A dose-escalation study of TNO155 (TN) in combination with spartalizumab (SPA) or ribociclib (RIB) in adults with advanced solid tumors

Abstract

BACKGROUND: NCT03114319 is an ongoing open-label phase I dose escalation/expansion trial of TN, an allosteric inhibitor of SHP2, in combination with the anti-PD-1 antibody, SPA, or the CDK4/6 inhibitor RIB in adults with advanced solid tumors. METHODS: Eligible patients (pts) were treated with either A) TN (5-50 mg BID, 20 or 60 mg QD) on a 2 weeks on/1 week off (2w/1w) schedule with SPA 300 mg once every 3 weeks (Q3W) or B) TN (20-60 mg QD, 20-40 mg BID), 2w/1w or 3w/1w with RIB (150-200 mg QD) continuously, 2w/1w, or 3w/1w (excludes data from Japan-specific escalation). A Bayesian hierarchical model was used to guide dose escalation. The primary objective was to characterize safety and tolerability; secondary objectives were pharmacokinetics (PK) and antitumor activity. RESULTS: As of March 23, 2023, 57 pts were enrolled in arm A (5 pts ongoing) and as of May 5, 2023, 46 pts were enrolled in arm B (2 pts ongoing). Preliminary PK analysis did not show evidence of any drug interaction in either arm. In Arm A, dose-limiting toxicities (DLTs) were reported with TN 20 mg QD, 20 mg BID, 60 mg QD, 40 mg BID, and 50 mg BID. In Arm B, DLTs were reported with TN 40 mg QD 2w/1w + RIB 200 mg QD, TN 60 mg QD 2w/1w + RIB 200 mg QD, TN 40 mg QD 3w/1w + RIB 150 mg QD 3w/1w, TN 30 mg BID 3w/1w + RIB 200 mg QD 3w/1w, TN 40 mg BID 3w/1w + RIB 200 mg QD 3w/1w, and TN 40 mg QD 2w/1w + RIB 200 mg QD 2w/1w. The most common treatment-emergent adverse events were increased aspartate aminotransferase (AST), alanine aminotransferase (ALT), and blood creatine phosphokinase (CPK) in arm A, and thrombocytopenia, anemia, and increased AST, ALT, and blood CPK in arm B. Declared recommended doses (RDs) were TN 60 mg QD 2w/1w + SPA 300 mg Q3W and TN 40 mg QD 2w/1w + RIB 200 mg QD 2w/1w. Per RECIST 1.1, best overall response in Arm A was partial response in 1 pt (head and neck squamous cell carcinoma), stable disease (SD) in 13 pts, progressive disease (PD) in 28 pts, and was not evaluable (NE) in 15 pts, and in Arm B, best overall response was SD in 6 pts, PD in 31 pts, and was NE in 9 pts. Change in tumor DUSP6 expression after treatment will be presented. CONCLUSIONS: TN + SPA and TN + RIB appeared well-tolerated at the RDs. Safety profiles of the combinations were consistent with those observed with each single agent.