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Adding Targeted Drug to Chemo Boosts Survival in Esophageal/GEJ Cancer


SAN FRANCISCO — Adding a Claudin (CLDN) inhibitor to chemotherapy significantly increased progression-free (PFS) and overall survival (OS) in locally advanced gastric/gastroesophageal junction (GEJ) cancer and CLDN 18.2 expression, a randomized trial showed.

Median PFS increased from 8.67 months with modified FOLFOX chemotherapy to 10.61 months with the addition of investigational zolbetuximab. Median OS improved significantly from 15.54 to 18.23 months, even though the control arm outperformed the a priori estimated survival.

Serious treatment-emergent adverse events (TEAEs) occurred in a similar proportion of patients in the two treatment arms, although substantially more patients discontinued zolbetuximab compared with placebo (13.6% vs 2.2%), reported Kohei Shitara, MD, of the National Cancer Center Hospital East in Kashiwa, Japan, at the ASCO Gastrointestinal Cancers Symposium.

“This study shows the longest median overall survival in a phase III trial for gastric cancer, and the survival benefit was consistently observed across different subgroups,” said Shitara. “Notable toxicities with this combination include nausea and vomiting, which many patients had during the first or second infusion of zolbetuximab. These results support zolbetuximab and FOLFOX as a new potential standard of care for patients with Claudin 18.2-positive advanced gastric and GEJ adenocarcinoma.”

Excluding immune checkpoint inhibitors from consideration, the positive results make zolbetuximab the first molecularly targeted therapy since trastuzumab (Herceptin) to demonstrate a statistically significant survival benefit in first line for advanced gastric cancer, noted ASCO invited discussant David H. Wang, MD, PhD, of UT Southwestern Medical Center in Dallas.

Although subgroup analysis showed a consistent effect of zolbetuximab, certain patients appeared to derive greater benefit: patients from Asia, those with limited disease, patients who had undergone gastrectomy, those who had primary tumors in the stomach, and a subgroup with an intestinal phenotype that would be expected to have greater expression of a tight junction protein (CLDN 18.2).

The results raised the question of why the control arm did so well, Wang continued. Given that all patients in the trial were CLDN 18.2+, one possible answer is that CLDN 18.2 expression might identify patients with a more favorable prognosis. Three-fourths of the study population had limited disease, another possible explanation. Effects of subsequent therapies also could have influenced survival.

The findings also pose an obvious practical question: How to choose between nivolumab (Opdivo) and zolbetuximab plus chemotherapy as first-line treatment.

“I would suggest that if you have higher PD-L1 expression levels, this would favor use of nivolumab,” said Wang. “If you have appropriate levels of Claudin 18 expression, which seem to be continuing to rise in terms of eligibility criteria, maybe this would be a reasonable test. Obviously, the combination of the two could be investigated in further trials.”

The trial also showed that CLDN 18.2 is a new predictive biomarker for advanced gastric cancer, Wang added. However, the immunohistochemistry assay is not yet widely available, and standardized interpretation of positivity will be needed.

Patients with gastric/GEJ cancer remain a major unmet clinical need, as median OS is less than 1 year for patients with locally advanced disease, for whom chemotherapy is standard of care, Shitara noted. Adding targeted therapies to chemotherapy has improved survival for specific subgroups, such as trastuzumab for HER2+ disease and nivolumab for patients with PD-L1 combined positive score ≥5.

The need to identify additional subsets who might benefit from targeted therapy sparked interest in CLDN 18.2, a tight junction protein expressed in normal gastric mucosa and retained in gastric/GEJ adenocarcinoma, Shitara continued. The protein can become exposed on the surface of cancer cells, making it a promising therapeutic target.

Zolbetuximab is a first-in-class IgG1 antibody that targets CLDN 18.2 to induce antibody-dependent cytotoxicity and complement-dependent cytotoxicity. In a phase IIb trial, zolbetuximab plus chemotherapy increased median PFS and OS in advanced CLDN 18.2+ gastric/GEJ cancer, as compared with chemotherapy alone.

Shitara reported findings from the phase III, global, randomized SPOTLIGHT trial that compared zolbetuximab and placebo in combination with FOLFOX chemotherapy. Eligible patients had previously untreated, unresectable locally advanced or metastatic gastric GEJ adenocarcinoma and moderate/strong CLDN 18.2 staining, defined as ≥75% of cells.

Investigators randomized 550 patients to the two treatment arms (median age about 62; about 62% male; around a third in Asia), and the primary endpoint was PFS. OS was a key secondary endpoint but was tested only if PFS differed significantly (P=0.025).

The primary analysis showed that the addition of zolbetuximab to chemotherapy reduced the hazard for progression or death by 24.9% and satisfied criteria for statistical significance (P=0.0086). The OS analysis showed that zolbetuximab was associated with a 25% reduction in the hazard ratio and also achieved statistical significance (P=0.0053). Subgroup analyses showed an advantage for the targeted drug in most patient groups.

Objective response rate did not differ significantly between groups but was higher in the placebo arm (62.1% vs 60.7%). Median duration of response also was similar (8 to 8.5 months).

Grade ≥3 TEAEs occurred more often in the zolbetuximab arm (86.7% vs 77.7%), but rates of serious TEAEs were similar (44-45%). Treatment-related adverse events (TRAEs) led to discontinuation more often in the zolbetuximab arm (38.0% vs 29.5%), including discontinuation of study drug (13.6% vs 2.2%).

SPOTLIGHT and the phase III GLOW trial “are being conducted to provide foundational data for regulatory submissions in the U.S., Europe, Asia and other countries globally,” according to zolbetuximab’s developer.

  • Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow

Disclosures

The study was supported by Astellas Pharma. Some co-authors are company employees.

Shitara disclosed relationships with Bristol Myers Squibb, Janssen, Takeda, AbbVie, Amgen, Astellas Pharma, Boehringer Ingelheim, Daiichi Sankyo, GlaxoSmithKline, Guardant Health, Lilly, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho, Chugai, and Eisai.

Wang disclosed a relationship with Novartis.

Primary Source

ASCO Gastrointestinal Cancers Symposium

Source Reference: Shitara K, et al “Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-18.2+(CLDN18.2+)/HER22 locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Primary results from phase 3 SPOTLIGHT study” GICS 2023; Abstract LBA292.





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