On April 12, 2022 Deciphera Pharmaceuticals, Inc. (NASDAQ: DCPH), a commercial-stage biopharmaceutical company developing innovative medicines to improve the lives of people with cancer, reported the presentation of preclinical data for DCC-3116, the Company’s first-in-class ULK kinase inhibitor, in combination with KRASG12C inhibitors in non-small cell lung cancer (NSCLC) models at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2022 in New Orleans, Louisiana (Press release, Deciphera Pharmaceuticals, APR 12, 2022, View Source [SID1234612052]).
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"Autophagy is recognized as a mechanism of drug resistance in cancer and an exciting target for drug development. The combination of a KRASG12C inhibitor with DCC-3116, a selective and potent inhibitor of the ULK1/2 protein kinases that are key autophagy regulators, has the potential to promote deeper and more durable clinical responses than a KRASG12C inhibitor alone," said Martin McMahon, Ph.D., Cumming-Presidential Chair of Cancer Biology in the Dept. of Dermatology, Senior Director for Preclinical Translation and Co-Leader of the Experimental Therapeutics Program in the Huntsman Cancer Institute. "The data I presented today provides strong preclinical rationale for this approach and underscores the importance of autophagy inhibition in the treatment of cancer, demonstrating a compelling rationale to study DCC-3116 in combination with KRASG12C inhibitors in clinical trials in non-small cell lung cancer patients."
Results from the preclinical studies, presented in an oral presentation titled "DCC-3116, a first-in-class selective inhibitor of ULK1/2 kinases and autophagy, combines with the KRASG12C inhibitor sotorasib resulting in tumor regression in NSCLC xenograft models" are summarized below. The presentation is available on-demand via the meeting’s website and on the Company’s website at www.deciphera.com/presentations-publications.
Summary of Preclinical Data and Findings
Results from the preclinical studies showed that KRASG12C inhibitors, sotorasib and adagrasib, activate ULK-mediated autophagy as an adaptive treatment resistance mechanism. DCC-3116 in combination with sotorasib and with adagrasib inhibited ULK kinase activation and the resulting autophagic flux in a KRASG12C mutated NSCLC cell line. Results demonstrated that DCC-3116 in combination with sotorasib and with adagrasib translated to deeper and longer tumor regressions in vivo. The study also demonstrated that DCC-3116 in combination with sotorasib outperformed both single agent sotorasib and the combination of sotorasib and chloroquine, a nonspecific lysosomal inhibitor of autophagy.
Results of the preclinical studies were as follows:
Treatment of mutant KRASG12C NSCLC cell lines with KRASG12C inhibitors, sotorasib and adagrasib, induced autophagy via activation of ULK1/2 kinases as measured by an increase in ULK-mediated phosphorylation of the key ULK autophagy substrate ATG13 and resulting increase in autophagic flux.
In mutant KRASG12C NSCLC cell lines, DCC-3116 inhibited ULK kinase activation by both sotorasib and adagrasib, as measured by a decrease in phosphorylated ATG13 and resulting autophagic flux.
In the H358 KRASG12C NSCLC xenograft model, the combination of DCC-3116 and sotorasib resulted in deeper and longer tumor regressions compared to all single agent sotorasib cohorts.
In the Calu-1 KRASG12C NSCLC xenograft model, the combination of DCC-3116 and sotorasib resulted in tumor regressions and outperformed both single agent sotorasib and the combination of sotorasib and chloroquine.
In the LU11554 KRASG12C NSCLC patient derived xenograft model, the efficacy for the combination of DCC-3116 with sotorasib or with adagrasib increased tumor growth inhibition compared to sotorasib or adagrasib alone.
DCC-3116 is currently being investigated in a Phase 1, multicenter, open-label, first-in-human study designed to evaluate the safety, tolerability, clinical activity, pharmacokinetics, and pharmacodynamics of DCC-3116 as a single agent and in combination with trametinib, an FDA approved MEK inhibitor, in patients with advanced or metastatic tumors with a mutant RAS or RAF gene. Initial data from the single agent dose escalation portion of the Phase 1 study is expected in the second half of 2022. The Company expects to initiate Phase 1 study dose escalation cohorts in the second half of 2022 in combination with trametinib in patients with selected mutations in advanced or metastatic pancreatic ductal adenocarcinoma, NSCLC, colorectal cancer, and melanoma. Planning is underway to add a combination with a KRASG12C inhibitor in NSCLC to the ongoing Phase 1 study, subject to feedback from regulatory authorities.
About DCC-3116
DCC-3116 is an investigational, orally administered, potent, and highly selective switch-control inhibitor designed to inhibit cancer autophagy, a key tumor survival mechanism in cancer cells, by inhibiting the ULK1/2 kinases, which have been shown to be the initiating factors that activates autophagy. DCC-3116 is currently being studied in a Phase 1, multicenter, open-label, first-in-human study as a single agent and in combination with trametinib, an FDA approved MEK inhibitor, in patients with advanced or metastatic tumors with a mutant RAS or RAF gene (NCT04892017).