KRAS G12C inhibitors—which at this point include AMG 510 (now labeled sotorasib) and MRTX849—are proving to be active in KRAS G12C–mutated tumors, especially non–small cell lung cancer (NSCLC).
KRAS G12C is a newly “druggable” target, joining what is still a limited list of some 3,000 potential targets that have been identified. Since KRAS is an integral part of the signaling pathways of many tumor types, KRAS-targeted agents will clearly impact cancer care, according to information presented during the ASCO20 Virtual Education Program.
Howard A. Burris III, MD, FACP, FASCO
As explained by Howard A. Burris III, MD, FACP, FASCO, Chief Medical Officer and President of Clinical Operations at Sarah Cannon, Nashville, and Chair of the ASCO Board of Directors: “Since its discovery in the early 1980s, the RAS oncogene has been studied extensively as an ideal target for a therapeutic approach, but
it has long been considered undruggable. Targeting the undruggable KRAS is now a reality, and multiple RAS inhibitors with different modes of action are now in the clinic,” Dr. Burris said.
In September 2019, AMG 510 was granted Fast Track approval for previously treated NSCLC with KRAS G12C mutations. Next in line, MRTX849, is turning out positive data as well. Several other agents are in clinical trials.
Across a Range of Malignancies
RAS mutations are observed across a range of malignancies, most frequently in pancreatic, colorectal, lung, and biliary tract tumors. RAS proteins, including KRAS, switch between an inactive or “off” state to an active or “on” state by binding to guanosine diphosphate (GDP) and guanosine triphosphate (GTP), respectively. KRAS is predominantly GDP-bound, but when activated by external stimuli, the inactive RAS-GDP converts to active RAS-GTP and activates many signaling pathways, resulting in tumor growth. The irreversible covalent KRAS inhibitors trap the KRAS protein in its inactive state.
David S. Hong, MD
“We know from genomic databases such as the American Association for Cancer Research (AACR) GENIE that KRAS G12C mutations are prevalent in about 14% of NSCLC and more than 3% of colorectal cancers, with varying prevalence in other tumor types,” said David S. Hong, MD, Professor at The University of Texas MD Anderson Cancer Center and Deputy Chair of the Department of Investigational Cancer Therapeutics. “At MD Anderson, we’ve also observed KRAS G12C mutations in less common tumor classes, such as gynecologic cancer and even hematologic malignancies.” In addition, Dr. Hong’s team has found concomitant mutations—TP53, STK11 in NSCLC and TP53, PIK3CA in colorectal cancer—which have therapeutic implications for combining other targeted agents with KRAS G12C inhibitors.
AMG 510: First to the Clinic
The development of KRAS inhibitors began with a landmark study in 2013, which described the first molecular inhibitors of KRAS G12C.1 This spurred research that ultimately culminated in the first to show efficacy in clinical trials: AMG 510, or sotorasib.
Dr. Hong was senior investigator of the multicenter, open-label, phase I, first-in-human trial of previously treated adults with locally advanced or metastatic tumors harboring KRAS G12C mutations. After a dose-finding phase (which determined the optimal dose to be 960 mg/d), the study enrolled more patients with NSCLC, colorectal cancer, and other tumors for the dose-expansion phase. The final analysis will include 129 patients.
At the European Society for Medical Oncology (ESMO) 2019 Congress, Govindan et al reported data on 76 patients, including 34 with NSCLC, 36 with colorectal cancer, and 6 with other cancers.2 Responses (to all doses) were achieved by 48% of the NSCLC population but only 3.4% of the colorectal cancer population, “suggesting a clear differential response in these two different histologies,” Dr. Hong shared.
Of the three patients with other tumor types, one responded. The disease control rates were 96% and 79% for NSCLC and colorectal cancer, respectively. Responses to the 960-mg dose trended higher for NSCLC, at 54%, and colorectal cancer, at 8%; disease control rates at this dose were 100% and 92%, respectively.
“Many patients, even with just stable disease, remained on study, with a median duration of about 10 weeks. Although the objective response rate in colorectal cancers was low, there was objective tumor regression in several of the patients,” he added.
