However, the most common KRAS mutations in PDAC are G12D (44%), G12V (34%) and G12R (20%) that are not amenable to treatment by KRAS G12C-directed cysteine-reactive KRAS inhibitors such as Sotorasib and Adagrasib that exhibit clinical efficacy in lung cancer...Recently, the KRAS G12D-directed MRTX1133 inhibitor has entered clinical trials and more of such inhibitors are in development. The other KRAS mutations may be targeted indirectly via inhibition of the cognate guanosine exchange factor (GEF) Son of Sevenless 1 that drives KRAS. These agents seem to provide the means to target the most frequent KRAS mutations in PDAC and to improve patient outcomes.

P1, N=175, Recruiting, Astellas Pharma Inc | Not yet recruiting --> Recruiting

P1/2, N=70, Not yet recruiting, Jiangsu HengRui Medicine Co., Ltd.

P1/2, N=150, Recruiting, Tyligand Bioscience (Shanghai) Limited

We observed that secondary mutations in KRASG12D can lead to acquired resistance to MRTX1133 and BI-2865, a novel pan-KRAS inhibitor, in human cancer cell lines. This evidence is critical for devising new strategies to counteract resistance mechanisms and, ultimately, enhance treatment outcomes in patients with KRASG12D-mutant cancers.

P1, N=175, Not yet recruiting, Astellas Pharma Inc

As a proof of concept, we identify two new, drug-like small molecules with the new method; these compounds specifically inhibit the growth of the PANC-1 cell line with KRAS mutation G12D in vitro and in vivo. Importantly, the two new compounds show significantly lower IC50 and higher specificity against the G12D KRAS mutant human pancreatic cancer cell line PANC-1, as compared to the recently described selective G12D KRAS inhibitor MRTX-1133.

P1, N=250, Recruiting, Quanta Therapeutics | Not yet recruiting --> Recruiting

P1, N=24, Recruiting, Neogene Therapeutics, Inc. | Not yet recruiting --> Recruiting

Further investigation of the immunological response using single-cell sequencing and multispectral imaging revealed that tumor regression was associated with suppression of neutrophils and influx of effector CD8+ T cells. Together, these findings demonstrate that both tumor cell-intrinsic and extrinsic events contribute to response to MRTX1133 and credential KRASG12D inhibition as a promising therapeutic strategy for a large percentage of PDAC patients.

P1, N=250, Not yet recruiting, Quanta Therapeutics

P1, N=24, Not yet recruiting, Neogene Therapeutics, Inc.

Herein, we report the design, synthesis, and biological evaluation of a series of KRAS PROTACs by connecting the analogues of MRTX1133 and the VHL ligand...This compound selectively and potently suppressed the growth of multiple KRAS mutant cancer cells, displayed favorable pharmacokinetic and pharmacodynamic properties in mice, and showed significant antitumor efficacy in the AsPC-1 xenograft mouse model. Further optimization of 8o appears to be promising for the development of a new chemotherapy for KRAS-driven cancers as the complementary therapeutic strategy to KRAS inhibition.

P1, N=322, Recruiting, Incyte Corporation | Not yet recruiting --> Recruiting

The results obtained in this work showed a profound inhibition of tumor growth, which was associated with a reduction in cell proliferation, an increase in apoptosis, and a reduction in the MAPK and PI3K/AKT/mTOR signaling pathways. In conclusion, these results demonstrate the high potency and efficacy of MRTX1133 in KRAS-PMP tumors and provide a rationale for clinical trials.

At 48 h of treatment, two distinct populations of cells can be observed based on the level of effectiveness of the drug in decreasing the total abundance of the KRAS protein in each respective cell, with results that are effectively masked in the bulk cell analysis. All mass spectrometry data and processed results are publicly available at www.massive.ucsd.edu at accessions PXD039597, PXD039601, and PXD039600.

These new inhibitors were found to have dose-dependent anti-tumor efficacy in the AsPC-1 xenograft mouse models with a tumor growth inhibition of approximately 70% at a dose of 20 mg/kg twice daily (i.p.). Despite the non-optimal pharmacokinetic properties similar to those of MRTX1133, the high in vitro and in vivo potency of these new inhibitors call for further profiling.

Preliminary results from phase I trials respectively evaluating RMC-6236, a pan-RAS inhibitor, and HRS-4642, a KRASG12D inhibitor, indicate that both are safe and show promising signs of antitumor activity. These are just two of the candidate RAS therapies in a burgeoning development space as the field looks ahead to drugs that hit more than just KRASG12C.

P1, N=60, Not yet recruiting, Shanghai YingLi Pharmaceutical Co. Ltd.

The recent approval of sotorasib (AMG510), a small-molecule, covalent, and selective KRASG12C inhibitor, for treating patients with non-small cell lung cancer represents a breakthrough in KRAS targeted therapy. Additionally, we discuss potential challenges and future directions for MRTX1133 therapy for PDAC, including overcoming intrinsic and acquired drug resistance, developing effective combination therapies, and improving MRTX1133's oral bioavailability and target spectrum. The promising results obtained from preclinical studies suggest that MRTX1133 could revolutionize the treatment of PDAC, bring about a paradigm shift in its management.

