Clinical response and pathway-specific correlates following TIGIT-LAG3 blockade in myeloma: the MyCheckpoint randomized clinical trial

Abstract

Persons with myeloma were randomized to receive an anti-TIGIT (T cell immunoreceptor) or anti-LAG3 (lymphocyte activation gene) antibody followed by combination with pomalidomide and dexamethasone ( NCT04150965 ). Primary and secondary endpoints were safety and efficacy, respectively. Therapy was well tolerated without dose-limiting toxicity. Durable clinical responses were observed in both the anti-TIGIT(three of six participants) and the anti-LAG3 (two of six participants) arms. Anti-LAG3 responders had higher naive cluster of differentiation 4 (CD4)-positive T cells and lower programmed cell death protein 1-positive effector T cells. Anti-TIGIT responders had higher CD226 expression, natural killer cell activation and lower CD112 expression. These data demonstrate the clinical activity of TIGIT-LAG3 blockade and identify pathway-specific response correlates in myeloma.

Fig 1.

Trial Schema and clinical response 1A. Patients with relapsed/refractory MM (RRMM) with 3 or more lines of prior therapy were randomly assigned to receive a cycle of therapy with either anti-Lag-3 or anti-TIGIT. For cycle 2 and beyond, the patients also received pomalidomide and dexamethasone. 1B. Spider plots showing reduction in clonal Ig (as percent change from baseline over time) in anti-Lag-3 cohort 1C. Spider plots showing reduction in clonal Ig (as percent change from baseline over time) in anti-TIGIT cohort.

Fig 2.

Correlates of response and resistance to therapy 2A. Bar graph showing staining for TIGIT in circulating immune cells before or after therapy in responders (Resp) or non-responders (NR) either before (Pre-Rx) or after cycle 1 (C1) or cycle 2 (C2) of therapy in patients treated with anti-TIGIT mAb. Loss of staining indicates receptor occupancy by therapeutic antibody. Note that receptor occupancy is seen both in patients with or without response to therapy. Statistical test compares staining in pre-therapy versus post-therapy samples. ** p<0.01, Mann Whitney. MMI: median metal intensity. 2B. Representative plots for TIGIT staining in bone marrow mononuclear cells in a patient with or without response to therapy. 2C. Expression of DNAM-1/CD226 in specified immune cells in blood and bone marrow and correlation with response to therapy in patients treated with anti-TIGIT antibody. Statistical test compares DNAM-1 expression in responders versus non-responders. *p<0.05, Mann Whitney 2D. Expression of CD112 in specified immune cells in blood and bone marrow and correlation with response to therapy in patients treated with anti-TIGIT antibody. Statistical test compares CD112 expression in responders versus non-responders. **p<0.01, Mann Whitney. 2E. Expression of PD-1 in specified immune cells in blood and bone marrow and correlation with response to therapy in patients treated with anti-Lag-3 antibody. Statistical test compares PD-1 expression in post-treatment samples from responders versus non-responders. *p<0.05, **p<0.01, ****p<0.0001, Mann Whitney. 2F. Representative plot showing the expression of PD-1 in T cells (expressed as percent positive cells) in a responder or non-responder to anti-Lag-3 therapy.