(P 134) PHASE II STUDY OF RUCAPARIB AND NIVOLUMAB IN PATIENTS WITH LEIOMYOSARCOMA

Objective: Despite immune infiltrates, drugs inhibiting PD-1 have demonstrated limited activity in patients with leiomyosarcoma (LMS). DNA-damaging agents such as PARP inhibitors have the potential to enhance the immune response by neoantigen release through the accumulation of DNA damage, upregulation of interferons and upregulation of PD-L1 leading to a more immune responsive tumor microenvironment (TME). Preclinical work suggests synergy between PD-1 and PARP inhibitors. The TOPACIO study, of niraparib and pembrolizumab in recurrent ovarian cancer demonstrated benefit in patients with BRCAwt or homologous recombination (HR) proficient tumors. In addition, most LMS, and particularly uterine LMS (uLMS) appear to harbor features of BRCAness, similar to ovarian and breast cancer providing further rationale for this study. The primary objective is to evaluate the efficacy of the PARP inhibitor rucaparib given in combination with the PD-1 inhibitor nivolumab in patients with advanced LMS. Secondary and exploratory objectives include demonstrating the safety and tolerability of this combination, determining the PFS and OS and to identify biomarkers of response.

Methods: This is an open-label, single-center, single arm, phase II study. Patients with advanced, measurable LMS are required to have had > 1 but no more than three prior lines of therapy, and available archival tissue. Patients are treated with rucaparib 600 mg, orally, twice daily, continuously and nivolumab 480 mg IV on D1 of a 28- day cycle. Re-staging scans are performed every 8 weeks. The primary objective of this study is to evaluate the efficacy, as assessed by the best ORR (CR+PR) by 24 weeks by RECIST 1.1. Based on a one-stage design if ≥ 3 patients respond by 24 weeks, the treatment will be considered effective (91% power; α = 8%).

Results: 20 patients with LMS have been enrolled. Median age is 58 (range 42-78). The majority of patients are female (85%) and have uLMS (75%). Median prior lines of therapy is 2. 17 patients are currently evaluable for the primary objective. To date there is one PR (-59%), in a patient with uLMS with a BRCA2 13q13.1 deletion. 8 (47.0%) patients have had a best response of stable disease. 4 patients remain on study including the patient with a PR. Median PFS is 7.8 weeks (95% CI: 7 - 39 wks) and OS is 9.4 months (95% CI: 7.4 mo - NE). All patients are evaluable for safety. The most common (≥25%) related, all-grade AEs were nausea (40%), fatigue (35%), diarrhea (30%), anorexia, taste change and vomiting (25% each). The most common related AEs ≥ grade 3 included febrile neutropenia, leukopenia and pneumonitis (n=2 each) and alk phos elevation, AST elevation, ALT elevation, anemia, fatigue, neutropenia (n= 1 each). AE’s leading to treatment discontinuation occurred in 2 patients for cytopenias (n=1) and worsening renal function (n=1).

Conclusion: To date the activity of this combination in patients with LMS has been minimal. Updated response data as well as correlative analyses will be provided at the meeting.