LBA11504 Randomized phase II trial of cabozantinib combined with PD-1 and CTLA-4 inhibition versus cabozantinib in metastatic soft tissue sarcoma.

Background: Cabozantinib (C) has been combined successfully with either PD-1 or CTLA-4 inhibition in cancer clinical trials. The combination of nivolumab (N) and ipilimumab (I) previously was evaluated in soft tissue sarcoma (STS) and demonstrated activity as well as an acceptable safety profile. Given these data, we hypothesize that C in combination with both I and N is a therapeutic strategy that will be more effective than C alone in metastatic STS that lack translocations. Additionally, we hypothesized that C priming would enhance the efficacy of combination I and N at the time of crossover. Methods: This is a 2:1 randomized phase 2 clinical trial evaluating the overall response rate (RR) of C 40mg orally daily in combination with I (1mg/kg IV) / N (3mg/kg) for 4 doses Q3W and then maintenance N 480mg Q4W compared to C 60mg oral alone, with crossover. Secondary endpoints include progression free survival (PFS), disease control rate (DCR), RR in crossover, quality of life by FACT-G7, RR by iRECIST and safety. Correlative and biomarker analysis are preplanned. Key patient selection includes ECOG 0-1, 1-2 lines of prior therapy, and sarcomas that lack of translocations. The trial was balanced for leiomyosarcoma (LMS), liposarcoma and UPS. Results: 69 patients were randomized to C+I/N and 36 patients were randomized to C alone. 19 patients crossed over to C+I/N at progression. 54/105 patients had LMS. RR of C+I/N was 11% (5 PR and 2 CR), while the RR of C was 6% (2 PR and 0 CR) (p = NS). C+I/N responding histologies included LMS, angiosarcoma, epithelioid sarcoma, and myxofibrosarcoma. C responding histologies included 2 PRs in LMS. There were also 2 LMS PRs in crossover to C+I/N. The median PFS for C+I/N was 5.4 months and for C was 3.8 months (p = 0.016). The DCR for C+I/N was 80% (41 SD, 5 PR, 2 CR), and 42% for C (11 SD, 2 PR) (p = 0.0004). The most common grade 3-4 adverse events affecting > 10% of patients included hypothyroidism, diarrhea, mucositis, oral dysesthesia, nausea, vomiting, elevated AST and ALT, anorexia, dysgeusia, headache, pruritis, maculopapular rash, and hypertension for C+I/N and hypothyroidism, diarrhea, oral dysesthesia, fatigue, palmar-plantar erythrodysesthesia, and hypertension for C. Conclusions: The combination of C+I/N was superior to C for the treatment of non-translocation STS for DCR and PFS. Most frequent responding histology was LMS. Correlative work is ongoing.