Lugano, Switzerland; Denver, CO, USA, 25 March 2021 - Clinical activity with a second drug inhibiting KRASG12C confirms its role as a therapeutic target in patients with advanced non-small-cell lung cancer (NSCLC) harbouring this mutation, according to results from a study with the KRASG12C inhibitor adagrasib reported at the European Lung Cancer Virtual Congress 2021. (1)
"As we strive to identify the oncogenic driver in more and more of our patients with NSCLC, it becomes critical that we develop therapies that can target these identified oncogenic drivers," said lead author Gregory Riely, from Memorial Sloan Kettering Cancer Center, New York, USA.
"KRAS mutations are the most frequent oncogenic driver that we see in patients with NSCLC and we've known about KRAS-mutant NSCLC for 30 years. We are now, finally, seeing drugs that can target this subgroup of patients," he said.
The multi-cohort phase 1/2 KRYSTAL-1 study evaluated adagrasib, a selective inhibitor of KRASG12C, in 79 patients with advanced or metastatic NSCLC harbouring a KRASG12C mutation. Most (92%) of the patients had previously been treated with chemotherapy and an anti-PD-(L)1.
Results showed that nearly half (45%) of the 51 patients evaluable for clinical activity had a partial response to treatment with adagrasib, and 26 patients had stable disease.
"The 45% response rate is unprecedented activity in patients with KRASG12C mutant NSCLC," commented Myung-Ju Ahn, from Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. "A response of this magnitude could not be expected with other chemotherapy or immunotherapy in pre-treated KRAS-mutated patients, suggesting that KRASG12C is a therapeutic target." She considered the finding is potentially practice-changing although further studies are needed as long-term follow-up data are currently limited.
The results with adagrasib are comparable to those with another KRASG12C inhibitor, sotorasib, reported earlier this year at the World Conference on Lung Cancer 2021. (2)
"Finding another promising targeted agent against KRASG12C mutant NSCLC sheds light on the treatment of these patients who currently have unmet medical need," said Ahn.
KRASG12C mutations occur in around 14% of patients with lung adenocarcinomas, the most common subtype of NSCLC, but there is currently no approved KRAS-targeting therapy.
"Having more KRASG12C inhibitors gives us additional opportunities to explore combinations of these inhibitors with other classes of agents, including immune checkpoint inhibitors as well as other small molecule MAP kinase inhibitor combinations," said Riely.
"The current data really set up future trials to establish the role for adagrasib in patients with KRASG12C mutant NSCLC. They provide a particular opportunity to explore this drug's activity in patients with KRASG12C mutant NSCLC that have been previously treated with platinum-based chemotherapies to potentially submit for regulatory approval." If approved, he suggested: "I think this would clearly set adagrasib as a preferred second-line therapy, compared with chemotherapy, for patients with KRAS mutant NSCLC."
"Given the low toxicity, adagrasib could potentially be combined with chemotherapy, immunotherapy or other molecules to increase activity in patients with KRASG12C mutant NSCLC," suggested Ahn.
Further data from KRYSTAL-1 showed an even greater response to adagrasib in the subpopulation of patients whose tumours had an STK11 mutation as well as a KRASG12C mutation. STK11 mutations have been associated with inferior responses to immune checkpoint inhibitors in patients with NSCLC. Riely noted: "Finding that the response rate was higher for patients with STK11 mutations suggests that this group of patients, who otherwise don't benefit from checkpoint inhibitors, may have even better response to adagrasib."
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1 https://www.esmo.org/meetings/european-lung-cancer-virtual-congress-2021 Abstract 99O_PR
'KRYSTAL-1: Activity and Preliminary Pharmacodynamic (PD) Analysis of Adagrasib (MRTX849) in Patients (Pts) With Advanced Non-Small- Cell Lung Cancer (NSCLC) Harboring KRASG12C Mutation' will be presented by Gregory Riely during the Proffered Paper Session on Thursday, 25 March, 14:35-15:55 CET on Channel 1. Journal of Thoracic Oncology, Volume 16, Number 4S, Supplement, April 2021
2 Abstract PS01.07. CodeBreaK 100: Registrational phase 2 trial of sotorasib in KRASp.G12C mutated non-small-cell lung cancer. IASLC 2021.
