opnurasib (JDQ443)

P2, N=42, Not yet recruiting, Maastricht University Medical Center | Initiation date: Nov 2023 --> Apr 2024

P1, N=48, Recruiting, Novartis Pharmaceuticals | Active, not recruiting --> Recruiting | N=30 --> 48

P1, N=30, Active, not recruiting, Novartis Pharmaceuticals | Recruiting --> Active, not recruiting

Erlotinib was used as internal standard and acetonitrile was utilized to treat 10 µl of the sample with protein precipitation in a 96-well plate format. Opnurasib in mouse plasma was stable up to 12 h at room temperature, and up to 8 h at room temperature in tissue homogenates (except for kidney up to 4 h). This presented method has been successfully applied to quantify opnurasib in preclinical samples from a mouse study and demonstrated its usability to support preclinical pharmacokinetic studies.

TBD

TBD

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.

To identify rational combination strategies that could help overcome or prevent some types of resistance, we evaluated the duration of tumor responses to JDQ443 ± TNO155, alone or combined with the PI3Kα inhibitor alpelisib and/or the CDK4/6 inhibitor ribociclib, in xenograft models derived from a KRASG12C-mutant NSCLC line and investigated the genetic mechanisms associated with loss of response to combined KRASG12C/SHP2 inhibition. Overall, KRAS G12C amplification and alterations of the MAPK/PI3K pathway were predominant mechanisms of resistance to combined KRASG12C/SHP2 inhibitors in preclinical settings. The biological nodes identified by CRISPR screening might provide additional starting points for effective combination treatments.

P1, N=48, Recruiting, Novartis Pharmaceuticals | Suspended --> Recruiting

JDQ443 demonstrates an acceptable safety and tolerability profile at 200 mg BID, with clinical activity in NSCLC pts. Enrollment is ongoing to the JDQ443 monotherapy DEx and the JDQ443+TNO155 and JDQ443+tislelizumab arms.

P2, N=42, Not yet recruiting, Maastricht University Medical Center

JDQ443+TNO155 was tolerated with notable toxicities of edema, cytopenias, and fatigue. MTD was not reached; the RD for further evaluation was selected based on collective safety, pharmacokinetics, and efficacy. Preliminary anti-tumor activity was observed, including in KRASG12C inhibitor previously-treated NSCLC.

P3, N=360, Recruiting, Novartis Pharmaceuticals | Trial completion date: May 2025 --> Dec 2025

P1/2, N=346, Recruiting, Novartis Pharmaceuticals | Trial completion date: Aug 2025 --> Jun 2027 | Trial primary completion date: Jun 2025 --> May 2027

P2, N=27, Recruiting, Canadian Cancer Trials Group | Not yet recruiting --> Recruiting

P1/2, N=475, Recruiting, Novartis Pharmaceuticals | Trial completion date: May 2025 --> Jan 2027 | Trial primary completion date: May 2025 --> Jan 2027

P2, N=27, Not yet recruiting, Canadian Cancer Trials Group | Initiation date: Jan 2023 --> May 2023

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. Clinical trial information: NCT04699188.

The KontRASt-02 study is currently enrolling pts. Clinical trial information: NCT05132075.

Reused with permission. Clinical trial information: NCT05445843.

P3, N=360, Recruiting, Novartis Pharmaceuticals | Trial completion date: Jan 2025 --> May 2025 | Trial primary completion date: Jan 2025 --> Apr 2025

However, not all patients respond (sotorasib - ORR = 37.1%, adagrasib - 43%, JDQ443 - 35%), motivating preclinical and clinical investigation into mechanisms of intrinsic and acquired resistance. Moreover, we observed distinct persister subpopulations with resistance to KRAS G12Ci combination co-targeting orthogonal pathways (SHP2, CDK4/6, PI3K, and MCL-1), raising the possibility that distinct epigenetic-transcriptional states contribute to differential drug response and clonal evolution of persisters. Collectively, these results suggest that more complete tumor regression may be achieved by orthogonal strategies that target different resistant populations within the same tumor.

KRASG12C mutant-inhibitors, including AMG-510 (sotorasib), MRTX849 (adagrasib), and JDQ443 have demonstrated efficacy in KRASG12C-mutant cancers, including NSCLC. Expression of the mutant KRAS alleles were readily confirmed from RNA sequencing data in all models. Gene expression analysis showed differential expression of MAPK pathway genes in monotherapy versus combination therapy treated groups.In summary, ulixertinib combined with adagrasib exhibited robust pre-clinical activity in a variety of xenograft models with KRASG12C and should be further evaluated.

Other secondary endpoints include progression-free survival, overall survival, safety, pharmacokinetics, and pt-reported outcomes. A comprehensive biomarker strategy aims to investigate predictors of treatment response and resistance in the study population.

P3, N=360, Recruiting, Novartis Pharmaceuticals | Trial completion date: May 2025 --> Jan 2025 | Trial primary completion date: Aug 2024 --> Jan 2025

P1/2, N=375, Recruiting, Novartis Pharmaceuticals | Trial completion date: Aug 2024 --> May 2025 | Trial primary completion date: Aug 2024 --> May 2025

P1/2, N=346, Recruiting, Novartis Pharmaceuticals | Initiation date: Jan 2022 --> Oct 2022

P1/2, N=346, Recruiting, Novartis Pharmaceuticals | Initiation date: Oct 2022 --> Jan 2022

P2, N=120, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

JDQ443 showed PK/PD activity in vivo and dose-dependent antitumor activity in mouse xenograft models. JDQ443 is now in clinical development, with encouraging early phase data reported from an ongoing Phase Ib/II clinical trial (NCT04699188).

P1/2, N=346, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

P2, N=120, Not yet recruiting, Novartis Pharmaceuticals

P3, N=360, Recruiting, Novartis Pharmaceuticals | Not yet recruiting --> Recruiting

P3, N=360, Ongoing, Novartis Pharma AG

P1/2, N=450, Not yet recruiting, Novartis Pharmaceuticals

P3, N=360, Not yet recruiting, Novartis Pharmaceuticals | Trial completion date: Nov 2025 --> May 2025 | Initiation date: Mar 2022 --> Jul 2022 | Trial primary completion date: Feb 2024 --> Aug 2024

JDQ443 in vivo activity against a panel of KRASG12C NSCLC (n=10) and CRC (n=9) PDX models was assessed either as a single agent or in combination with TNO155 (SHP2 inhibitor [i]), trametinib (MEKi), or ribociclib (CDK4/6i). JDQ443 demonstrates significant activity against a broad range of KRASG12C solid tumor models, both in vitro and in vivo, that is increased when combined with agents targeting both upstream and downstream components of the RAS signaling pathway. The combination benefit of JDQ443 + TNO155 over JDQ443 alone is maintained at reduced doses for both agents.

JDQ443 is structurally unique and forms novel interactions with KRAS in the switch II pocket. 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). 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.

P3, N=360, Not yet recruiting, Novartis Pharmaceuticals

No abstract available

P1/2, N=345, Recruiting, Novartis Pharmaceuticals | Trial completion date: Mar 2022 --> Aug 2024 | Trial primary completion date: Mar 2022 --> Aug 2024