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Novartis Enters KRAS G12C Space With Positive Phase I/II Data in Lung, Colorectal Cancer

NEW YORK – Novartis is advancing new studies of its investigational KRAS G12C inhibitor after positive data from a Phase I/II trial in lung and colorectal cancer showed promising anti-tumor activity.

Novartis researchers presented data from the Phase I/II KontRASt-01 trial at the American Association for Cancer Research's annual meeting in New Orleans this past week. The Phase I portion of the study evaluated Novartis' JDQ443 in patients with advanced KRAS G12C-mutated solid tumors, and the Phase II portion of the study focused on advanced KRAS G12C-mutant colorectal and non-small cell lung cancer. Patients needed to have received prior standard-of-care therapy, be intolerant of or ineligible for approved therapies, and no prior KRAS inhibitor treatment.

Of 39 evaluable patients in the study, 11 patients (28.2 percent) had a confirmed or unconfirmed response with all of the responses in patients with NSCLC and colorectal cancer. Among the NSCLC cohort, 9 of 11 patients (45 percent) saw a response across dose levels. In the recommended Phase II dose of 200 mg, the response rate in NSCLC was 57 percent, or four of seven patients.

Based on this data, Novartis is expanding its JDQ443 monotherapy NSCLC and colorectal cancer cohorts in the KontRASt-01 trial. The company is also beginning to enroll patients with KRAS G12C-mutant solid tumors in combination arms of the trial. One arm will evaluate JDQ443 plus Novartis' SHP2 inhibitor TNO115 in solid tumors, and another arm will enroll solid tumor patients for treatment with JDQ443 and Novartis' anti-PD1 drug tislelizumab. The company expects to complete the study in 2024, Andrea Myers, global program head for lung cancer at Novartis, said in an emailed statement.

Finally, Novartis is also planning a randomized Phase III trial, KontRASt-02, of JDQ443 versus docetaxel in previously treated patients with advanced or metastatic KRAS G12C-mutant NSCLC. That trial has not opened yet, but the company expects to begin enrolling patients by mid-2022. The trial will enroll 360 patients, and the estimated completion date is also in 2024, according to Myers.

"KRAS G12C mutations are most commonly found in lung cancer, but can be found in about 3 percent to 4 percent of colorectal cancers, and even more rarely in other solid tumors," Myers said. "Based on the promising early clinical data from KontRASt-01, we have planned the Phase III study, KontRASt-02 in NSCLC, while we continue to grow our experience with other tumor types within KontRASt-01 to inform next steps."

These advancing studies put Novartis squarely in the race to develop drugs targeting KRAS mutations. Its main competitors in the G12C space are Amgen's Lumakras (sotorasib) and Mirati Therapeutics' adagrasib. Lumakras has already been approved in KRAS-mutant NSCLC, and Mirati has submitted a new drug application to the US Food and Drug Administration for adagrasib in the same indication.

For comparison, the Phase II trial that led to accelerated approval for Lumakras in NSCLC showed a 38 percent response rate. Mirati's NDA submission earlier this year was also based on data from a Phase II study that showed a 43 percent response rate in KRAS G12C-mutant NSCLC.

After the initial progress in NSCLC, both Amgen and Mirati are also exploring the drug in other tumor types. Lumakras saw limited efficacy in KRAS G12C-mutant colorectal cancer in an early trial, which led to Amgen pivoting to combination strategies in this setting. Amgen also recently reported data showing promising efficacy of Lumakras monotherapy in KRAS G12C-mutant pancreatic cancer, and the firm expanded enrollment in its pancreatic cancer cohort.

Researchers noted in a publication of preclinical research studying JDQ443 that the drug binds to KRAS in a different way than Lumakras and adagrasib in that it does not interact with H95, an adjacent histidine residue in the KRAS G12C binding pocket. JDQ443 occupies "different regions of the pocket and [exploits] new interactions," according to the preclinical research published in Cancer Discovery this month. However, the researchers, led by Andreas Weiss, a senior investigator at Novartis, noted that these interactions may have implications in clinical use down the line.

"These unique features may result in distinct resistance or tolerability profiles that may have implications for its combination use," the authors wrote. "In preclinical settings, JDQ443, sotorasib, and adagrasib show overall comparable profiles with one notable exception being their interactions with H95. All three compounds are in clinical development, and the most relevant comparisons between them will come from their respective clinical activities and their unique potentials for combination strategies."

Myers said it was too early to comment on potential discussions with the FDA about approval pathways for JDQ443, but noted Novartis has "extensive experience with the expedited programs available at the FDA."