Presentation by Dr Misagh Karimi, MD, City of Hope
In a presentation at the 2023 Best of GI Cancer conference, Dr Misagh Karimi from City of Hope in Orange County, CA highlighted one of the key presentations from the past year’s American Society for Clinical Oncology (ASCO) Gastrointestinal (GI) Cancers Symposium. The SPOTLIGHT trial focused on first line (1L) treatment for patients with locally advanced unresectable, or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinomas. SPOTLIGHT was a randomized phase III trial that examined the efficacy of zolbetuximab, an antibody drug that specifically targets a molecule on tumor cells known as Claudin 18.2 (CLDN 18.2), when used in combination with chemotherapy treatment in patients with mG/GEJ cancer. CLDN 18.2 is a cell surface protein that is expressed on mG/GEJ tumors and prior studies demonstrated that binding of CLDN 18.2 with zolbetuximab activates the immune system against tumor cells by causing antibody-dependent and complement-dependent cytotoxic pathways. In an earlier, Phase 2b study, zolbetuximab used in combination with chemotherapy improved progression-free survival (PFS) as well as overall survival (OS) when compared to chemotherapy alone.
SPOTLIGHT Study Design
Patients in the SPOTLIGHT trial had moderate to strong CLDN 18.2 expression in their tumors (with > 75% of the cells having CLDN 18.2 expression using immunohistochemical staining defined as “+2”), and patients also had to have negative expression of human epidermal growth factor receptor 2 (HER2-); they also had to have a ‘good’ performance status (PS) of 0 or 1. First line treatment patients (~280 patients in each arm of the trial) were randomized to treatment with zolbetuximab with “modified FOLFOX 6” or mFOLFOX 6, a standard chemotherapy regimen used in mG/GEJ cancers. The primary endpoint of the trial was PFS, and secondary endpoints included OS, overall response rate (ORR), and Duration of Response (DoR).
Efficacy Results
Results for the primary endpoint of PFS, at 24 months showed a significantly higher PFS for patients treated with the combination of zolbetuximab + mFOLFOX6 as compared with those who received mFOLFOX6 alone (median PFS = 24% versus 15%). For the key secondary endpoint of OS, there was a significant benefit of the combination over mFOLFOX6 alone both at 24 months (39% versus 28%) and at 36 months (21% versus 9%). Notably, the median OS of 18.2 months versus 15.5 months, respectively (hazard ratio = 0.75; P=0.0053) is the longest observed for gastric cancer in a phase III study. Further, there appeared to be a similar benefit of adding zolbetuximab across all of the relevant patient subgroups, with benefits in OS observed. Dr Karimi noted the clinically significant improvement in both PFS and OS that was observed in the trial, and was optimistic for a forthcoming approval of zolbetuximab + mFOLFOX6 as a potentially new standard of care for patients with CLDN 18.2+/HER2- unresectable mG/GEJ cancers.
Safety and Tolerability Results
Toxicity of the combination regimen was, overall, manageable. Adverse events (AEs) observed in the trial were mainly GI in nature, including nausea, vomiting and decreased appetite, which were more common in the zolbetuximab arm versus the mFOLFOX6 arm. Other events such as diarrhea, peripheral sensory neuropathy, neutropenia and anemia were largely similar between the two treatment groups. The most common treatment emergent AEs with the combination were nausea and vomiting, which are considered “on target” AEs, and these events occurred most often within the first cycle of zolbetuximab.
Conclusions and Practice Implications
Dr Karimi expects that results from SPOTLIGHT will likely result in approval of zolbetuximab for treatment of patients with CLDN 18.2 positive disease. He also noted additional trials underway with zolbetuximab, which include the GLOW trial, a phase III trial investigating the combination of zolbetuximab with CAPEOX, another chemotherapy regimen, which has also yielded positive results, as well as the ongoing ILUSTRO study which is investigating the use of zolbetuximab in combination with pembrolizumab, an immunotherapy drug.
Quick Summary
Claudin 18.2 (CLDN 18.2) is a cell surface protein that is expressed on metastatic gastric/gastroesophageal (mG/GEJ tumors).
Binding of CLDN 18.2 with an antibody (zolbetuximab), results in activation of anti-tumor immune cell function via antibody-dependent and complement-dependent cytotoxicity pathways.
The SPOTLIGHT trial examined the use of the CLDN 18.2-targeting drug zolbetuximab in combination with chemotherapy (mFOLFOX6) for patients with mG/GEJ adenocarcinomas.
Efficacy results showed a significant benefit of the combination therapy with zolbetuximab in progression-free and overall survival.
Safety results showed a manageable toxicity profile for the zolbetuximab regimen, with adverse events mostly GI in nature (nausea, vomiting, decreased appetite).
Approval is expected for the zolbetuximab combination based on results from the SPOTLIGHT trial.
See more from the 2023 Best of GI Cancer Conference here.
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