Another novel oral KRAS inhibitor—adagrasib (MRTX849)—has shown promise in early clinical trials, according to investigators of the KRYSTAL-1 study who reported findings at the virtual 32nd EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics.1,2 The conference is jointly provided by the American Association for Cancer Research (AACR), the National Cancer Institute (NCI), and the European Organisation for Research and Treatment of Cancer (EORTC).
The agent joins another KRAS inhibitor, sotorasib (AMG 510),3 in showing that the formerly “undruggable” KRAS mutation might succumb to targeted treatment after all. In two presentations of data from the phase I/II KRYSTAL-1 trial, oral adagrasib given twice daily showed activity, especially in non–small cell lung cancer (NSCLC) but also in colorectal cancer and other solid tumors.
“Adagrasib achieved a 45% response rate in patients with advanced NSCLC and KRAS G12C mutations. Durable responses were observed, as was a broad disease control rate.”— Pasi A. Jänne, MD
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“Adagrasib achieved a 45% response rate in patients with advanced NSCLC and KRAS G12C mutations. Durable responses were observed, as was a broad disease control rate,” said Pasi A. Jänne, MD, Director of the Lowe Center for Thoracic Oncology at Dana-Farber Cancer Institute and Professor of Medicine at Harvard Medical School, Boston.
Adagrasib Properties
Adagrasib targets the KRAS G12C mutation, which occurs in approximately 14% of NSCLC, 4% of colorectal tumors, and 2% of pancreatic cancers. The drug works by irreversibly and selectively binding to KRAS G12C in its inactive state, blocking its signaling to other cells and preventing tumor cell growth and proliferation.
“Adagrasib was optimized for desired properties of a KRAS G12C inhibitor,” Dr. Jänne said. It is a potent covalent inhibitor with high selectivity for mutant KRAS and favorable pharmacokinetic properties, including oral bioavailability, long half-life (24 hours), and extensive tissue distribution, he said.
“Our hypothesis was that continuous exposure of adagrasib above a target threshold enables inhibition of KRAS-dependent signaling for the complete dose interval and maximizes the depth and duration of antitumor activity,” he explained.
The phase I/Ib part of KRYSTAL-1 enrolled 110 patients with previously treated advanced NSCLC, colorectal cancer, and other solid tumors (pancreatic, ovarian, endometrial, cholangiocarcinoma) harboring the KRAS G12C mutation. Additional patients were enrolled in phase II. All patients had received standard treatments, including chemotherapy and immunotherapy.
Non–Small Cell Lung Cancer Subset
Dr. Jänne presented the results for 79 patients with NSCLC in the phase I/II group treated with adagrasib monotherapy at 600 mg orally twice a day.1 The median number of prior lines of therapy was three in the phase I group and two in the phase II group; for about 90% of patients, treatment had included an anti–PD-1/PD-L1 inhibitor.
He reported confirmed objective responses in 45% and a disease control rate of 96% in 51 evaluable patients in phase II followed for a median of 3.6 months. “This means 49 of the 51 patients showed a partial or complete response or had stable disease,” he said.
Among the 14 patients in phase I/Ib who have been followed the longest (median = 9.6 months), 6 (43%) responded; in 4 of these patients, treatment has been ongoing for more than 11 months, he reported.
In a preclinical model, adagrasib penetrated the brain and cerebrospinal cord and led to tumor regression. Such activity is also being observed in patients, he added.
Also encouraging is the robust activity seen in patients with concurrent STK11 co-mutations. In an exploratory analysis, 9 of 14 patients (64%) with concurrent KRAS and STK11 mutations responded—a higher response rate than was seen with a KRAS mutation alone, he added.
“I’m thrilled to see how well adagrasib is working…. It’s super exciting,” Dr. Jänne commented. “The fact that we are seeing responses in 45% of patients, which indicates that adagrasib may be an effective therapy, is incredibly meaningful, as it opens up the possibility of a new treatment option for this subset of patients with lung cancer.”
Data in Other Solid Tumors
Updated results with adagrasib in 31 patients with colorectal cancer and other solid tumors were presented by Melissa L. Johnson, MD, Associate Director of the Lung Cancer Research Program and Drug Development at the Sarah Cannon Research Institute, Tennessee Oncology, Nashville.2
“We believe that preventing feedback loops [that cause KRAS hyperactivity] may lead to more durable responses in the tumor over a longer period and better tumor shrinkage.”— Melissa L. Johnson, MD
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Of 18 evaluable patients, 3 (17%) had a confirmed response, and 2 are still receiving treatment. Disease control was achieved by 17 (94%), and 12 of these patients continue on the drug. Among the six patients with other solid tumors, partial responses were confirmed in one patient with endometrial cancer and one with pancreatic cancer. There were two unconfirmed responses. All six patients remain on treatment.
