A randomized phase II trial of cabozantinib combined with PD-1 and CTLA-4 inhibition in metastatic soft tissue sarcoma.

Abstract

TPS11583 Background: Soft tissue sarcomas (STS) are rare malignancies with poor prognosis in the metastatic setting. Current standard therapy includes anthracycline based chemotherapy. Cabozantinib is a multikinase inhibitor that has demonstrated efficacy in solid tumors such as renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC). A phase II study of cabozantinib in advanced STS is underway. Cabozantinib in combination with immune checkpoint blockade has shown clinical benefit in several tumor types including HCC, RCC, non-small cell lung cancer, and urothelial carcinoma. Since cabozantinib may alter PD-1 expression in regulatory T-cells and promote an immune permissive environment, we hypothesize that combining cabozantinib with immune checkpoint inhibition is a therapeutic strategy that will be more effective than cabozantinib alone. Additionally, the design of the trial will allow assessment of whether pretreatment with cabozantinib will enhance the efficacy of nivolumab and ipilimumab alone. Methods: This is an open label, multicenter, randomized phase II clinical trial of cabozantinib (60mg orally daily as a single agent, 40mg in combination) with or without combination Ipilimumab (ipi, 1mg/kg IV every 3 weeks for 4 doses) and Nivolumab (nivo, 3mg/kg IV every 3 weeks for four doses, then 480mg IV every 4 weeks) in patients (pts) with unresectable or metastatic STS refractory to up to two lines of chemotherapy. 105 pts with non-translocation driven sarcomas will be enrolled at three US sites and randomized 2:1 to the combination group. Pts will be stratified by prior pazopanib use and balanced for histologies. Patients who progress on arm A will cross over to combination therapy (arm B). The primary efficacy endpoint is objective response rate (ORR) by RECIST 1.1. 35 patients in Cohort A (cabozantinib alone) and 70 patients in Cohort B (cabozantinib plus ipi/nivo) will be required to detect an increase of the ORR from 10% in cohort A to 30% in cohort B with 81% power with a one-sided alpha level of 10%. Key eligibility criteria include: at least 18 years of age, ECOG performance status of 0 or 1, ≤2 prior lines of therapy and measurable disease. Exclusion criteria include: translocation-driven sarcoma except alveolar soft part sarcoma (ASPS), prior immunotherapy, and chronic use of corticosteroids or other immunosuppression. Secondary endpoints are safety, overall and progression free survival, disease control rate, and response rate to ipilimumab and nivolumab after cabozantinib pretreatment. Mandatory tumor biopsies pre-treatment and at 6 weeks will be obtained. Peripheral blood will be collected for circulating immune phenotyping. Enrollment will occur at 3 participating institutions and is expected to be completed in 2022. Clinical trial information: NCT04551430.

Case report: Robust response of metastatic clear cell sarcoma treated with cabozantinib and immunotherapy

“…The Children Oncology Group published a phase I study of cabozantinib for resistant solid tumor malignancies (e.g., medullary thyroid carcinoma, wilms tumor, synovial sarcoma), with good tolerability ( 43 ). Recently, data emerging in clinical trials evaluating cabozantinib as soft tissue sarcoma treatment, show promising results, with high tolerability of treatment and effective stabilization of the disease ( 44 , 45 ) and when cabozantinib is combined with immune checkpoint inhibitors ( 46 ).…”

“…The question arises is there contribution of the immunotherapy to the lasting effect of cabozantinib? Early reports imply there is ( 46 ). In kidney cancer this combination is now the standard of care.…”

Therapeutic advances in leiomyosarcoma

“…Only 1 patient with non-uterine LMS achieved a partial response ( 61 ). An ongoing phase 2 trial is testing the combination of cabozantinib (small molecule inhibitor of receptor tyrosine kinases, VEGF, MET, and AXL) with ipilimumab and nivolumab, and is currently enrolling patients (NCT04551430) ( 62 ). Another combination approach involves immune checkpoint blockade with PARPi.…”

Special Issue: “Pediatric Orthopedic Malignancy: Types, Symptoms, and Treatment”

“…Recently, the efficacies of various immunotherapies, including dendritic-cell-based immunotherapy, chimeric antigen receptor-modified T cell therapy, adoptive T cell therapy, and immune check inhibitors, have been investigated in several clinical trials [ 49 , 50 , 51 , 52 , 53 ]. For instance, a combination therapy with cabozantinib, nivolumab, and ipilimumab for metastatic soft tissue sarcoma lacking translocation was reported in a randomized phase 2 clinical trial (NCT04551430) [ 54 ]. The trial involved 69 patients receiving the combination and 36 patients receiving cabozantinib alone with a crossover [ 54 ].…”

“…For instance, a combination therapy with cabozantinib, nivolumab, and ipilimumab for metastatic soft tissue sarcoma lacking translocation was reported in a randomized phase 2 clinical trial (NCT04551430) [ 54 ]. The trial involved 69 patients receiving the combination and 36 patients receiving cabozantinib alone with a crossover [ 54 ]. The combination demonstrated a higher overall disease control rate (80% vs. 42%, cabozantinib with nivolumab and ipilimumab, and cabozantinib alone, respectively), and improved progression-free survival (5.4 vs. 3.8 months, cabozantinib with nivolumab and ipilimumab and cabozantinib alone, respectively) [ 54 ].…”