AMG 510 also appears to have a favorable pharmacokinetic profile, with cellular assays predictive of activity and drug concentrations that exceeded the necessary 90% of maximal inhibition. Most treatment-related adverse events were grades 1 and 2. “What is encouraging here is the overall tolerability of sotorasib, which bodes well for combining it with other therapies,” said Dr. Hong.
“What is encouraging here is the overall tolerability of sotorasib, which bodes well for combining it with other therapies."— David S. Hong, MD
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Updated data on the colorectal cancer cohort were presented during the ASCO20 Virtual Scientific Program,3 showing that at a dose of 960 mg/d, the response rate with AMG 510 in 25 patients was 12%, and the disease control rate was 80%. Median progression-free survival was 4.2 months, and overall survival had not been reached after a median follow-up of almost 8 months. With this dose, tumor shrinkage was observed in almost half the study patients with available post-baseline tumor data. Some anticancer activity was also observed in patients with pancreatic, appendiceal, and endometrial cancers, but these subsets are too small to draw firm conclusions, Dr. Hong said.
Activity With MRTX849
MRTX849, a selective and covalent small-molecule inhibitor of KRAS G12C, yielded tumor shrinkage in 65% of KRAS G12C–positive cell line– and patient-derived xenograft models of multiple tumor types.4
Clinical data on MRTX849 were presented at the 2019 AACR–National Cancer Institute–European Organisation for Research and Treatment of Cancer conference.5 The study included 12 patients with metastatic mutated tumors (active brain metastases included) and no available treatment options. The initial MRTX849 dose of 150 mg once daily was escalated to doses up to 1,200 mg daily. A twice-daily dose of 600 mg is currently being evaluated in the expansion phase, based on early signs of antitumor activity, safety, and a favorable pharmacokinetic profile.
“The numbers here are smaller, but the response rates in NSCLC and colorectal cancer are similar to those with sotorasib,” Dr. Hong reported.
Of the 12 evaluable patients, partial responses (all unconfirmed) were seen in 3 of 6 patients with NSCLC and 1 of 4 patients with colorectal cancer, with disease control rates of 100% and 75%, respectively. Adverse events were mainly grade 1, most commonly diarrhea and nausea. Two patients had grade ≥ 3 toxicities, including fatigue and decreased appetite.
More Drugs in Development
Both AMG 510 and MRTX849 are covalent irreversible inhibitors of KRAS G12C, leading to the inactive bound state, but they are structurally different, with half-lives of 5.5 hours and 24 hours, respectively. “Whether this will lead to any meaningful clinical difference is not clear,” commented Dr. Hong. For both, he added, “a relatively brief exposure to the drug at concentrations sufficient to completely occupy the existing pool of KRAS G12C would be predicted to completely inhibit the protein for about 24 hours.”
There are at least five KRAS G12C inhibitors in development, with more likely to come: AMG 510, MRTX849, JNJ 7469915, LY3499446, and GDC-6036, so far. “Who will win the race to be the first approved? Is there room for more than one? Time will tell,” Dr. Hong commented.
Questions Remain
Many fundamental and clinical questions are yet to be answered about KRAS G12C and its inhibitors.
- What are the underlying mechanisms in the differential response rates between patients with NSCLC and those with colorectal cancer?
- Are there intrinsic mechanisms of resistance (ie, through co-alterations or comutations)?
- What are the mechanisms of resistance after KRAS G12C inhibition?
- How does inhibition of KRAS G12C affect the tumor immune microenvironment?
- Will response rates and progression-free or overall survival with these drugs meet a threshold high enough to warrant accelerated approval in the third-line or later setting of advanced NSCLC and colorectal cancer?
- Is there a place for KRAS G12C monotherapy in the first- or second-line setting of advanced NSCLC?
- Can KRAS G12C inhibitors penetrate the central nervous system?
- Can KRAS G12C inhibition be a truly tumor-agnostic therapy?
- What combinations of KRAS G12C inhibitors are tolerable, synergistic, or can overcome resistance?
Overcoming Resistance With Combinations
The next step is to determine how best to combine KRAS G12C inhibitors with other therapies, both for improved outcomes and to deter resistance. Four possible mechanisms of resistance may lend themselves to combination therapy: (1) incomplete KRAS blockade; (2) bypass signaling activation (either via upstream RTK activation or downstream second messengers); (3) increased cell proliferation and antiapoptotic signaling; and (4) insufficient immune cell infiltration (a host-associated immune defect).
