Phase 2 Study of Cabozantinib (XL184) with Nivolumab and Ipilimumab for the Treatment of Poorly Differentiated Neuroendocrine Carcinomas (ETCTN10315)

Abstract Background Poorly differentiated neuroendocrine carcinomas (NECs) are aggressive malignancies with limited treatment options. The low activity of immune checkpoint inhibitors (ICI) is in part due to an immunosuppressive tumor microenvironment. We hypothesized that adding cabozantinib to dual ICIs may improve clinical outcomes for patients. Methods Patients with advanced or metastatic, poorly differentiated NECs, excluding small cell lung and Merkel cell carcinoma, who progressed on first line systemic therapy enrolled on this Simon’s two-stage trial. Patients received cabozantinib 40 mg daily, 3 mg/kg nivolumab plus 1 mg/kg ipilimumab every 3 weeks for four cycles, followed by maintenance cabozantinib nivolumab. Primary endpoint was ORR. Results Of 17 patients enrolled, 16 were evaluable. ORR was 12.5% (2/16; 95%CI: 1.6-38.3%), with 2 durable (27 and 17 months). Median PFS was 2.7 months (95%CI: 1.8-5.6 months). Grade 3–4 treatment-related adverse events occurred in 9 patients (56%). The most frequent grade ≥3 toxicities were elevated liver enzymes, fatigue, and hypertension. Only one patient discontinued treatment due to toxicity. The study was terminated after the first stage, as it did not meet the threshold for proceeding to stage 2. Conclusion Toxicities were consistent with the known safety profiles of cabozantinib and dual immune checkpoint blockade. Long-term responses were observed in a small subset of patients, but the study did not meet the prespecified efficacy threshold for continued accrual. ClinicalTrials.gov identifier NCT04079712