P1, N=80, Recruiting, Shanghai YingLi Pharmaceutical Co. Ltd.

The combination of MRTX1133 and cetuximab serves as a potential and promising therapeutic approach for colorectal cancer with KRAS mutation. KRAS is a frequent genetic mutation not only in colorectal cancer, but also in pancreatic and lung cancer, and the results of this study open new avenues for potential treatment of many cancer patients.

Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.

No abstract available

P1, N=290, Recruiting, Revolution Medicines, Inc.

Mechanistically, inhibition of KRAS in advanced PDAC and human patient derived organoids induces FAS expression in cancer cells and facilitates CD8 T cell-mediated death. Collectively, this study provides a rationale for a synergistic combination of MRTX1133 with ICB in clinical trials.

MRTX1257 predominantly reduced proliferation of XG7 cells, whereas MRTX1133 led to potent cell death induction of KARPAS620 and KP6 cells. Combinations of MRTX1257 with investigational or established anti-MM drugs, including melphalan, bortezomib or pomalidomide, led to no antagonism and in some cases – including combination with MEKi trametinib – caused supra-additive effects... This study documents mutant-specific activity of KRAS G12C and G12D inhibitors in MM cells and provides functional insights into the pharmacological inhibition of KRAS in MM. Ongoing in vitro and in vivo studies are examining the targeting of genes/pathways associated with escape from KRAS inhibition, as a framework for future efforts to improve the rates, depth and durability of responses to KRAS inhibition in MM.

Conclusions HRS-4642 showed a tolerable safety profile and preliminary anti-tumor activity in advanced solid tumors harboring KRAS G12D mutation. Dose escalation is ongoing and expected to proceed to dose expansion soon.

The inhibitors targeting G12D mutation (such as MRTX1133) have been recently developed, whereas those targeting other mutations are still lacking...In addition, we recently demonstrated that the combination of sotorasib with DT2216 (a BCL-X-selective degrader) synergistically inhibits G12C-mutated pancreatic cancer cell growth in vitro and in vivo...This chapter will review KRAS biochemistry, signaling pathways, different mutations, emerging KRAS-targeted therapies, and combination strategies. Finally, we discuss challenges associated with KRAS targeting and future directions, emphasizing pancreatic cancer.

Blockade of activated EGFR with clinically used antibodies or kinase inhibitors suppressed the EGFR/wild-type RAS signaling axis, sensitized MRTX1133 monotherapy, and caused the regression of KRAS-mutant CRC organoids and cell line-derived xenografts. Overall, this study uncovers feedback activation of EGFR as a prominent molecular event that restricts KRAS inhibitor efficacy and establishes a potential combination therapy consisting of KRAS and EGFR inhibitors for patients with KRAS-mutated CRC.

Our studies reveal strong synergy between MRTX1133 & 5-FU in human pancreatic & colon cancer models at much lower than IC50 dosage which is important for avoiding side effects. This is the first description that effect of KRAS G12D inhibitor MRTX1133 is active on KRAS G12V. The surprising synergy in KRAS G12V samples with combination therapy and the important synergistic change in cytokine patterns suggests potential strong immune stimulatory anti-cancer effects of MRTX1133 & 5FU against mCRC and pancreatic cancer cells regardless of KRAS G12D mutation which should be considered when including patients with respective mutations in clinical trials.

Additionally, more CD8+ T cells in the tumor-draining lymph nodes of MRTX1133-treated mice were IFNγ+ (P < 0.001), illustrating a systemic immune effect from MRTX1133. Our findings indicate that T cells play an important role in MRTX1133’s demonstrated efficacy, suggesting a “vaccine effect” from mutant KRAS inhibition and offering a rationale for testing novel combinations of mutant KRAS inhibitors with cancer immunotherapies.

The systemic clearance in rats and dogs was high to moderate, respectively and despite low apparent permeability, demonstrated good oral bioavailability in each species. The current PK profile and preclinical proof-of-concept data support advancement of QTX3046 into IND enabling studies to support potential clinical investigation in KRASG12D-driven solid tumor indications.

TCR sequencing of T cells from tumors and blood harvested from treated mice revealed a significant increase in T cell diversity, as well as an increase in the number of shared TCR clones among all KRASG12D(ON) inhibitor-treated samples, suggesting cancer-associated antigen recognition.Overall, in these preclinical experiments, RMC-9805 exhibited direct anti-tumor effects and indirectly transformed the TME through inhibition of cancer cell-intrinsic KRASG12D oncogenic signaling. The increased antigen presentation, recognition, and T cell infiltration induced by inhibition of mutant KRAS may permit a more favorable environment for immune-directed ‘companion’ therapies, such as checkpoint inhibitors, cellular therapies, and/or vaccines.&lsqb;1] Timar, J. et al, 2020 &lsqb;2] Hamarsheh, S. et al, 2020 &lsqb;3] Sumimoto, H. et al, 2016

Furthermore, RMC-9805 combination therapies drove regressions in CRC models relatively less responsive to monotherapy. Supported by these findings, RMC-9805 is currently in IND-enabling development to permit clinical evaluation of single agent and combination strategies in patients with KRASG12D tumors.

P1/2, N=304, Recruiting, Mirati Therapeutics Inc. | Not yet recruiting --> Recruiting