Based on preclinical observations, agents that inhibit MEK or the PI3 kinase mTOR pathway might enhance the activity of KRAS G12C inhibitors. Tapping into the epidermal growth factor receptor (EGFR) signaling feedback process with EGFR inhibitors on board may also be beneficial. Given its effects on cell proliferation, add-on chemotherapy could boost responses, and inhibitors of cyclin-dependent kinases 4/6 could be synergistic with KRAS G12C inhibitors. Finally, since KRAS G12C inhibition seems to affect the tumor immune microenvironment, pairing KRAS G12C inhibitors with anti–PD-1 agents could pay off. These hypotheses are being tested in a number of clinical trials.
DISCLOSURE: Dr. Burris has been employed by HCA Healthcare/Sarah Cannon; has served as an institutional consultant or advisor to AstraZeneca, Celgene, Forma Therapeutics, and Incyte; has received institutional research funding from Agios, Arch, Array BioPharma, Arvinas, AstraZeneca, Bayer, Bind Therapeutics, BioAtla, BioMed Valley Discoveries, Boehringer Ingelheim, Bristol Myers Squibb, CicloMed, CytomX Therapeutics, eFFECTOR Therapeutics, Foundation Medicine, Gilead Sciences, GlaxoSmithKline, Harpoon Therapeutics, Incyte, Janssen, Jounce Therapeutics, Kymab, Lilly, MacroGenics, MedImmune, Merck, miRNA Therapeutics, Moderna Therapeutics, Novartis, Pfizer, Revolution Medicines, Roche/Genentech, Seattle Genetics, Takeda/Millennium, Tesaro, TG Therapeutics, Verastem, and Vertex; has provided institutional expert testimony for Novartis; has held uncompensated institutional relationships with Daiichi Sankyo and Pfizer; and has served as a consultant for Novartis (paid to his institution). Dr. Hong holds stock or other ownership interests in MolecularMatch, Oncorena, and Presagia; has served as a consultant or advisor to Acuta Capital, Alpha Insights, Axiom Biotechnologies, Bayer, Genentech, GLG, GroupH, Guidepoint Global, Infinity Pharmaceuticals, Medscape, Merrimack, Numab, Pfizer, Prime Oncology, Seattle Genetics, Takeda, Trieza Therapeutics, and WebMD; has received research funding from AbbVie, Adaptimmune, Adlai Norte, Amgen, AstraZeneca/MedImmune, Bayer, Daiichi Sankyo, Fate Therapeutics, Genentech, Infinity Pharmaceuticals, Kite Pharma, Kura, MedImmune, Mirati Therapeutics, Molecular Templates, NCI-CTEP, Pfizer, Seattle Genetics, Shattuck Labs, TCR2 Therapeutics, and TP Therapeutics; and has been reimbursed for travel, accommodations, or other expenses by AACR, ASCO, Bayer Schering Pharma, Genmab, and SITC.
REFERENCES
1. Ostrem JM, Peters U, Sos ML, et al: K-Ras (G12C) inhibitors allosterically control GTP affinity and effector interactions. Nature 503:548-551, 2013.
2. Govindan R, Fakih MG, Price TJ, et al: Phase I study of AMG 510, a novel KRAS G12C mutant solid tumors. 2019 ESMO Congress. Poster Discussion. Presented September 28, 2019.
3. Fakih M, Desai J, Kuboki Y, et al: CodeBreak 100: Activity of AMG 510, a novel small molecule inhibitor of KRAS G12C, in patients with advanced colorectal cancer. ASCO20 Virtual Scientific Program. Abstract 4018.
4. Patricelli MP, Janes MR, Li LS, et al: Selective inhibition of oncogenic KRAS output with small molecules targeting the inactive state. Cancer Discov 6:316-329, 2016.
5. Janne PA, Papadopoulos K, Ou I, et al: A phase 1 clinical trial evaluating the pharmacokinetics, safety and clinical activity of MRTX849, a mutant-selective small molecular KRAS G12C inhibitor, in advanced solid tumors. EORTC-NCI-AACR Molecular Targets and Cancer Therapeutics Conference. Concurrent Session 5. Presented October 28, 2019.
