opnurasib (JDQ443) / Novartis - LARVOL DELTA

Multicenter study of the impact of trial eligibility criteria on enrollment to KRAS G12C inhibitor trials in patients with non-small cell lung cancer. (ASCO 2025) - " We extracted EC for Phase I-III trials of six KRAS G12C inhibitors (sotorasib, adagrasib, olomorasib, divarasib, JDQ443 and RMC-6291) that were published or made available by sponsors. Our data indicate substantial differences between the real-world population of patients treated with KRAS G12C inhibitors and those who were trial eligible. Efforts should focus on improving clinical trial generalizability without compromising safety."

Clinical • Lung Cancer • Nephrology • Non Small Cell Lung Cancer • Oncology • Renal Disease • Solid Tumor • KRAS

KontRASt-02: Study of JDQ443 in Comparison With Docetaxel in Participants With Locally Advanced or Metastatic KRAS G12C Mutant Non-small Cell Lung Cancer (clinicaltrials.gov) - P3 | N=96 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Oct 2025 ➔ Mar 2026 | Trial primary completion date: Oct 2025 ➔ Feb 2026

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

KontRASt-01: Study of JDQ443 in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation (clinicaltrials.gov) - P1/2 | N=344 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Apr 2026 ➔ Aug 2026 | Trial primary completion date: Apr 2026 ➔ Aug 2026

Trial completion date • Trial primary completion date • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Clinical spectrum and outcomes of KRAS mutated advanced stage NSCLC (ELCC 2025) - "KRAS inhibitors (sotorasib or opnurasib) were given in 18 (26%) G12C pts, with a median PFS of 7.6 mo. In real-world 98% of pts with stage IV KRAS mutant NSCLC received first-line therapy and 53% received further line therapy. In real-world 98% of pts with stage IV KRAS mutant NSCLC received first-line therapy and 53% received further line therapy. There was no influence of KRAS subtype (G12C vs non-G12C) on OS. At disease progression, a median PFS 5.2 mo for docetaxel-treated and 7.6mo for oral KRASi-treated was noted in KRAS G12C pts."

Clinical • IO biomarker • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1

KontRASt-02: Study of JDQ443 in Comparison With Docetaxel in Participants With Locally Advanced or Metastatic KRAS G12C Mutant Non-small Cell Lung Cancer (clinicaltrials.gov) - P3 | N=96 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: May 2025 ➔ Oct 2025 | Trial primary completion date: May 2025 ➔ Oct 2025

Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Neoadjuvant Platform Trial in Non-Small Cell Lung Cancer (clinicaltrials.gov) - P2 | N=4 | Active, not recruiting | Sponsor: Canadian Cancer Trials Group | Recruiting ➔ Active, not recruiting | N=27 ➔ 4

Enrollment change • Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor

KontRASt-03: Platform Study of JDQ443 in Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation (clinicaltrials.gov) - P1/2 | N=74 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Jun 2025 ➔ Dec 2025 | Trial primary completion date: Apr 2025 ➔ Nov 2025

Metastases • Trial completion date • Trial primary completion date • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

KontRASt-01: Study of JDQ443 in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation (clinicaltrials.gov) - P1/2 | N=344 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Aug 2025 ➔ Apr 2026 | Trial primary completion date: Aug 2025 ➔ Apr 2026

Metastases • Trial completion date • Trial primary completion date • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

KontRASt-01: Study of JDQ443 in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation (clinicaltrials.gov) - P1/2 | N=344 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Mar 2026 ➔ Aug 2025 | Trial primary completion date: Mar 2026 ➔ Aug 2025

Metastases • Trial completion date • Trial primary completion date • Colorectal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

KontRASt-02: Study of JDQ443 in Comparison With Docetaxel in Participants With Locally Advanced or Metastatic KRAS G12C Mutant Non-small Cell Lung Cancer (clinicaltrials.gov) - P3 | N=95 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: Sep 2024 ➔ May 2025

Metastases • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Study of Efficacy and Safety of JDQ443 Single-agent as First-line Treatment for Patients With Locally Advanced or Metastatic KRAS G12C- Mutated Non-small Cell Lung Cancer With a PD-L1 Expression < 1% or a PD-L1 Expression ≥ 1% and an STK11 Co-mutation. (clinicaltrials.gov) - P2 | N=96 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial primary completion date: Nov 2026 ➔ Nov 2024

IO biomarker • Metastases • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1 • STK11

KontRASt-01: Study of JDQ443 in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation (clinicaltrials.gov) - P1/2 | N=344 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | Trial completion date: Jan 2027 ➔ Mar 2026 | Trial primary completion date: Jan 2027 ➔ Mar 2026

Enrollment closed • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A Phase II Study of Neoadjuvant Opnurasib KRAS G12C Inhibitor in Patients With Surgically Resectable Non-Small Cell Lung Cancer (CCTG IND.242A): A Substudy of the IND.242 Platform Master Protocol. (PubMed, Clin Lung Cancer) - "Secondary objectives include safety and tolerability of the treatment regimen, objective response rate (ORR) by RECIST 1.1 for the neoadjuvant treatment period, pathological complete response (pCR) rate, event-free survival (EFS) at 2 years, and surgical outcomes. Exploratory objectives are to explore patient related outcomes (PROs) and identify potential predictive biomarkers of response and mechanisms of resistance on tissue and peripheral blood samples."

