Dueling KRASG12C Inhibitors Achieve Responses
Agents from Mirati Therapeutics and Amgen elicit responses, stable disease in lung, colorectal tumors
Scientists have long thought that RAS family proteins are undruggable, and efforts to block mutant RAS function have failed. However, in recent months, two companies—Mirati Therapeutics and Amgen—have presented clinical data on the KRAS inhibitors MRTX849 and AMG 510, respectively. In a pair of phase I trials, the agents elicited responses in patients with advanced solid tumors, including non–small cell lung
Subsequently, at the 2019 World Conference on Lung Cancer in September, Ramaswamy Govindan, MD, of the Siteman Cancer Center at Washington University School of Medicine in
St. Louis, MO, reported on 23 evaluable patients with NSCLC. He called attention to the 13 patients who received the highest dose of AMG 510 under evaluation, 960 mg,
Tumor tissue from a mouse with Kras- mutant lung cancer.
cancer (NSCLC), colorectal cancer, and appendix cancer, suggesting that KRAS might be druggable after all.
Targeting KRAS has been difficult due to its small size, smooth surface, and rapid, tight binding to GTP. However, MRTX849 and AMG 510 take advantage of a small pocket discovered in KRASG12C, circumventing these obstacles. The drugs covalently and irreversibly bind KRASG12C when a glycine replaces a cysteine. This change prevents GTP binding, thus locking the protein in an inactive state and inhibiting downstream signaling, explained Pasi Jänne, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA. “It was thought to be an undruggable target because one could not develop an
irreversible inhibitor that could outcompete binding in the cell.” Research on MRTX849 was presented at the 2019 EORTC-
NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Boston, MA, in October and concurrently published in CaNcer Discovery. Scientists established that the agent is a highly selective KRASG12C inhibitor and observed tumor regression in 65% of 26 cell lines and patient-derived xenografts from multiple tumor types, prompting initiation of a phase I trial (Cancer Discov 2020;10:54–71).
At the symposium, Jänne reported on 12 evaluable patients with metastatic disease: six with NSCLC, four with colorectal cancer, and two with appendix cancer. All patients lacked brain metastases and had received at least one prior therapy.
During the trial, most received 600 mg of the drug twice per day. Overall, three patients with NSCLC had unconfirmed partial responses and one patient with colorectal cancer had a confirmed partial response. All other patients experienced
stable disease. Eleven patients continue to receive the therapy, with most having been on treatment for about 10 weeks; one patient has been on treatment for almost 40 weeks. Patients primarily experienced adverse events classified as grade 1 and 2, most commonly diarrhea and nausea.
The trial, which is ongoing, also includes patients with other solid tumors that harbor a KRASG12C mutation.
Similarly positive data for AMG 510, Amgen’s KRASG12C inhibitor, have been published in Nature and reported at conferences in patients with NSCLC (Nature 2019;575:217– 23). At the 2019 American Society of Clinical Oncology Annual Meeting in June, researchers presented data showing that five of 10 evaluable patients with NSCLC who received AMG 510 had a partial response, and four experienced stable disease.
noting that seven of them achieved a partial response and six had stable disease, a 100% disease-control rate. Of the 34
enrolled patients with NSCLC, only three experienced grade 3 side effects (anemia and diarrhea); nine others reported mild side effects.
Data on a cohort of patients with metastatic colorectal cancer taking AMG 510 weren’t as robust. At the European Society of Medical Oncology Congress in Barcelona at the end of September, researchers reported that of 12 patients with the disease who received the 960 mg dose, only one achieved a
partial response. Asked why the response rate might be so much lower, Marwan Fakih, MD, of City of Hope Comprehensive Cancer Center in Duarte, CA, who presented the findings, said, “NSCLC and colorectal cancer are biologically different. It is too early to speculate as to the potential mechanisms of resistance in colorectal [cancer] versus NSCLC.”
However, because 10 of the 12 patients with colorectal cancer had stable disease, “the disease-control rate remained high at 92%, supporting the potential utility of AMG 510 in
chemotherapy-resistant KRASG12C colorectal cancer,” Fakih said. “I think everybody is excited,” said Kwok-Kin Wong,
MD, PhD, of the Laura and Isaac Perlmutter Cancer Center at NYU Langone Medical Center in New York, NY, who was not involved in the trials. Having two compounds in the class “showing clinical activity in a very small cohort
of patients really, really further cements and validates the concept that KRAS is now druggable,” he added.
Fakih and Wong agreed that future research should explore how to combine KRAS inhibitors with other targeted therapies to improve responses. The recent CaNcer Discovery article, for example, found that combining MRTX849 with EGFR, CDK4/6, mTOR, or SHP2 inhibitors led to better responses in tumor models. It “shows that not all KRASG12C-driven cancers are created equal,” Wong said. “You really need to think about all the other mutations.”
As for how the Mirati and Amgen agents compare, Jänne said that data are too preliminary to draw conclusions. But noting that KRAS is the most common oncogenic driver, he considers the activity of both agents encouraging. “Given the clinical impact of KRAS-mutant cancer, not just lung cancer but all cancers … I think there continues to be a need to develop new and novel approaches here, because it would have a major impact for treatment.” –CatheriNe Caruso aNd SuzaNNe Rose ■
10 | CANCER DISCOVERY JANUARY 2020 aacrjournals.org
Published OnlineFirst December 10, 2019; DOI: 10.1158/2159-8290.CD-ND2019-012
Dueling KRASG12C Inhibitors Achieve Responses
Cancer Discov 2020;10:10. Published OnlineFirst December 10, 2019.
Reprints and Subscriptions
Sign up to receive free email-alerts related to this article or journal.
To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected].
To request permission to re-use all or part of this article, use this link http://cancerdiscovery.aacrjournals.org/content/10/1/10.
Click on “Request Permissions” which will take you to the Copyright Clearance Center’s (CCC) Rightslink site.