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99O_PR - KRYSTAL-1: Activity and Preliminary Pharmacodynamic (PD) Analysis of Adagrasib (MRTX849) in Patients (Pts) With Advanced Non-Small- Cell Lung Cancer (NSCLC) Harboring KRASG12C Mutation
G.J. Riely1, S-H.I. Ou2, I. Rybkin3, A. Spira4, K. Papadopoulos5, J.K. Sabari6, M. Johnson7, R.S. Heist8, L. Bazhenova9, M. Barve10, J.M. Pacheco11, K. Velastegui12, C. Cilliers12, P. Olson12, J.G. Christensen12, T. Kheoh12, R.C. Chao12, P.A. Jänne13
1Thoracic Oncology Service, Division of Solid Tumor, Department of Medicine, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, USA,
2University of California Irvine, Orange, AL, USA, 3Henry Ford Cancer Institute, Henry Ford Hospital, Detroit, USA, 4Research Institute, Virginia Cancer Specialist, Fairfax, USA, 5Clinical Research department, South Texas Accelerated Research Therapeutics (START), San Antonio, TX, USA, 6Perlmutter Cancer Center, New York University Langone Health, New York, NY, USA, 7Lung Cancer Research, Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN, USA, 8Massachusetts General Hospital, Boston, MA, USA, 9Medicine, Moores Cancer Center - UC San Diego Health, La Jolla, CA, USA, 10Mary Crowley Cancer Research, Dallas, TX, USA, 11Division of Medical Oncology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA, 12Mirati Therapeutics, Inc., San Diego, CA, USA, 13Lowe Center for Thoracic Oncology, Dana Farber Cancer Institute, Boston, MA, USA
Background: KRAS, the most frequently mutated oncogene in cancer, is a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRASG12C mutations occur in approximately 14% of NSCLC (adenocarcinoma). Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRASG12C that irreversibly and selectively binds to KRASG12C, locking it in its inactive state and was optimized for favorable PK properties, including oral bioavailability, long half-life (~24 h), and extensive tissue distribution.
Methods: KRYSTAL-1 (NCT03785249) is a multi-cohort phase I/II study evaluating adagrasib in pts with advanced or metastatic solid tumors, including NSCLC, harboring a KRASG12C mutation previously treated with chemotherapy and an anti-PD-(L)1. Exploratory endpoints include correlative analysis of co-occurring genetic alterations in tumor tissue at baseline and evaluation of the modulation of PD markers, including transcriptomics, in pretreatment and on-study biopsies.
Results: As of 30 August 2020, 79 pts with pretreated NSCLC were treated with adagrasib 600 mg BID (phase I/Ib and phase II). Most commonly reported (>20%) TRAEs included: nausea (54%), diarrhea (48%), vomiting (34%), fatigue (28%), and increased ALT (23%). Among the 51 pts evaluable for clinical activity, 45% (23/51) had a partial response (PR) and 26 pts had stable disease (SD). In a subpopulation of pts with STK11-comutations, ORR was 64% (9/14). Preliminary PD and mechanistic biomarker analyses on pre- and post-treatment tumor NSCLC biopsies (n=3) demonstrate downregulation of KRAS/MAPK pathway genes including DUSP6 and SPRY4. In pts with tumors harboring STK11-comutations, there was minimal expression of immune transcripts (eg, CD4 and CD8) at baseline and these transcripts were increased after treatment with adagrasib suggesting a potential immune response to therapy.
Conclusions: Adagrasib is tolerable and has demonstrated clinical activity in pts with previously treated KRASG12C-mutant NSCLC. Additional PD and mechanistic data will be presented.
Clinical trial identification: NCT03785249
Editorial acknowledgement: Editorial support was provided by Robin Serody of Axiom Healthcare Strategies.
Legal entity responsible for the study: Mirati Therapeutics, Inc.
Funding: Mirati Therapeutics, Inc.