Journal • P2 data • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ALK • EGFR • KRAS

A Phase 1 Study to Evaluate the Pharmacokinetics of JDQ443 in Participants With Hepatic Impairment Compared to Matched Healthy Control Participants. (clinicaltrials.gov) - P1 | N=33 | Terminated | Sponsor: Novartis Pharmaceuticals | N=48 ➔ 33 | Trial completion date: Aug 2024 ➔ Apr 2024 | Recruiting ➔ Terminated | Trial primary completion date: Aug 2024 ➔ Apr 2024; Sponsor Decision

Enrollment change • Trial completion date • Trial primary completion date • Trial termination • Hepatology • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor

KontRASt-03: Platform Study of JDQ443 in Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation (clinicaltrials.gov) - P1/2 | N=74 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | N=346 ➔ 74

Enrollment change • Metastases • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

KontRASt-03: Platform Study of JDQ443 in Combinations in Patients With Advanced Solid Tumors Harboring the KRAS G12C Mutation (clinicaltrials.gov) - P1/2 | N=346 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | Trial completion date: Jun 2027 ➔ May 2025 | Trial primary completion date: May 2027 ➔ Mar 2025

Enrollment closed • Metastases • Trial completion date • Trial primary completion date • Colorectal Cancer • Gastrointestinal Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Impact of trial eligibility criteria on enrollment to KRAS G12C inhibitor trials in patients with non-small cell lung cancer. (ASCO 2024) - " We extracted EC for Phase I-III trials among six KRAS G12C inhibitors: sotorasib, adagrasib, LY3537982 , divarasib, JDQ443 and RMC-6291. Our findings suggest that most patients with KRAS G12C mutations would not have been eligible for relevant trials, including > 75% of patients who received KRAS G12C inhibitors off-trial after accelerated FDA approval. EC did not expand after early phase trials demonstrated evidence of safety. These data should guide sponsor and FDA considerations in the development of trial protocols for targeted therapies, as fewer barriers to trial participation would enable trials to be completed more quickly and would improve the generalizability of trial results."

Clinical • Lung Cancer • Nephrology • Non Small Cell Lung Cancer • Oncology • Renal Disease • Solid Tumor • KRAS

KontRASt-02: Study of JDQ443 in Comparison With Docetaxel in Participants With Locally Advanced or Metastatic KRAS G12C Mutant Non-small Cell Lung Cancer (clinicaltrials.gov) - P3 | N=95 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Trial completion date: Dec 2025 ➔ May 2025 | Trial primary completion date: Apr 2025 ➔ Sep 2024

Metastases • Trial completion date • Trial primary completion date • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

KontRASt-02: Study of JDQ443 in Comparison With Docetaxel in Participants With Locally Advanced or Metastatic KRAS G12C Mutant Non-small Cell Lung Cancer (clinicaltrials.gov) - P3 | N=95 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting | N=360 ➔ 95

Enrollment change • Enrollment closed • Metastases • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

STRIDER: JDQ443 for KRAS G12C NSCLC Brain Metastases (clinicaltrials.gov) - P2 | N=0 | Withdrawn | Sponsor: Maastricht University Medical Center | N=42 ➔ 0 | Not yet recruiting ➔ Withdrawn

Enrollment change • Trial withdrawal • Brain Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Study of Efficacy and Safety of JDQ443 Single-agent as First-line Treatment for Patients With Locally Advanced or Metastatic KRAS G12C- Mutated Non-small Cell Lung Cancer With a PD-L1 Expression < 1% or a PD-L1 Expression ≥ 1% and an STK11 Co-mutation. (clinicaltrials.gov) - P2 | N=96 | Active, not recruiting | Sponsor: Novartis Pharmaceuticals | Recruiting ➔ Active, not recruiting

Enrollment closed • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS • PD-L1 • STK11

ABCB1 attenuates brain exposure to the KRASG12C inhibitor opnurasib whereas binding to mouse carboxylesterase 1c influences its plasma exposure. (PubMed, Biomed Pharmacother) - "Opnurasib (JDQ443) is a newly developed oral KRASG12C inhibitor, with a binding mechanism distinct from the registered KRASG12C inhibitors sotorasib and adagrasib...The Abcb1a/b transporter activity could be almost completely reversed by co-administration of elacridar, a dual ABCB1/ABCG2 inhibitor, increasing the brain penetration without any behavioral or postural signs of acute CNS-related toxicity...Plasma Ces1c therefore likely binds opnurasib, increasing its retention in plasma. The obtained pharmacokinetic insights may be useful for further optimization of the clinical efficacy and safety of opnurasib, and might reveal potential drug-drug interaction risks."

Journal • Preclinical • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • ABCB1 • ABCG2 • CYP3A4 • KRAS • SLCO1C1

STRIDER: JDQ443 for KRAS G12C NSCLC Brain Metastases (clinicaltrials.gov) - P2 | N=42 | Not yet recruiting | Sponsor: Maastricht University Medical Center | Initiation date: Nov 2023 ➔ Apr 2024

Trial initiation date • Brain Cancer • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

Discovery of JDQ443, a structurally novel, potent and selective covalent oral inhibitor of KRASG12C (ACS-Sp 2024) - "We will share some aspects on the development of a feasible synthetic route for fast SAR exploration. JDQ443 showed dose dependent antitumor efficacy in KRAS G12C -mutated cell-derived models and is currently in clinical development as monotherapy as well as in combination."

Colorectal Cancer • Gastrointestinal Cancer • Lung Adenocarcinoma • Lung Cancer • Non Small Cell Lung Cancer • Oncology • Solid Tumor • KRAS

A Phase 1 Study to Evaluate the Pharmacokinetics of JDQ443 in Participants With Hepatic Impairment Compared to Matched Healthy Control Participants. (clinicaltrials.gov) - P1 | N=48 | Recruiting | Sponsor: Novartis Pharmaceuticals | Active, not recruiting ➔ Recruiting | N=30 ➔ 48

Enrollment change • Enrollment open • Hepatology • Lung Cancer • Oncology • Small Cell Lung Cancer • Solid Tumor