JDQ443, an investigational selective, covalent, and orally bioavailable KRASG12C inhibitor, shows 57% confirmed ORR at recommended dose of 200 mg twice daily in Phase Ib study in patients with advanced non-small cell lung cancer (NSCLC)
Ongoing investigation of JDQ443 in single agent and multiple combination strategies designed to enhance efficacy of G12C targeted therapy and improve outcomes of patients with KRAS G12C-driven cancers. Phase III study anticipated to begin mid 2022

Innovation in targeted protein degradation also highlighted with debut for protein degrader DKY709, an investigational molecular glue
Basel, April 11, 2022 — Novartis today announced promising clinical data for JDQ443, an investigational selective, covalent, and orally bioavailable KRASG12C inhibitor at the annual meeting of American Association for Cancer Research (AACR). Comprehensive information on the discovery of JDQ443 is also included in a poster being presented on Wednesday 13th April with further details published in the journal Cancer Discovery1.

Preliminary data (Phase Ib) from the KontRASt-01 study (NCT04699188) showed that JDQ443, discovered at Novartis, demonstrated anti-tumor activity, high systemic exposure at its recommended dose, and a favorable safety profile based on initial clinical data in patients with KRAS G12C-mutated solid tumors2. The data were submitted as a late-breaking abstract and will be presented today in an oral session.

KRAS mutations are the most frequent oncogenic drivers in NSCLC, the most common type of lung cancer3. The most common form of KRAS mutation is G12C4. JDQ443 inhibits this mutated form of KRAS in a structurally distinct way, trapping KRAS G12C in a GDP-bound, inactive state while avoiding direct interaction with H95, a recognized route for resistance5,6. In preclinical models, JDQ443 potently inhibited KRAS G12C cellular signalling and proliferation in a mutant-selective manner and demonstrated dose-dependent antitumor activity7.

“After decades without a breakthrough, we as an industry are entering a transformative era in targeted treatment for KRAS-mutated cancers,” said Jeff Legos, Executive Vice President, Global Head of Oncology & Hematology Development at Novartis. “But challenges remain, in particular drug resistance. We believe that JDQ443 may have the potential for overcoming such challenges. 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.”

Also at AACR, Novartis debuted its targeted protein degradation platform with presentations on DKY709, a potential first-in-class “molecular glue” protein degrader that is designed to target the zinc finger transcription factor Helios (IKZF2)8. Transcription factors, similar to KRAS G12C, are historically "undruggable" targets. Clinical data were drawn from a study (NCT03891953) of advanced solid tumors in which DKY709 is being investigated as a monotherapy and in combination with the anti–PD-1 antibody spartalizumab. The discovery and structure of DKY709 were also presented on April 9th at AACR9.

About JDQ443 and the KontRASt-01 Study2
KontRASt-01 (NCT04699188) is a phase Ib/II open-label, multi-center, dose escalation study of JDQ443, in patients with advanced solid tumors harboring the KRAS G12C mutation, including NSCLC and colorectal cancer. The study began in February 2021 and is currently recruiting. The escalation part will further characterize the safety and tolerability profile of JDQ443 as a single agent and JDQ443 in combination with other agents in advanced solid tumor patients. The estimated primary completion date of the study is 2024.

The preliminary data presented at AACR were drawn from the monotherapy dose escalation arm of the KontRASt-01 study. Patients had a median of 3 prior lines of anti-neoplastic therapy. The recommended monotherapy dose of 200 mg taken orally twice daily (BID) will be taken forward for further studies in phase II dose expansion. Efficacy data (cutoff of 05 Jan 2022) from the pooled Phase Ib JDQ443 single agent cohort (n=39) showed:

57% (4/7) confirmed overall response rate (ORR) at 200 mg BID in NSCLC
45% (9/20) confirmed and unconfirmed ORR across doses in NSCLC
35% (7/20) confirmed ORR across doses in NSCLC
PD/PK modeling predicts sustained, high-level target occupancy at the recommended dose of 200 mg BID
Ongoing enrollment to the KontRASt-01 study continues across a number of arms:

JDQ443 single agent expansion (Ph II) in KRAS G12C-mutated NSCLC
JDQ443 single agent expansion (Ph II) in KRAS G12C-mutated CRC
JDQ443 + TNO155 (SHP2 inhibitor) dose escalation (Ph Ib) in KRAS G12C-mutated solid tumors
JDQ443 + tislelizumab dose escalation (Ph Ib) in KRAS G12C-mutated solid tumors
A Phase III study, KontRASt-02 (NCT05132075) of JDQ443 versus docetaxel in patients with previously treated, locally advanced or metastatic KRAS G12C-mutated NSCLC is anticipated to begin enrolling patients by mid-2022.

Novartis in Lung Cancer
The needs in lung cancer are urgent and significant. Each year, more than 2 million people are newly diagnosed globally10, and lung cancer remains the number one cause of cancer-related death worldwide11.There are two main types of lung cancer—small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). NSCLC accounts for approximately 85% of lung cancer diagnoses12.

Novartis is making bold investments in advancing the science to research treatments that may make an impact for patients around the world. The company is committed to working with the scientific and medical communities to reimagine the treatment of lung cancer and pursue advances in medicine that could extend the survival of people living with lung cancer.

With one of the most diverse lung cancer development programs in the industry, Novartis is developing therapies that may block cancer growth and activate the body’s immune system; working to understand the relationship between chronic inflammation and tumor growth and progression; and exploring the potential for advanced nuclear medicine to fight the disease. Through these programs, Novartis aims to redefine possibilities in lung cancer and pursue a trajectory to make lung cancer history.

Targeted Protein Degradation at Novartis
Targeted protein degradation (TPD) offers first-in-class potential for multiple previously undruggable targets. The approach induces proximity of a target to a ubiquitin ligase, thereby tagging the target for destruction by the cell. Novartis is making an enterprise scale investment in TPD innovation, focusing on the discovery of molecular glues and bifunctional degraders, as well as the development of chemical libraries and the discovery of structural insights.

Disclaimer
This media update contains forward-looking statements within the meaning of the United States Private Securities Litigation Reform Act of 1995. Forward-looking statements can generally be identified by words such as “potential,” “can,” “will,” “plan,” “may,” “could,” “would,” “expect,” “anticipate,” etc. etc..

References

Weiss A, Lorthiois E, Barys L, et al. Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent and Selective, Covalent Oral Inhibitor of KRASG12CCancer Discovery 2022
Tan D, Shimizu T, Solomon B, et al. KontRASt-01: A Phase Ib/II, dose-escalation study of JDQ443 in patients with advanced, KRAS G12C-mutated solid tumors. AACR 2022.
Skoulidis F & Heymach JV. Nat Rev Cancer 2019;19:495–509.
Arbour KC, et al. Clin Cancer Res 2018;24:334–340.
Cotesta S et al. EFMC-ISMC 2021; Poster LE054
Awad MM, et al. New Engl J Med 2021;384:2382–2392
Brachmann SM et al. AACR-NCI-EORTC 2021
D’Hennezel, E. Characterization of a first-in-class molecular glue degrader to modulate T cell activity in cancer. AACR 2022.
Bonazzi, S. Discovery of a first-in-class molecular glue degrader for immuno-oncology indications. AACR 2022.
Ferlay J, Ervik M, Lam F, et al. Global Cancer Observatory: Cancer Today. Lyon: International Agency for Research on Cancer; 2020 (https://gco.iarc.fr/today, accessed March 2022).
Lemjabbar-Alaoui H, Hassan OU, Yang Y-W, et al. Lung cancer: biology and treatment options. Biochim Biophys Acta. 2015. 1856(2):189-210.
WHO above + American Cancer Society. About Lung Cancer. Available at https://www.cancer.org/cancer/non-small-cell-lung-cancer/about/what-is-non-small-cell-lung-cancer.html. Accessed September 10, 2021.
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Novartis Media Relations
E-mail: media.relations@novartis.com