Disclosure: G.J. Riely: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Takeda ; Advisory/Consultancy: Mirati Therapeutics. S-H.I. Ou: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Takeda; Advisory/Consultancy: TP Therapeutics; Speaker Bureau/Expert testimony: Genentech; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Takeda; Shareholder/Stockholder/Stock options: Turning Point Therapeutics. I. Rybkin: Advisory/Consultancy: AstraZeneca.
A. Spira: Shareholder/Stockholder/Stock options: Lilly; Advisory/Consultancy: Incyte; Advisory/Consultancy: Amgen; Advisory/Consultancy: Novartis; Advisory/Consultancy: Mirati Therapeutics, Inc; Advisory/Consultancy: Gritstone ; Advisory/Consultancy: Jazz Pharmaceuticals; Honoraria (self): CytomX Therapeutics; Honoraria (self): AstraZeneca/MedImmune; Honoraria (self): Merck; Honoraria (self): Takeda; Honoraria (self): Amgen; Honoraria (self): Janssen Oncology; Honoraria (self): Novartis; Honoraria (self): Bristol Myers Squibb; Honoraria (self): Bayer. K. Papadopoulos: Advisory/Consultancy: Bayer; Advisory/Consultancy: ArQule; Advisory/Consultancy: Basilea. M. Johnson: Spouse/Financial dependant: Otsuka; Travel/Accommodation/Expenses: Abbvie; Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: Genentech; Travel/Accommodation/Expenses: Incyte; Travel/Accommodation/Expenses: Merck; Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Sanofi. R.S. Heist: Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Novartis; Advisory/Consultancy: Tarveda; Advisory/Consultancy: Apollonia; Honoraria (self): Chugai/Roche.
L. Bazhenova: Shareholder/Stockholder/Stock options: Epic Sciences; Advisory/Consultancy, Research grant/Funding (self): Beyond Spring Pharmaceuticals; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Takeda; Advisory/Consultancy: Roche; Advisory/Consultancy: Blueprint Medicines; Advisory/Consultancy: G1; Advisory/Consultancy: Bayer; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Novartis; Advisory/Consultancy: Regeneron; Advisory/Consultancy: Merck; Advisory/Consultancy: Johnson & Johnson; Advisory/Consultancy: BMSi; Advisory/Consultancy: Daichi Sankyo; Advisory/Consultancy: Neuvogen. J.M. Pacheco: Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Hengrui; Advisory/Consultancy: Gerson Lehrman; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Travel/Accommodation/Expenses: Takeda. K. Velastegui: Full/Part-time employment: Mirati Therapeutics, Inc. C. Cilliers: Full/Part-time employment: Mirati Therapeutics, Inc.
P. Olson: Full/Part-time employment: Mirati Therapeutics, Inc. J.G. Christensen: Leadership role, Shareholder/Stockholder/Stock options, Officer/Board of Directors: Mirati Therapeutics, Inc; Advisory/Consultancy: BridgeBio; Leadership role, Shareholder/Stockholder/Stock options: BCTG Acquisition; Shareholder/Stockholder/Stock options: Bluebird Bio. T. Kheoh: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics, Inc; Shareholder/Stockholder/Stock options: Tocagen.
R.C. Chao: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics, Inc. P.A. Jänne: Shareholder/Stockholder/Stock options: Gatekeeper Pharmaceuticals; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Loxo; Research grant/Funding (self): Revolution Medicines; Advisory/Consultancy, Research grant/Funding (self): Takeda; Research grant/Funding (self): Puma Biotechnology; Advisory/Consultancy, Research grant/Funding (self): Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (self): Lilly; Advisory/Consultancy, Research grant/Funding (self): Daichi Sankyo; Research grant/Funding (self): Astellas; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Merrimack; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: Chugai; Advisory/Consultancy: Mirati Therapeutics, Inc; Advisory/Consultancy: Araxes; Advisory/Consultancy: Ignyta; Advisory/Consultancy: Novartis; Advisory/Consultancy: Biocartis; Advisory/Consultancy: Voronoi; Advisory/Consultancy: SFJ Pharmaceuticals; Advisory/Consultancy: Silicon Therapeutics. All other authors have declared no conflicts of interest.
Journal of Thoracic Oncology