Novartis, Amgen, Mirati, and Yifan Bio Announce Latest Advances in Targeting KRAS Signaling Pathway

KRAS was once considered an "undruggable" cancer target, but last year, Lumakras (sotorasib), a KRAS G12C inhibitor developed by Amgen, received accelerated FDA approval for the treatment of patients with previously treated non-small cell lung cancer (NSCLC) carrying the KRAS G12C mutation, marking a significant milestone in overcoming the "undruggability" of KRAS. At the AACR Annual Meeting, several companies presented the latest results of investigational therapies targeting the KRAS pathway.

JDQ443, developed by Novartis, is a covalent KRAS G12C inhibitor that irreversibly locks KRAS G12C in its inactive state. At the AACR Annual Meeting, researchers presented preliminary results from the Phase 1/2 clinical trial. Patients received treatment with four different doses of JDQ443. The trial identified the recommended dose for Phase 2. Among patients treated with the recommended dose, the ORR was 57% (4/7). Novartis is set to initiate a Phase 3 clinical trial to evaluate its efficacy in treating non-small cell lung cancer patients with KRAS G12C mutations.

▲Introduction to JDQ443 (Image Source: Novartis Official Website)

Today, the discovery and preclinical optimization research of JDQ443 was also published in the journal *Cancer Discovery*. The study indicates that JDQ443 has a unique structure that inhibits KRAS G12C activity by binding to the "switch II pocket" of KRAS G12C. Additionally, in preclinical animal models, the combination of JDQ443 and the SHP2 inhibitor TNO155 demonstrated a synergistic effect, achieving better results at lower doses. Currently, Novartis is evaluating the effects of JDQ443 in combination with TNO155 or JDQ443 in combination with tislelizumab, an anti-PD-1 antibody developed by BeiGene, in clinical trials.

▲Design of JDQ443 and its binding mode with KRAS (Image Source: Reference [4])

Amgen announced two-year long-term efficacy results of sotorasib in treating non-small cell patients with KRAS G12C mutation. Data analysis showed that among 174 patients who had received various therapies, sotorasib achieved an objective response rate of 40.7% and a disease control rate of 83.7%. The median duration of response was 12.3 months. Five patients achieved complete response, and 65 patients achieved partial response. The median progression-free survival was 6.3 months, the median overall survival was 12.5 months, and 32.5% of the patients were still alive after two years.

Mirati Therapeutics Discloses Chemical Structure of SOS1 Inhibitor MRTX0902 for the First TimeThe protein SOS1 promotes the conversion of KRAS protein from an inactive state to an active state. By inhibiting SOS1, MRTX0902 can keep KRAS in an inactive state for a longer period. Mirati’s KRAS G12C inhibitor adagrasib binds to the inactive form of the KRAS G12C mutant, and combining MRTX0902 with adagrasib may allow more KRAS G12C mutants to bind to adagrasib, enhancing its efficacy. Meanwhile, MRTX0902 could also serve as an indirect approach to target other KRAS mutation-driven cancers.

▲Characteristics of MRTX0902 (Source: Mirati official website)

In preclinical experiments, the combination of MRTX0902 and adagrasib led to a significant reduction in tumor volume in KRAS G12C mouse models. This investigational therapy is currently in the preclinical research stage supporting an IND application, with the IND submission expected in the second half of this year.

▲MRTX0902 in combination with adagrasib (MRTX849) led to a significant reduction in tumor volume in KRAS G12C mouse models (Image source: Mirati official website)

China's Yifang Biotech also announced the clinical trial data of its KRAS G12C inhibitor D-1553. In a Phase 1 clinical study involving patients with advanced or metastatic solid tumors carrying the KRAS G12C mutation, D-1553 was well tolerated in 22 patients, with no dose-limiting toxicity observed. Among 21 evaluable patients, a confirmed objective response rate of 19.0% was observed, with a disease control rate of 85.7%. Another study led by Professor Lu Shun from Shanghai Chest Hospital involved 59 patients with KRAS G12C-mutant NSCLC, including 52 evaluable patients, showing an objective response rate of 40.4% and a disease control rate of 90.4%.

We look forward to the smooth development of these innovative therapies targeting the KRAS pathway, bringing more and more effective KRAS-targeted treatments to patients.

References:

[1] LUMAKRAS® (SOTORASIB) CODEBREAK 100 STUDY SHOWS TWO-YEAR OVERALL SURVIVAL OF 32.5% IN PATIENTS WITH KRAS G12C-MUTATED ADVANCED NON-SMALL CELL LUNG CANCER. Retrieved April 11, 2022, from https://www.amgen.com/newsroom/press-releases/2022/04/lumakras-sotorasib-codebreak-100-study-shows-twoyear-overall-survival-of-325-in-patients-with-kras-g12cmutated-advanced-nonsmall-cell-lung-cancer

[2] Design and Discovery of MRTX0902, a potent selective and orally bioavailable SOS1 inhibitor. Retrieved April 11, 2022, from https://www.mirati.com/presentation-publication/design-and-discovery-of-mrtx0902-a-potent-selective-and-orally-bioavailable-sos1-inhibitor/

[3] AACR: Novartis hops on KRAS craze with early data, seeking to improve on undruggable target. Retrieved April 11, 2022, from https://www.fiercebiotech.com/biotech/aacr-novartis-joins-kras-bandwagon-early-data-seeking-improve-undruggable-target

[4] Weiss et al., (2022). Discovery, Preclinical Characterization, and Early Clinical Activity of JDQ443, a Structurally Novel, Potent and Selective, Covalent Oral Inhibitor of KRASG12C. Cancer Discovery, https://doi.org/10.1158/2159-8290.CD-22-0158

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