Adagrasib: a novel inhibitor for KRAS^G12C-mutated non-small-cell lung cancer

Abstract

Adagrasib is a recently US FDA-approved novel KRAS^G12C targeted therapy with clinical efficacy in patients with advanced, pretreated KRAS^G12C-mutated non-small-cell lung cancer. KRYSTAL-I reported an objective response rate of 42.9% with median duration of response of 8.5 months. Treatment-related adverse events were primarily gastrointestinal and occurred in 97.4% of patients, with grade 3+ treatment-related adverse events occurring in 44.8% of patients. This review details the preclinical and clinical data for adagrasib in the treatment of non-small-cell lung cancer. We also outline practical clinical administration guidelines for this novel therapy, including management of toxicities. Finally, we discuss the implications of resistance mechanisms, summarize other KRAS^G12C inhibitors currently in development and outline future directions for adagrasib-based combination therapies.

Plain language summary

Adagrasib for the treatment of non-small-cell lung cancer: Adagrasib is a new oral (taken by mouth) treatment option for patients with non-small-cell lung cancer (NSCLC) with KRAS^G12C mutations. KRAS is a gene that regulates signaling pathways, which are responsible for cell growth and division. A mutation in KRAS can cause cells to multiply and cause cancer. Clinical trials have shown that adagrasib causes cancer reduction or resolution in 42.9% of people with NSCLC with KRAS^G12C mutations who receive the drug. Side effects of adagrasib are primarily gastrointestinal (nausea, vomiting, diarrhea). This review outlines guidelines for the management of side effects. New studies are looking at how adagrasib can be safely combined with other therapies to better treat NSCLC with KRAS^G12C mutations.

Tweetable abstract

Adagrasib is a novel KRASG12C targeted therapy. In this review, we summarize data supporting adagrasib use in KRAS^G12C-mutated non-small-cell lung cancer and provide expert summary for clinical administration, toxicity management and future directions.

Keywords::

• adagrasib
• KRAS
• lung cancer
• NSCLC
• targeted therapy

Acknowledgments

Figures created by author MZ Guo with BioRender.com subscription.

Financial& competing interests disclosure

There was no funding provided for this work. MZ Guo has no financial or nonfinancial disclosures. KA Marrone has received honoraria from AstraZeneca; consulting fees from AstraZeneca, Amgen, Puma Biotechnology, Janssen and Mirati Therapeutics; and research funding (institution) from Bristol-Myers Squibb and AstraZeneca. A Spira has stock and other ownership interests in Eli Lilly; honoraria from CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novarits, Bristol-Myers Squibb and Bayer; consulting fees from Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals and Takeda; consulting fees (institution) from Array BioPharma, AstraZeneca/MedIMmune, Merck and Bristol-Myers Squibb; research funding from LAM therapeutics; and research funding (institution) from Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, Abbvie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics and Rubius. S Rosner has no financial or nonfinancial disclosures. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

There was no funding provided for this work. MZ Guo has no financial or nonfinancial disclosures. KA Marrone has received honoraria from AstraZeneca; consulting fees from AstraZeneca, Amgen, Puma Biotechnology, Janssen and Mirati Therapeutics; and research funding (institution) from Bristol-Myers Squibb and AstraZeneca. A Spira has stock and other ownership interests in Eli Lilly; honoraria from CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novarits, Bristol-Myers Squibb and Bayer; consulting fees from Incyte, Amgen, Novartis, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals and Takeda; consulting fees (institution) from Array BioPharma, AstraZeneca/MedIMmune, Merck and Bristol-Myers Squibb; research funding from LAM therapeutics; and research funding (institution) from Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, Abbvie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics and Rubius. S Rosner has no financial or nonfinancial disclosures. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.