KontRASt-01 Update: Safety and Efficacy of JDQ443 in KRAS G12C-Mutated Solid Tumors Including Non-Small Cell Lung Cancer (NSCLC)

Purpose/Objective(s) KRAS G12C oncogenic mutations occur in ∼13% of NSCLCs and up to 4% of other solid tumors. JDQ443 is a selective, covalent, orally bioavailable KRASG12C inhibitor that irreversibly traps KRASG12C in the inactive, GDP-bound state. Clinical activity was seen in initial cohorts of patients (pts) treated with JDQ443 monotherapy, and 200 mg twice daily (BID) was selected as the recommended dose (RD) for expansion (Tan DS, et al. AACR 2022; Abstract CT033). Materials/Methods KontRASt-01 (NCT04699188) is a Phase Ib/II, open-label, multicenter, dose-escalation (DEs), and dose-expansion (DEx) trial of JDQ443 as a monotherapy or in combination with TNO155 (SHP2 inhibitor) and/or tislelizumab (anti–PD-1 monoclonal antibody). Primary objectives of DEs are to assess safety/tolerability and identify the RD and regimens for future studies. The primary objective of DEx is to assess efficacy. Key inclusion criteria: advanced, KRAS G12C-mutated solid tumors; previous standard-of-care treatment; age ≥ 18 years; and ECOG PS 0-1. Prior KRASG12C inhibitor treatment is not permitted for the JDQ443 monotherapy arm and is allowed for the JDQ443 + TNO155 and JDQ443 + tislelizumab DEs arms. Results As of October 28, 2022, 84 pts were treated with JDQ443 monotherapy, orally, continuously, in DEs, DEx, and food effect (FE) cohorts at 200 mg once daily (QD; n = 10), 400 mg QD (n = 11), 200 mg BID (n = 56), and 300 mg BID (n = 7). Median age was 61 years (range 26-83); median prior lines of therapy was 3 (range 1-7); and indications included NSCLC (n = 38), colorectal cancer (n = 42), and others (n = 4). Median duration of exposure was 14.6 weeks (range 0.1-68.4) for all pts and 15.1 weeks (0.1-68.1) for pts treated at 200 mg BID. Among pts treated at 200 mg BID, 40 (71.4%) and 4 (7.1%) experienced treatment-related adverse events (TRAEs) of any grade (Gr) and of Gr 3, respectively. There were no Gr 4/5 TRAEs at any dose level. The most common TRAEs (any Gr, occurring in ≥ 10% of pts) at 200 mg BID were fatigue (17.9%), edema (14.3%), diarrhea (16.1%), nausea (16.1%), vomiting (10.7%), and peripheral neuropathy (10.7%). Gr 3 TRAEs were neutropenia in 2 pts, ALT and AST increase in 1 pt, and myalgia in 1 pt. One pt receiving 200 mg BID required a dose reduction due to a TRAE of Gr 2 peripheral neuropathy. Among response evaluable pts with NSCLC treated in DEs and FE cohorts, the confirmed overall response rate was 41.7% (10/24 pts) across dose levels and 54.5% (6/11 pts) at the RD of 200 mg BID. Combination JDQ443 + TNO155 and JDQ443 + tislelizumab arms are enrolling. Additional data will be available at the time of presentation. Conclusion JDQ443 demonstrates an acceptable safety and tolerability profile at 200 mg BID, with clinical activity in pts with NSCLC. Enrollment is ongoing to the JDQ443 monotherapy DEx and the JDQ443 + TNO155 and JDQ443 + tislelizumab combination arms. KRAS G12C oncogenic mutations occur in ∼13% of NSCLCs and up to 4% of other solid tumors. JDQ443 is a selective, covalent, orally bioavailable KRASG12C inhibitor that irreversibly traps KRASG12C in the inactive, GDP-bound state. Clinical activity was seen in initial cohorts of patients (pts) treated with JDQ443 monotherapy, and 200 mg twice daily (BID) was selected as the recommended dose (RD) for expansion (Tan DS, et al. AACR 2022; Abstract CT033). KontRASt-01 (NCT04699188) is a Phase Ib/II, open-label, multicenter, dose-escalation (DEs), and dose-expansion (DEx) trial of JDQ443 as a monotherapy or in combination with TNO155 (SHP2 inhibitor) and/or tislelizumab (anti–PD-1 monoclonal antibody). Primary objectives of DEs are to assess safety/tolerability and identify the RD and regimens for future studies. The primary objective of DEx is to assess efficacy. Key inclusion criteria: advanced, KRAS G12C-mutated solid tumors; previous standard-of-care treatment; age ≥ 18 years; and ECOG PS 0-1. Prior KRASG12C inhibitor treatment is not permitted for the JDQ443 monotherapy arm and is allowed for the JDQ443 + TNO155 and JDQ443 + tislelizumab DEs arms. As of October 28, 2022, 84 pts were treated with JDQ443 monotherapy, orally, continuously, in DEs, DEx, and food effect (FE) cohorts at 200 mg once daily (QD; n = 10), 400 mg QD (n = 11), 200 mg BID (n = 56), and 300 mg BID (n = 7). Median age was 61 years (range 26-83); median prior lines of therapy was 3 (range 1-7); and indications included NSCLC (n = 38), colorectal cancer (n = 42), and others (n = 4). Median duration of exposure was 14.6 weeks (range 0.1-68.4) for all pts and 15.1 weeks (0.1-68.1) for pts treated at 200 mg BID. Among pts treated at 200 mg BID, 40 (71.4%) and 4 (7.1%) experienced treatment-related adverse events (TRAEs) of any grade (Gr) and of Gr 3, respectively. There were no Gr 4/5 TRAEs at any dose level. The most common TRAEs (any Gr, occurring in ≥ 10% of pts) at 200 mg BID were fatigue (17.9%), edema (14.3%), diarrhea (16.1%), nausea (16.1%), vomiting (10.7%), and peripheral neuropathy (10.7%). Gr 3 TRAEs were neutropenia in 2 pts, ALT and AST increase in 1 pt, and myalgia in 1 pt. One pt receiving 200 mg BID required a dose reduction due to a TRAE of Gr 2 peripheral neuropathy. Among response evaluable pts with NSCLC treated in DEs and FE cohorts, the confirmed overall response rate was 41.7% (10/24 pts) across dose levels and 54.5% (6/11 pts) at the RD of 200 mg BID. Combination JDQ443 + TNO155 and JDQ443 + tislelizumab arms are enrolling. Additional data will be available at the time of presentation. JDQ443 demonstrates an acceptable safety and tolerability profile at 200 mg BID, with clinical activity in pts with NSCLC. Enrollment is ongoing to the JDQ443 monotherapy DEx and the JDQ443 + TNO155 and JDQ443 + tislelizumab combination arms.