatment in CLDN18.2 positive and HER2-negative gastric cancers. Furthermore, PM1032 was generally well tolerated, with no significant abnormalities observed in toxicity studies, including the liver and stomach. In summary, PM1032 demonstrated good PK and an exceptional safety profile in rhesus monkeys supporting further investigation in clinical studies.

A systematic literature review of phase 2, 3, or unknown phase randomized, global trials of 1L therapies (capecitabine + cisplatin [CX]; capecitabine + oxaliplatin [CAPOX]; fluorouracil + cisplatin [CF]; oxaliplatin + folinic acid + fluorouracil [FOLFOX]; S-1 + cisplatin [SC]; nivolumab + CAPOX/FOLFOX; pembrolizumab + CF/CAPOX or CX; and zolbetuximab + CAPOX/FOLFOX) in adults with LA unresectable or mG/GEJ adenocarcinoma... This NMA examined the relative benefit of different targeted therapies when combined with chemotherapy. Zolbetuximab + FOLFOX/CAPOX for CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma confers a significant PFS and OS benefit, similar to that achieved with PD-1/PD-L1 inhibitors + CF/CAPOX or FOLFOX/CAPOX. >*Based on pts in ITT populations regardless of PD-L1 CPS status.

In SPOTLIGHT, pts (N = 565) were randomized 1:1 to zolbetuximab + mFOLFOX6 vs PBO + mFOLFOX6... In SPOTLIGHT and GLOW, slower infusion rate and use of antiemetic combinations may have helped to mitigate N/V. These strategies will be important to support continued treatment and allow pts to achieve maximum clinical benefit with zolbetuximab + chemotherapy. Clinical trial information: NCT03504397 and NCT03653507.

Methods Pts were randomly assigned 1:1 to zolbetuximab IV 800 mg/m2 (cycle 1, day [D] 1) followed by 600 mg/m2 (every 3 weeks) + mFOLFOX6 IV (D1, 15, 29) for four 42-day cycles or to PBO + mFOLFOX6; pts without progressive disease (PD) continued with zolbetuximab or PBO, + folinic acid and 5-FU at investigator's discretion, until PD or discontinuation criteria were met...Most common TEAEs with zolbetuximab + mFOLFOX6 were nausea (zolbetuximab arm: 82.4% vs PBO arm: 61.5%), vomiting (67.4% vs 36.3%), and decreased appetite (48.7% vs 34.9%); incidences of serious TEAEs were similar between arms (47.0% vs 46.4%). Conclusions With longer follow-up, zolbetuximab + mFOLFOX6 continued to demonstrate statistically significant improvement in PFS and OS compared with PBO + mFOLFOX6, with no new safety signals—supporting zolbetuximab + mFOLFOX6 as a potential new option for 1L treatment of pts with CLDN18.2+, HER2–, LA unresectable or mG/GEJ adenocarcinoma.

Background The phase 3 GLOW study showed statistically significant improvement with 1L zolbetuximab + capecitabine + oxaliplatin (CAPOX) vs placebo (PBO) + CAPOX in PFS (final; median 8.2 vs 6.8 mo, HR 0.69 [95% CI 0.54, 0.87], P = 0.0007) and OS (interim; median 14.4 vs 12.2 mo, HR 0.77 [95% CI 0.62, 0.97], P = 0.0118) in pts with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma. Most common TEAEs with zolbetuximab + CAPOX were nausea (zolbetuximab arm: 68.9% vs PBO arm: 50.2%), vomiting (66.1% vs 31.3%), and decreased appetite (41.3% vs 34.5%); incidences of serious TEAEs were similar between arms (48.0% vs 50.6%). Conclusions Zolbetuximab + CAPOX continued to demonstrate statistically significant improvement in PFS and OS compared with PBO + CAPOX, with no new safety signals, supporting zolbetuximab + CAPOX as a potential new option for 1L treatment of patients with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma.