Dr Klempner on the FDA Approval of Zolbetuximab for CLDN18.2+, HER2– Gastric or GEJ Adenocarcinoma 

Samuel J. Klempner, MD, gastrointestinal oncologist, Massachusetts General Hospital, discusses the clinical implications of the FDA approval of zolbetuximab-clzb (Vyloy) for the first-line treatment of adult patients with Claudin 18.2 (CLDN18.2)–positive, HER2-negative, locally advanced unresectable or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma.

 in combination with fluoropyrimidine- and platinum-containing chemotherapy for patients with gastric or GEJ adenocarcinoma whose tumors express CLDN18.2, a novel biomarker in gastroesophageal cancers.

This approval was supported by data from the phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) trials, which demonstrated that zolbetuximab significantly improved progression-free survival and overall survival in patients with CLDN18.2-positive gastric and GEJ adenocarcinoma.

Zolbetuximab works by targeting CLDN18.2, leading to tumor cell destruction through antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. According to Klempner, this mechanism, combined with chemotherapy, has shown synergistic effects, making zolbetuximab plus chemotherapy an effective first-line treatment option for patients with CLDN18.2-positive disease.

 demonstrated that at a median follow-up of 12.94 months for the zolbetuximab group (n = 283) and 12.65 months for the placebo group (n = 282), zolbetuximab plus mFOLFOX6 (5-fluorouracil, leucovorin, and oxaliplatin) elicited a median progression-free survival (PFS) of 10.6 months (95% CI, 8.9-12.5) compared with 8.7 months (95% CI, 8.2-10.3) for placebo plus mFOLFOX6 (HR, 0.751; 95% CI, 0.598-0.942; 1-sided 

 = .0066). An overall survival (OS) benefit was also observed in the zolbetuximab group (HR, 0.750; 95% CI, 0.601-0.936; 

 met its primary end point, showing that zolbetuximab plus CAPOX (capecitabine plus oxaliplatin) reduced the risk of progression or death by 31.3% compared with placebo plus CAPOX (HR, 0.687; 95% CI, 0.544-0.866; 1-sided 

 = .0007). Patients treated in the experimental arm (n = 254) achieved a median PFS of 8.2 months (95% CI, 7.5-8.8) compared with 6.8 months (95% CI, 6.1-8.1) for those given placebo plus CAPOX (n = 253). The respective 12- and 24-month PFS rates were 35% and 14% in the zolbetuximab arm, compared with 19% and 7%, respectively, in the placebo arm.

The median OS was 14.4 months (95% CI, 12.3-16.5) for the experimental arm vs 12.2 months (95% CI, 10.3-13.7) for the control arm (HR, 0.771; 95% CI, 0.615-0.965; 1-sided 

Klempner concludes that this approval marks a significant milestone, introducing a new biomarker and targeted therapy for a patient population that has seen limited treatment advancements in recent years. The introduction of CLDN18.2 as a target offers oncologists a valuable tool for personalizing treatment, which may lead to better patient outcomes. He emphasizes the importance of integrating CLDN18.2 testing into diagnostic protocols to identify candidates for zolbetuximab, further underscoring the growing role of biomarker-driven therapies in the management of gastric and GEJ cancers.

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Samuel J. Klempner, MD, discusses the FDA approval of zolbetuximab for CLDN18.2+, HER2–, locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma.

Dr Klempner on the FDA Approval of Zolbetuximab for CLDN18.2+, HER2– Gastric or GEJ Adenocarcinoma

Sam Klempner, MD, faculty member, Oncology, Massachusetts General Hospital, Medicine, Harvard Medical School, discusses the investigation of adagrasib (MRTX849) in 

 G12C–mutated metastatic colorectal cancer (mCRC). 

Adagrasib is currently being evaluated in the phase 3 KRYSTAL-10 trial (NCT04793958) in patients with mCRC harboring a 

 G12C mutation, Klempner says. Eligible patients progressed on at least 1 prior line of therapy, and those enrolled are randomly assigned to standard-of-care chemotherapy or treatment with adagrasib plus cetuximab (Erbitux), Klempner explains. 