“I think the clinical activity of adagrasib is highly encouraging in these patients … with some evaluable patients still on treatment after 11 months,” said Dr. Johnson.
Adagrasib’s half-life reportedly enables it to inhibit KRAS continuously between doses. This helps to prevent what is known as a feedback loop, which occurs when the KRAS pathway is not completely inhibited and becomes hyperactive, leading to tumor regrowth. “We believe that preventing feedback loops may lead to more durable responses in the tumor over a longer period and better tumor shrinkage,” she said.
Toxicity and Forthcoming Data
In the full data set of 110 patients, the principal toxicities (of any grade) were nausea (54%), diarrhea (51%), vomiting (35%), fatigue (32%), and increased liver enzymes (20%). Grade 3 or 4 toxicities were seen in 30%, mostly fatigue (6%). Two deaths occurred: one from pneumonitis in a patient with recurrent pneumonitis and one from cardiac failure. About 7% of patients discontinued treatment because of treatment-related adverse events.
KEY POINTS
- The novel KRAS inhibitor adagrasib (MRTX849) led to confirmed responses in 45% of patients with advanced pretreated NSCLC in the phase I/II KRYSTAL-1 trial.
- Among 14 patients with the longest follow-up (9.6 months), 6 responded, and 4 remain on treatment more than 11 months later.
- Patients with co-mutations in STK11 had a 64% response rate.
- The confirmed response rate in colorectal cancer was 17%.
As the KRYSTAL-1 trial continues, researchers will evaluate adagrasib in combination with other targeted therapies, such as cetuximab for colon cancer and afatinib or pembrolizumab for NSCLC. It will also be combined with TNO155 (a SHP2 inhibitor) and palbociclib, in other studies.
DISCLOSURE: The study was funded by Mirati Therapeutics. Dr. Jänne has consulted for Mirati Therapeutics, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Chugai Pharmaceuticals, Eli Lilly, Araxes Pharma, Ignyta, Takeda Oncology, Voronoi, Novartis, SFJ Pharmaceuticals, Biocartis, Loxo Oncology, Sanofi, Transcenta, AstraZeneca, and Daiichi Sankyo; he owns stock in Gatekeeper Pharmaceuticals and Loxo and receives postmarketing royalties from Dana-Farber Cancer Institute–owned intellectual property on EGFR mutations licensed to LabCorp. Dr. Johnson has an immediate family member who has served as a consultant or advisor to Astellas Pharma and Otsuka; has served as an institutional consultant or advisor to AbbVie, Achilles Therapeutics, Association of Community Cancer Centers, AstraZeneca, Atreca, Boehringer Ingelheim, Calithera Biosciences, Genentech/Roche, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Incyte, Janssen Oncology, Lilly, Loxo, Merck, Mirati Therapeutics, Novartis, Pfizer, Ribon Therapeutics, and Sanofi; has received institutional research funding from AbbVie, Acerta Pharma, Adaptimmune, Amgen, Apexigen, Arcus Biosciences, Array BioPharma, AstraZeneca, Atreca, BeiGene, Birdie, Boehringer Ingelheim, Checkpoint Therapeutics, Corvus Pharmaceuticals, CytomX Therapeutics, Daiichi Sankyo, Dynavax, EMD Serono, Genentech/Roche, Genmab, Genocea Biosciences, GlaxoSmithKline, Gritstone Oncology, Guardant Health, Hengrui Pharmaceutical, Immunocore, Incyte, Janssen, Jounce Therapeutics, Kadmon, Lilly, Loxo, Lycera, Merck, Mirati Therapeutics, Neovia Oncology, Novartis, OncoMed, Pfizer, Regeneron, Ribon Therapeutics, Sanofi, Shattuck Labs, Stem CentRx, Syndax, Takeda, Tarveda Therapeutics, TCR2 Therapeutics, University of Michigan, and WindMIL; and has been reimbursed for travel, accommodations, or other expenses by AbbVie, Astellas Pharma, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Clovis Oncology, Daiichi Sankyo, EMD Serono, Exelixis, Genentech, Incyte, Janssen Oncology, Lilly, Merck, Novartis, Pfizer, Sanofi, Sysmex, and Vapotherm.
REFERENCES
1. Janne PA, Rybkin II, Spira AI, et al: KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in advanced/metastatic non-small-cell lung cancer harboring KRAS G12C mutation. 2020 EORTC-NCI-AACR Symposium. Abstract LBA3. Presented October 25, 2020.
2. Johnson ML, Ou SHI, Barve M, et al: KRYSTAL-1: Activity and safety of adagrasib (MRTX849) in patients with colorectal cancer and other solid tumors harboring a KRAS G12C mutation. 2020 EORTC-NCI-AACR Symposium. Abstract LBA4. Presented October 25, 2020.
3. Hong DS, Fakih MG, Strickler JH, et al: KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med 383:1207-1217, 2020.
