A phase 2, open-label, multi-center, single-arm study of atezolizumab and bevacizumab in the treatment of second line and beyond, recurrent/metastatic endometrial cancer.

2576 Background: The treatment paradigm for advanced/recurrent endometrial cancer (EC) is undergoing rapid transformation. Currently, use of immune checkpoint inhibitors (ICI) is standard of care for deficient mismatch repair (dMMR) tumors in the front line setting and ICI “can” be used in proficient MMR (pMMR). The purpose for this study is to evaluate an alternative ICI and anti-angiogenic regimen, atezolizumab plus bevacizumab in pts with recurrent EC with no prior ICI use and to identify blood-based correlates of non-responders early in treatment. Methods: This multicenter, single-arm, open label phase 2 trial (NCT03526432) enrolled pts with recurrent EC who had relapsed following platinum based chemotherapy. No prior ICI was allowed. Treatment consisted of atezolizumab 1,200 mg plus bevacizumab 15 mg/kg iv on day 1 every 21 days until progression or toxicity. The primary endpoint was objective response rate (ORR). Peripheral whole blood was collected at baseline and after 2 cycles of therapy, and high-dimensional immune profiling was performed. Results: Sixty-five pts were enrolled and received at least one dose of trial treatment. Fifty-six pts were response-evaluable (45 with pMMR tumors, 7 with dMMR tumors and 4 with unknown MMR status). Median age was 65 years. All pts had received at least one prior chemotherapy and 22 pts (39.3%) received prior radiation therapy. The ORR was 33.9%; 95% CI, 21.8 to 47.8; (19/56 patients), which include 5 complete and 14 partial responses; median duration of response (DOR) was 16 months. In addition, 63% of pts survived progression-free for at least 6 months. The median PFS was 8.8 months (95% CI, 5.5 to 12.0). The median OS was 41.55 months (95% CI, 27.0 – 57.5). The most common grade 3 or 4 adverse events were hypertension (21.5%), fatigue (7.7%) and diarrhea (7.7%). In peripheral blood analysis, non-responders demonstrated expansion of a suppressive myeloid population characterized by PD-L1⁺CD16+ monocytes. There was an increase of ICOS⁺ Tregs consistent with an immunosuppressive phenotype. Within the effector T cell compartment, central memory CD8⁺ T cells expressing Fas and CD27 expanded in non-responders. Conclusions: The combination of atezolizumab and bevacizumab in patients with recurrent EC and post cytotoxic chemotherapy has efficacy in both dMMR and pMMR populations and a toxicity profile that appears more favorable than other treatments. This data suggests atezolizumab and bevacizumab could be considered as an alternative regimen in the recurrent, metastatic setting among pts who are ICI naïve and for whom there are concerns regarding the adverse events of treatment. Peripheral whole blood analysis of non-responders correlated with immune angiogenic escape mechanism with higher levels of ICOS+Tregs, Fas+CD27+ CD8T cells, and PDL1+ CD16+ monocytes. Clinical trial information: NCT3526432 .