The co-primary end points of the trial are progression-free survival and overall survival, Klempner continues. The trial is expected to enroll approximately 420 patients, and it is currently open and accruing globally, Klempner concludes.

Sam Klempner, MD, discusses the investigation of adagrasib in KRAS G12C–mutated metastatic colorectal cancer. 


Dr. Klempner on the Investigation of Adagrasib in KRAS G12C–Mutated mCRC

Sam Klempner, MD, faculty member, Oncology, Massachusetts General Hospital, Medicine, Harvard Medical School, discusses the incidence of 

 G12C mutations in patients with metastatic colorectal cancer (CRC), the viability of the target in this disease, the efficacy of adagrasib (MRTX849) in combination with cetuximab (Erbitux) in this patient population, and the importance of genetic testing.

 G12C mutations occur with varying prevalence across different types of solid tumors, including gastrointestinal cancers like CRC, Klempner says. Data from retrospective studies have indicated that approximately 3% to 4% of patients with CRC harbor these mutations. These mutations appear to be associated with an inferior prognosis—even compared with other 

 mutations, Klempner adds. Moreover, those with 

 G12C mutations typically derive a shorter duration of benefit from standard frontline chemotherapy options, according to Klempner.

The phase 1b/2 KRYSTAL-1 trial (NCT03785249) evaluated the safety, tolerability, and clinical activity of adagrasib monotherapy and in combination with cetuximab in patients with 

 G12C–mutated tumors, including CRC. Data presented at the 2022 ESMO Congress showed that the activity displayed by adagrasib plus cetuximab confirmed preclinical observations of combining a KRAS G12C inhibitor with an EGFR inhibitor, Klempner says. With a longer follow-up of 17.5 months, the combination elicited a confirmed objective response rate of 46%, with a disease control rate of 100% in 28 evaluable patients with 

Ninety-three percent of patients experienced a decrease in tumor volume, according to Klempner. Moreover, many patients achieved deep responses, with more than a 50% decrease in the tumor volume, Klempner adds. Patients treated with the combination also experienced durable responses, with a median duration of response of 7.6 months. The median time to response with the doublet was rapid, at 1.4 months, Klempner adds. At data cutoff, 5 patients were still receiving treatment with the combination, Klempner says. Treatment-related adverse effects were observed in all 32 patients (100%). 

The most frequent toxicities were nausea (63%), diarrhea (56%), vomiting (53%), dermatitis acneiform (47%), fatigue (47%), and dry skin (41%). The combination was tolerable and had a manageable safety profile.

 G12C mutations represent a viable target in CRC, Klempner adds. The relatively high rates of responses achieved with the doublet, and the durability of those responses, suggest that the regimen may be more beneficial for this subgroup of patients with CRC compared with other options available in the late-line setting, such as regorafenib (Stivarga) and trifluridine/tipiracil (TAS-102; Lonsurf), Klempner says.

 G12C mutations underscores the importance of performing genetic testing in all patients with CRC, Klempner adds. Moreover, if these kinds of mutations are detected, all efforts should be made to identify clinical trials that may be appropriate for this patient subset, Klempner concludes.

Sam Klempner, MD, discusses the incidence of KRAS G12C mutations in patients with metastatic colorectal cancer, the viability of the target in this disease, the efficacy of adagrasib in combination with cetuximab in this patient population, and the importance of genetic testing.

Sam Klempner, MD

Articles

Dr Klempner on the FDA Approval of Zolbetuximab for CLDN18.2+, HER2– Gastric or GEJ Adenocarcinoma

Dr. Klempner on the Investigation of Adagrasib in KRAS G12C–Mutated mCRC

Dr. Klempner on the Significance of KRYSTAL-1 Data in KRAS G12C–Mutant CRC