Highlights
The Phase II trial evaluating the combination of the multi-kinase inhibitor cabozantinib and the PD-1 inhibitor nivolumab in advanced extrapancreatic neuroendocrine tumors (epNETs) demonstrated a high rate of stable disease (90%) but a very low objective response rate (5%).
Due to the failure to reach the predefined response threshold in the first stage of the Simon’s two-stage design, enrollment was terminated early.
Median progression-free survival (PFS) was 5.6 months, suggesting that while the combination provides disease stabilization, it does not significantly induce tumor shrinkage in this specific patient population.
Translational proteomic analysis indicated that certain immune and angiogenic profiles might correlate with longer therapy duration, pointing toward potential biomarkers for future investigation.
Background: The Therapeutic Landscape of epNETs
Extrapancreatic neuroendocrine tumors (epNETs) represent a heterogeneous group of malignancies arising from various anatomical sites, including the gastrointestinal tract and lungs. For patients with advanced or metastatic disease, treatment options have historically focused on somatostatin analogs, targeted therapies such as sunitinib or everolimus, and peptide receptor radionuclide therapy (PRRT). While these agents can delay disease progression, objective response rates (ORR) remain modest, and there is a critical unmet need for therapies that induce significant tumor regression.
Immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the treatment of many solid tumors. However, neuroendocrine tumors are generally considered immunologically “cold,” characterized by a low tumor mutational burden (TMB) and limited PD-L1 expression. Consequently, single-agent PD-1 or PD-L1 inhibition has shown disappointing results in most NET subtypes, necessitating the exploration of combination strategies to enhance the immune response.
Synergy Hypothesis: Cabozantinib and PD-1 Inhibition
Cabozantinib is a potent multi-kinase inhibitor targeting VEGFR, MET, and AXL. Beyond its anti-angiogenic properties, cabozantinib is known to modulate the tumor microenvironment (TME). Preclinical and clinical evidence suggests that cabozantinib can reduce the prevalence of immunosuppressive cells, such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), while increasing the infiltration of effector T cells. This immunomodulatory effect provides a rational basis for combining cabozantinib with nivolumab, a PD-1 inhibitor, to overcome the immune resistance typically seen in epNETs.
Study Design and Methodology
This study was an open-label, single-arm, phase II trial conducted to evaluate the efficacy and safety of the cabozantinib and nivolumab combination in patients with advanced, well-differentiated epNETs. The trial utilized a Simon’s two-stage design. In the first stage, 19 patients were enrolled. If a minimum number of objective responses were not observed, the trial would not proceed to the second stage.
Intervention Protocol
Participants received nivolumab at a dose of 240 mg intravenously on days 1 and 15 of a 28-day cycle. Cabozantinib was administered orally at 40 mg once daily. This dose of cabozantinib is slightly lower than the standard monotherapy dose (60 mg) to mitigate potential cumulative toxicities when combined with immunotherapy.
Study Endpoints
The primary endpoint was the objective response rate (ORR) as defined by RECIST v1.1. Secondary endpoints included ORR by immune-related response criteria (irRECIST), progression-free survival (PFS), and safety. Exploratory objectives sought to correlate clinical outcomes with immune and angiogenic proteomic profiles in the blood and tumor tissue.
Results: Clinical Efficacy and Survival Data
Of the 19 patients enrolled in the first stage, 18 were evaluable for clinical response. The demographic and baseline characteristics reflected a typical advanced epNET population with prior exposure to standard therapies.
Efficacy Outcomes
The primary endpoint of ORR was not met. Only one patient (5.6%) achieved a confirmed partial response (PR). However, the vast majority of patients—16 out of 18 (90%)—achieved stable disease (SD) as their best response. One patient (5.6%) experienced primary progressive disease (PD). Because the ORR did not meet the predefined threshold for the first stage, the trial was terminated, and further enrollment was halted.
Survival Data
The median progression-free survival (PFS) was 5.6 months (95% CI, 3.5 to 9.9). While this PFS is comparable to some other targeted therapies in this setting, it did not represent a significant breakthrough over existing monotherapy options. The high rate of stable disease suggests a cytostatic effect rather than a cytotoxic or immunologic clearance of the tumor.
Safety and Tolerability Profile
The safety profile of the combination was generally consistent with the known side effects of the individual agents, although some notable events occurred. Grade 3 toxicities attributed to the study drugs included:
1. Fatigue (n=2, 10%)
2. Elevated transaminases (n=1, 5%)
3. Tumor lysis syndrome (n=1, 5%)
The occurrence of tumor lysis syndrome is relatively rare in neuroendocrine tumors, which are typically slow-growing, and may reflect a specific metabolic vulnerability in some patients when exposed to this combination. Overall, the 40 mg dose of cabozantinib was manageable but still required careful monitoring for immune-related adverse events and VEGF-related toxicities.
Translational Insights: Proteomic Correlations
Exploratory analyses of immune and angiogenic proteomic profiles were conducted to identify potential drivers of clinical benefit. The researchers observed certain trends in proteomic signatures that were associated with a longer duration on therapy. Specifically, markers related to vascular remodeling and specific immune cell activation patterns appeared more favorable in patients with prolonged stable disease. These findings suggest that while the combination may not induce rapid shrinkage, it may influence the tumor biology in a subset of patients who derive long-term stabilization.
Expert Commentary: Why Did the Combination Underperform?
The results of this trial underscore the persistent difficulty of utilizing immunotherapy in well-differentiated neuroendocrine tumors. Several factors may contribute to the limited response rate observed:
Tumor Heterogeneity
Extrapancreatic NETs encompass a wide range of primary sites (e.g., small bowel, lung, unknown primary). The biological drivers of these tumors vary significantly, and a “one-size-fits-all” approach with nivolumab and cabozantinib may not address the specific immune evasion mechanisms of each subtype.
The Cold Tumor Microenvironment
Despite cabozantinib’s ability to modulate the TME, it appears that for most epNETs, this modulation is insufficient to overcome the profound lack of pre-existing immune infiltration. The “cold” nature of these tumors remains a formidable barrier to current checkpoint inhibitor strategies.
Comparison with Pancreatic NETs
Interestingly, some studies have suggested that pancreatic NETs (pNETs) might be slightly more responsive to certain combinations than epNETs. The specific focus on extrapancreatic cases in this trial highlights the need for site-specific investigations in neuroendocrine tumor research.
Conclusion and Future Directions
The combination of cabozantinib and nivolumab demonstrated limited objective activity in patients with advanced extrapancreatic neuroendocrine tumors. While the high rate of stable disease indicates some level of biological impact, the failure to meet the primary ORR endpoint suggests that this combination is unlikely to become a new standard of care for the general epNET population.
Future research should focus on identifying the small subset of patients who do derive benefit, perhaps through more sophisticated genomic or proteomic screening. Additionally, alternative strategies—such as combining ICIs with bispecific antibodies, CAR-T cell therapy, or novel vaccines—may be required to truly “heat up” the neuroendocrine tumor microenvironment and achieve durable clinical responses.
References
Perez KJ, Horick N, Baginska J, et al. Phase II trial of cabozantinib in combination with nivolumab for advanced extrapancreatic neuroendocrine tumors (epNET). Clin Cancer Res. 2025 Nov 20. doi: 10.1158/1078-0432.CCR-25-2337.
