Adagrasib Shows Promising Results in Pretreated KRAS-Mutant NSCLC

Lung cancer is one of the leading causes of cancer-related mortality with approximately 235,000 new cases diagnosed in the United States each year.¹ While the 5-year survival rate varies depending on stage at diagnosis, the overall 5-year relative survival rate is approximately 21%.¹ The majority of lung cancer diagnoses are non–small-cell lung cancer (NSCLC), accounting for 80% to 85% of total lung cancer cases.¹ There are 3 main subtypes of NSCLC: adenocarcinoma, large-cell carcinoma, and squamous-cell carcinoma, with adenocarcinoma being the most common subtype of NSCLC.¹ These tumors start in the glandular cells in the lungs and occur primarily in current or former smokers.¹ It is also the most common lung cancer type found in non-smokers.¹

KRAS^G12C mutations occur in approximately 15% to 25% of lung adenocarcinoma cases.² The KRAS mutation is a key mediator in the RAS/MAPK signaling cascade leading to unregulated cell growth and disease progression, making the disease more aggressive and difficult to treat.² In advanced NSCLC, KRAS^G12C has been associated with shorter overall survival (6.4 months) when compared with other KRAS mutations and wild-type KRAS (10.3 months and 16.1 months).³ Adagrasib is a novel therapy developed to target the KRAS^G12C mutation. This inhibitor targets KRAS^G12C to irreversibly lock the mutant KRAS protein in an inactive state.⁴ In addition, adagrasib has a long 24-hour half-life, which conveys more sustained antitumor activity.⁴

Adagrasib was evaluated in the KRYSTAL-1 study, a large, multicohort, phase 1/2 trial with a subpopulation of 79 patients who had advanced NSCLC with a KRAS^G12C mutation. These patients were previously treated with chemotherapy and an anti–PD-L1 agent. Drug safety, pharmacokinetics, and clinical activity and efficacy were the primary end points evaluated in the study. The study results were presented at the European Lung Cancer Virtual Congress in March 2021.

Participants received 600 mg of adagrasib twice a day.⁵ In total, 51 patients were evaluated for response to treatment. Partial response was found in 45% of patients, and 50% of patients had stable disease.⁵ Further analysis of pharmacodynamic markers and mechanistic biomarkers indicated an immune response with adagrasib therapy. In addition, adagrasib demonstrated a response rate of 64% in a subpopulation of NSCLC patients who had an STK11 mutation along with the KRAS^G12C mutation.⁵

Adagrasib therapy appeared to be well tolerated in patients. The most common treatment-related adverse effects were gastrointestinal: nausea (54%), diarrhea (48%), and vomiting (34%).⁵ Other frequent adverse events were fatigue (28%) and an increase in alanine aminotransferase (23%).⁵ Hyponatremia occurred in 3% of patients.⁵

This study demonstrated the efficacy and tolerability of adagrasib in previously treated patients with NSCLC tumors harboring the KRAS^G12C mutation.

References

1. American Cancer Society. Cancer Facts & Figures 2021. www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2021.html. Accessed May 20, 2021.
2. Ferrer I, Zugazagoitia J, Herbertz S, et al. KRAS-Mutant non-small cell lung cancer: from biology to therapy. Lung Cancer. 2018;124:53-64.
3. Liu SY, Sun H, Zhou JY, et al. Clinical characteristics and prognostic value of the KRAS G12C mutation in Chinese non-small cell lung cancer patients. Biomark Res. 2020;8.
4. American Association for Cancer Research. Another KRAS inhibitor holds its own. Cancer Discov. 2020;10:OF2.
5. Riely GJ, Ou S-HI, Rybkin I, et al. 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. J Thorac Oncol. 2021;16(4_suppl):S751-S752.