Subgroup Analysis Highlights Potential of Cabozantinib in GI Neuroendocrine Tumors

Exelixis, Inc. has released findings from a subgroup analysis of the phase 3 CABINET study, which examined cabozantinib’s effects on extra-pancreatic neuroendocrine tumors (epNET), specifically those originating in the gastrointestinal (GI) tract. The data suggests that cabozantinib significantly improves progression-free survival (PFS) in patients with advanced GI neuroendocrine tumors (NET), compared to a placebo. These findings were presented on January 24, 2025, at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium.

Dr. Jonathan Strosberg, an expert in neuroendocrine tumors, emphasized the challenges of treating GI NET after disease progression due to limited options. He noted that cabozantinib’s demonstrated improvement in PFS provides a promising new avenue for patients facing this condition, potentially establishing the drug as a standard of care.

Study Findings and Clinical Implications

The subgroup analysis involved 116 out of the 203 patients in the epNET cohort. The primary tumor locations were:

• Ileum/cecum: 54%
• Small intestine (unspecified): 20%
• Non-cecum colon or rectum: 11%
• Stomach: 4%
• Duodenum: 3%
• Jejunum: 3%
• Non-specified midgut site: 3%

Cabozantinib’s impact was measured against a placebo, showing a hazard ratio of 0.50 (95% confidence interval: 0.28-0.88) and a statistically significant P-value of 0.007. Median PFS for patients on cabozantinib was 8.5 months, compared to 5.6 months for those on placebo. Additionally, one patient in the cabozantinib group achieved partial response, while stable disease was observed in 48 patients, versus 30 in the placebo group. The results suggest potential benefits across clinical factors such as tumor grade, functional status, concurrent somatostatin analog use, and prior treatments with Lu-177 dotatate or everolimus.

Dr. Amy Peterson, Chief Medical Officer at Exelixis, reiterated the significance of these findings, highlighting cabozantinib’s potential as a much-needed treatment option for GI NET. She confirmed that Exelixis is actively collaborating with the U.S. Food and Drug Administration (FDA) as it reviews a supplemental New Drug Application (sNDA) for cabozantinib in previously treated advanced NET. The FDA’s decision is expected by April 3, 2025.

Safety Profile and Regulatory Progress

Cabozantinib’s safety profile remained consistent with previously known data. No new safety concerns were identified. However, common grade 3/4 adverse events included:

• Hypertension (19% in cabozantinib group vs. 4% in placebo group)
• Diarrhea (13% vs. 4%)
• Fatigue (10% vs. 4%)

Three grade 5 adverse events occurred in the cabozantinib group, including one case of cardiac arrest and two unspecified events.

The CABINET trial was halted early in August 2023 following a unanimous recommendation from the Alliance for Clinical Trials in Oncology’s independent Data and Safety Monitoring Board. The decision was based on significant PFS improvements observed in an interim analysis. Final PFS results were presented at the 2024 European Society of Medical Oncology Congress and published in the New England Journal of Medicine. In August 2024, the FDA accepted the sNDA for cabozantinib, with a target decision date set for April 3, 2025.

Commentary by SuppBase Columnist Alice Winters

The results of the CABINET trial’s GI NET subgroup analysis reinforce cabozantinib’s potential as a valuable therapeutic option for patients facing limited treatment choices. However, while the findings are promising, there are several critical factors to consider.

First, although cabozantinib improved PFS, the absolute extension—2.9 months compared to placebo—raises questions about clinical significance versus statistical significance. Is a median PFS of 8.5 months truly transformative, or does it reflect incremental progress that still leaves much to be desired? While the hazard ratio of 0.50 is impressive, real-world applications must weigh efficacy against tolerability.

Speaking of tolerability, the safety profile remains a concern. Hypertension, diarrhea, and fatigue—each affecting more than 10% of patients—are not trivial side effects. Moreover, the occurrence of three fatal events underscores the need for cautious implementation, especially in a population already managing complex comorbidities.

From a regulatory perspective, the FDA’s upcoming decision will be pivotal. Given the trial’s early termination due to PFS benefits, cabozantinib’s approval for this indication seems probable. However, approval alone does not guarantee widespread clinical adoption. Physicians and patients will need to balance modest survival gains against the risk of adverse effects.

Finally, market positioning is another crucial factor. Will cabozantinib be cost-effective relative to existing treatments like everolimus or Lu-177 dotatate? How will insurance coverage and pricing influence accessibility? These questions remain open, but they will shape the real-world impact of cabozantinib’s potential label expansion.

In summary, cabozantinib presents a compelling case for expanded use in GI NET, but its clinical application will require careful consideration of efficacy, safety, and cost-effectiveness. The coming months will determine whether this treatment truly shifts the landscape or merely adds another option to an already complex therapeutic puzzle.