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Supplementary Data from Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent, and Selective Covalent Oral Inhibitor of KRASG12C

Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRASG12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRASG12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with inhibitors of SHP2, MEK, or CDK4/6. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRASG12C-mutated tumors.Significance:JDQ443 is a structurally novel covalent KRASG12C inhibitor with a unique binding mode that demonstrates potent and selective antitumor activity in cell lines and in vivo models. In preclinical models and patients with KRASG12C-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155.See related video: https://vimeo.com/720726054This article is highlighted in the In This Issue feature, p. 1397

Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor of GDP-bound KRASG12C that forms novel interactions with the switch II pocket. JDQ443 potently inhibits KRASG12C-driven cellular signaling and demonstrates selective antiproliferative activity in KRASG12C-mutated cell lines, including those with G12C/H95 double mutations. In vivo, JDQ443 induces AUC exposure-driven antitumor efficacy in KRASG12C-mutated cell-derived (CDX) and patient-derived (PDX) tumor xenografts. In PDX models, single-agent JDQ443 activity is enhanced by combination with inhibitors of SHP2, MEK, or CDK4/6. Notably, the benefit of JDQ443 plus the SHP2 inhibitor TNO155 is maintained at reduced doses of either agent in CDX models, consistent with mechanistic synergy. JDQ443 is in clinical development as monotherapy and in combination with TNO155, with both strategies showing antitumor activity in patients with KRASG12C-mutated tumors. Significance: JDQ443 is a structurally novel covalent KRASG12C inhibitor with a unique binding mode that demonstrates potent and selective antitumor activity in cell lines and in vivo models. In preclinical models and patients with KRASG12C-mutated malignancies, JDQ443 shows potent antitumor activity as monotherapy and in combination with the SHP2 inhibitor TNO155. See related video: https://vimeo.com/720726054 This article is highlighted in the In This Issue feature, p. 1397

Background: KRAS G12C oncogenic mutations occur in ~13% of non-small cell lung cancers (NSCLCs) and up to 4% of other solid tumors. JDQ443 is a selective, covalent, orally bioavailable, investigational KRASG12C inhibitor that irreversibly traps KRASG12C in the inactive, GDP-bound state. JDQ443 is structurally unique and forms novel interactions with KRAS in the switch II pocket. Methods: KontRASt-01 (NCT04699188) is a Phase Ib/II, open-label, multicenter, dose-escalation and dose-expansion trial of JDQ443 as monotherapy or in combination with TNO155 (SHP2 inhibitor) and/or tislelizumab (anti-PD-1 monoclonal antibody). Primary objectives of dose escalation are to assess safety and tolerability, and identify the maximum tolerated doses (MTDs) and/or recommended doses (RDs) and regimens for future studies. The primary objective of dose expansion is to assess efficacy. Key inclusion criteria: advanced, KRAS G12C-mutated solid tumors; previous standard-of-care treatment; age ≥18 yrs; ECOG PS 0-1. Key exclusion criteria for the JDQ443 monotherapy arm: active brain metastases, prior KRASG12C inhibitor treatment. Here, we present preliminary results for JDQ443 monotherapy dose escalation. Results: As of Nov 3, 2021, 39 pts were treated with JDQ443 PO continuously across 4 dose levels: 200 mg once daily (QD) (n=10), 400 mg QD (n=11), 200 mg twice daily (BID) (n=11), and 300 mg BID (n=7). Median age was 60 yrs (range 26-76), median prior lines of therapy was 3 (range 1-7), and indications included NSCLC (n=20) and colorectal cancer (CRC) (n=16). Median duration of exposure was 9.1 wks (range 0.9-21), with ongoing treatment in most pts (61.5%) at the time of cut-off. Treatment-related adverse events (TRAEs) occurred in 25 (64.1%) pts. Most TRAEs were Grade (Gr) 1-2. Four Gr 3 TRAEs occurred in 4 (10.3%) separate pts; there were no Gr 4-5 TRAEs. The most common TRAEs (occurring in ≥10% of pts) were fatigue (25.6%), nausea (15.4%), edema (12.8%), pruritus (10.3%), and vomiting (10.3%). There was one DLT (Gr 3 fatigue) and one treatment-related serious AE (Gr 3 photosensitivity reaction), each in separate pts treated at 300 mg BID. TRAEs led to dose reduction in 1 pt and discontinuation in 1 pt. A MTD was not reached. The RD was declared as 200 mg BID. At the RD, PK and PD modeling for JDQ443 predicted average KRASG12C target occupancy of >90% in >82% of pts. Using an efficacy cut-off date of Dec 13, 2021, for the 20 pts with NSCLC among the same 39 pts, the ORR (confirmed complete response or partial response) by RECIST 1.1 was 30.0% (6/20) across dose levels and 43.0% (3/7) at the RD. Additional data will be available at the time of presentation. Conclusions: JDQ443 demonstrates an acceptable safety and tolerability profile, with early signs of clinical activity in pts with NSCLC. Enrollment is ongoing to NSCLC and CRC dose-expansion groups for JDQ443 monotherapy at the RD, and to JDQ443 + TNO155 dose escalation. Citation Format: Daniel S. Tan, Toshio Shimizu, Benjamin Solomon, Rebecca S. Heist, Martin Schuler, Maria J. De Miguel Luken, Anas Gazzah, Martin Wermke, Christophe Dooms, Herbert H. Loong, Neeltje Steeghs, Enriqueta Felip, Conor E. Steuer, Eric van Cutsem, Ross A. Soo, Ashley C. Jaeger, Jaeyeon Kim, Kun Xu, Xueying Chen, Xiaoming Cui, Heather Burks, Anna Farago, Philippe A. Cassier. KontRASt-01: A phase Ib/II, dose-escalation study of JDQ443 in patients (pts) with advanced, KRAS G12C-mutated solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT033.

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 KRASG12C inhibitor that binds under the switch II loop, and irreversibly traps KRASG12C in a GDP-bound, inactive state. In preclinical models, JDQ443 potently inhibited KRASG12C 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.

Two isomeric salicylic aldehyde nucleobases have been prepared and incorporated into various DNA duplexes. Reaction with ethylenediamine leads to formation of the well-known salen ligand inside the DNA double helix. Addition of transition-metal ions such as Cu 2+ , Mn 2+ , Ni 2+ , Fe 2+ , or VO 2+ results in the formation of metal-salen-base-pair complexes, which were studied by using UV and circular dichroism (CD) spectroscopy. HPLC and ESI mass spectrometric measurements reveal an unusually high stability of the DNA-metal system. These metal-salen complexes act as interstrand cross-links and thereby lead to a strong stabilization of the DNA duplexes, as studied by thermal de- and renaturing experiments. Complex formation is strong enough to override sequence information even when the pre-organization of the ligand precursors is unfavorable and the DNA duplex is distorted by the metal complexation. Furthermore, melting-point studies show that the salen complex derived from ligand 2 fits better into the DNA duplex, in accordance with results obtained from the crystal structure of the corresponding copper-salen complex 8.