Novartis Releases Positive Phase 1b/2 Clinical Data for JDQ443 for Treatment of NSCLC

The investigational selective, covalent, and orally bioavailable KRASG12C¬ inhibitor shows a 57% confirmed overall response rate at the recommended dose of 200 mg twice daily.

Novartis released positive clinical data for JDQ443, an investigational selective, covalent, and orally bioavailable KRASG12C­ inhibitor at the American Association for Cancer Research (AACR) Annual Meeting 2022, according to a statement from the company.

Additionally, comprehensive information on the discovery of JDQ443 was also included in a poster presented on April 13, 2022, with further details being published in the journal, Cancer Discovery.

Preliminary data from the KontRASt-01 study showed that JDQ443 demonstrated anti-tumor activity, high systemic exposure at its recommended dose, and a favorable safety profile for individuals with KRAS G12C-mutated solid tumors.

The KontRASt-01 was a phase 1b/2 dose-escalation, multi-center, open-label study of the drug in individuals with advanced solid tumors harboring the KRAS G12C mutation, including colorectal cancer and NSCLC.

The study began in February 2021 and is recruiting to further characterize the safety profile of the drug as both a single agent and in combination with other agents. The estimated primary completion date of the study is 2024.

Investigators found that there was an approximately 57% confirmed overall response rate (ORR) at the 200 mg dose, twice a day, for individuals with NSCLC. Additionally, there was an approximately 45% confirmed and unconfirmed ORR across doses in NSCLC.

There was an approximately 35% confirmed ORR across doses in NSCLC, and the pharmacodynamics/pharmacokinetics modeling predicted sustained, high-level target occupancy at the recommended dose of 200 mg twice daily.

Ongoing open enrollment of the study continues across several arms for single-agent expansion in KRAS G12C-mutated NSCLC and colorectal cancer, as well as with TNO155 and tislelizumab against KRAS G12C-mutated solid tumors.

A phase 3 study, KontRASt-02 of JDQ443 versus docetaxel for locally advanced, metastatic, or previously treated individuals with KRAS G12C-mutated NSCLC is anticipated to begin enrolling participants by mid-2022.

“After decades without a breakthrough, we as an industry are entering a transformative era in targeted treatment for KRAS-mutated cancers,” Jeff Legos, executive vice president and global head of oncology and hematology development at Novartis, said in a statement. “Today’s preliminary data are an encouraging signal that we are on the right path as we continue to investigate single-agent and multiple-combination strategies designed to enhance efficacy of G12C targeted therapy and improve outcomes of patients with KRAS G12C-driven cancers.”.

Additionally, Novartis also debuted its targeted protein degradation platform with presentation on DKY709, a potential first-in-class “molecular glue” protein degrader that is designed to target the zing finger transcription factor Helios.

Transcription factors, which are similar to KRAS G12C, are historically “undruggable” targets, according to the statement.

The clinical data were drawn from a study that investigated DKY709 as a monotherapy and in combination with the anti-PD-1 antibody spartalizumab as treatment for advanced solid tumors.

The discovery and structure of DKY709 were also presented at the AACR Annual Meeting 2022 on April 9, 2022.

Reference

Novartis announces early clinical data for unique KRASG12C inhibitor at American Association for Cancer Research annual meeting. Novartis. News release. April 11, 2022. Accessed April 12, 2022. https://www.novartis.com/news/media-releases/novartis-announces-early-clinical-data-unique-krasg12c-inhibitor-american-association-cancer-research-annual-meeting