Leukocyte immunoglobulin-like receptor (LILRB2)-targeted JTX-8064 plus the anti-PD1 inhibitor JTX-4014 (pimivalimab) in immune-checkpoint inhibitor (ICl) pretreated patients (pts) with advanced or metastatic renal cell cancer (mRCC): Results from the multi-stage phase 1-2 INNATE trial.

Abstract

4531 Background: Disease progression following treatment of mRCC pts with ICl-based therapy (tx) is nearly universal, warranting evaluation of novel immunotherapeutic approaches. LILRB2 is an immune checkpoint molecule expressed primarily in cells of myeloid origin (e.g., monocytes/macrophages). Inhibition of LILRB2 reprograms macrophages from an immunosuppressive (M2) to an immunostimulatory (M1) phenotype. JTX-8064 is a humanized monoclonal antibody that binds to LILRB2, blocking its interaction with MHC1 molecules. Preclinical studies suggest that JTX-8064 can overcome anti-PD(L)1 resistance mechanisms. Here we report the results of an expansion cohort of previously-treated mRCC pts in INNATE, a multi-stage phase 1-2 trial of JTX-8064 in combination with anti-PD1 agents in solid tumors. Methods: Pts with pathologically-confirmed clear cell mRCC progressing on or after anti-PD(L)1 tx in the most recent prior line, acceptable end-organ function, and ECOG PS 0-1 were treated with JTX-8064 700 mg and JTX-4014 500 mg IV q3 weeks. Primary endpoint was overall response rate (ORR); secondary endpoints were safety, disease control rate (DCR), progression-free survival (PFS), & overall survival (OS). A Simon 2-stage design (n=10+19) was employed where ORR >= 20% was deemed to be of further interest versus null hypothesis of ORR <= 5%, with alpha=0.05. Results: 31 pts were enrolled, with median age of 64 years (range 38-85); 84% males; 16% Hispanic; 93% White; 45% PS=0; 71% one prior tx line. Of 28 pts evaluable for response, 1 CR, 1 PR, 14 SD (6 SD>= 6 months), and 11 PD were seen for an ORR of 7% & DCR of 54%.Median PFS was 4 months (95%CI: 2, 6.8); 12-month OS was 75% (95%CI: 55,88). Tx-related adverse events (AE) of all grades were reported in 11 pts (45%), most commonly fatigue (16%) & diarrhea (10%). Only 4 protocol-related G3-4 AEs were reported: thrombocytopenia (G4); diplopia, diarrhea, & bradycardia (all G3). Three on-study deaths (hypotension; cardiorespiratory arrest; & unknown) were deemed unrelated to protocol tx. Conclusions: While ORR did not meet the protocol-defined efficacy target, evidence of anti tumor activity was seen in ICI pre-treated mRCC pts with combination JTC-8064 + JTX-4014. Treatment was reasonably well-tolerated. Identification & evaluation of clinical and molecular phenotypes most likely to benefit from LILRB2-targeted therapies are warranted. Clinical trial information: NCT04669899 .