KontRASt: A Phase Ib/II, open-label, multi-center, dose-escalation study of JDQ443 in patients with advanced solid tumors harboring the KRAS G12C mutation

Background Kirsten rat sarcoma virus (KRAS) is a GTPase that regulates cell signaling pathways involved in cell proliferation, survival, and tumorigenesis. Somatic mutations in KRAS resulting in a glycine to cysteine substitution at codon 12 (KRAS G12C) lead to a shift toward active, GTP-bound KRAS and increased oncogenic signaling. KRAS G12C mutations occur in approximately 13% of non-squamous, non-small cell lung cancer (NSCLC) cases, and at lower frequencies in other solid tumor malignancies. JDQ443 (NVP-JDQ443) is a selective, covalent, and orally bioavailable investigational KRAS^G12C inhibitor that binds under the switch II loop, and irreversibly traps KRAS^G12C in a GDP-bound, inactive state. In preclinical models, JDQ443 potently inhibited KRAS^G12C cellular signaling and proliferation in a mutant-selective manner and demonstrated dose-dependent anti-tumor activity. In patients with KRAS G12C-mutated solid tumors, JDQ443 may have clinically significant antitumor activity alone and in combination with TNO155, an investigational, SHP2 inhibitor, and in combination with PD-1 blockade. Methods This is a Phase Ib/II, open-label, dose-escalation study with four arms: (A) JDQ443 monotherapy; (B) JDQ443 + TNO155; (C) JDQ443 + anti–PD-1; and (D) JDQ443 + TNO155 + anti–PD-1. Each arm has a dose-escalation portion followed by dose expansion at the maximum tolerated dose (MTD) and/or recommended dose (RD). The escalations are conducted in adult patients with advanced KRAS G12C-mutated solid tumors who have previously received standard-of-care therapies. Dose escalation is guided by an adaptive Bayesian hierarchical logistic regression model following the escalation with overdose control principle. Expansions are planned for patients with advanced (metastatic or unresectable), KRAS G12C-mutated NSCLC who have received prior immune checkpoint inhibitor therapy and platinum-based chemotherapy, and for patients with advanced, KRAS G12C-mutated colorectal cancer who have received prior fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy. The primary objectives of dose escalation are to assess the safety and tolerability of JDQ443 alone and in combinations, and to identify the MTD and/or the RD, and regimens for future studies. The primary objective of dose expansion is to evaluate the antitumor activity via overall response rates for JDQ443, both alone and in combinations, in selected populations. Secondary objectives for both escalation and expansion are to evaluate the antitumor activity and characterize the pharmacokinetics of JDQ443 alone and in combinations, and to assess the immunogenicity of anti–PD-1 in combination with JDQ443 or TNO155. Safety and tolerability will also be further assessed during dose expansion. The study is currently enrolling to the dose-escalation portions of Arm A (JDQ443 monotherapy) and Arm B (JDQ443 + TNO155). NCT04699188 Citation Format: Benjamin Solomon, Rebecca S Heist, Daniel SW Tan, Philippe A Cassier, Christophe Dooms, Eric Van Cutsem, Conor E Steuer, Neeltje Steeghs, Martin Schuler, Anas Gazzah, Martin Wermke, Enriqueta Felip, Herbert HF Loong, Maria J De Miguel Luken, Ross A Soo, Ashley Jaeger, Kun Xu, Xueying Chen, Xiaoming Cui, Heather Burks, Anna F Farago, Toshio Shimizu. KontRASt: A Phase Ib/II, open-label, multi-center, dose-escalation study of JDQ443 in patients with advanced solid tumors harboring the KRAS G12C mutation [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr LBA038.