Zolbetuximab in Gastric or Gastroesophageal Junction Adenocarcinoma

A partir des données de deux essais de phase III incluant 1 072 patients atteints d'un adénocarcinome de l'estomac ou de la jonction oesogastrique HER2- de stade localement avancé et non résécable ou de stade métastatique, cette étude évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité de l'ajout du zolbétuximab (un anticorps monoclonal ciblant la claudine 18.2) à une chimiothérapie

Résumé en anglais

Zolbetuximab is an IgG1 monoclonal antibody targeting claudin 18.2. In the final analysis of progression-free survival and the interim analysis of overall survival of two phase 3 trials — SPOTLIGHT1 (ClinicalTrials.gov number, NCT03504397) and GLOW2 (NCT03653507) — zolbetuximab plus first-line chemotherapy led to significantly longer progression-free survival and overall survival than placebo plus chemotherapy among patients with human epidermal growth factor receptor 2 (HER2)–negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors were positive for claudin 18.2 (see definition of claudin 18.2 positivity in the Supplementary Appendix, available with the full text of this letter at NEJM.org). The trial protocols are available at NEJM.org.

Here, we report the results of the planned final analysis of overall survival and an updated analysis of additional efficacy and safety end points with a combined analysis across the two trials.
Eligible patients were randomly assigned to receive zolbetuximab or placebo, in addition to chemotherapy (which was a modified regimen of folinic acid, fluorouracil, and oxaliplatin in the SPOTLIGHT trial or a regimen of capecitabine plus oxaliplatin in the GLOW trial). The primary end point in each trial was progression-free survival; overall survival was the key secondary end point, and objective response, duration of response, safety, and patient-reported outcomes were secondary end points. Full details of the methods have been reported previously1-3 and are also provided in the Supplementary Appendix.
A total of 1072 patients were randomly assigned to the zolbetuximab group (537 patients) or the placebo group (535) (Fig. S1 in the Supplementary Appendix). Enrollment according to country and the characteristics of the patients were representative of the global patient population, except that the numbers of Black patients were low (Tables S1, S2, and S3).
In the combined analysis, the median progression-free survival was 9.2 months in the zolbetuximab group and 8.2 months in the placebo group (hazard ratio for progression or death, 0.71; 95% confidence interval [CI], 0.61 to 0.83) (Figure 1A). A total of 377 of 537 patients (70.2%) in the zolbetuximab group and 424 of 535 patients (79.3%) in the placebo group died. The median overall survival was 16.4 months in the zolbetuximab group and 13.7 months in the placebo group (hazard ratio for death, 0.77; 95% CI, 0.67 to 0.89) (Figure 1B). The types of subsequent anticancer therapies were balanced between the treatment groups (Table S4). Prespecified subgroup analyses, individual trial results, and data on antitumor response are presented in Figures S2 through S6 and Tables S5, S6, and S7.

During the treatment period, the most common adverse events that were observed with zolbetuximab were nausea (in 76.0% of the patients who received zolbetuximab and in 56.2% of those who received placebo) and vomiting (in 66.8% and 34.2%, respectively), and no new safety findings were observed as compared with results at earlier data-cutoff dates (Tables S8, S9, and S10). The trends in the mean changes from baseline in the global health status and quality-of-life scores were similar in the two treatment groups (Fig. S7).
Zolbetuximab plus chemotherapy resulted in longer progression-free survival and overall survival than placebo plus chemotherapy among patients with HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors were positive for claudin 18.2. No new safety signals were observed.