Adagrasib Shows Promising Results in Pretreated KRAS Mutation–Positive NSCLC

Lung cancer is one of the main causes of cancer-related death in the United States, with approximately 235,000 new cases identified each year.¹ Whereas the 5-year survival rate varies based on the stage of the cancer at the time of diagnosis, the overall 5-year relative survival rate is approximately 21%.¹ Non–small-cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 80% to 85% of all cases.¹ Adenocarcinoma, large-cell carcinoma, and squamous-cell carcinoma are the 3 primary subtypes of NSCLC, with adenocarcinoma being the most common.¹ These tumors begin in the glandular cells of the lungs and are more common in those who currently smoke or have previously smoked.¹ It is also the most frequent type of lung cancer in nonsmokers.¹

KRAS^G12C mutations are found in approximately 15% to 25% of patients with lung cancer.² The KRAS mutation is a crucial mediator in the RAS/MAPK signaling cascade, which leads to uncontrolled cell growth and disease development, making the disease more aggressive and challenging to treat.² When compared with other KRAS mutations and KRAS wild-type, KRAS^G12C has been linked to a lower overall survival (6.4 months) in advanced NSCLC (10.3 months and 16.1 months, respectively).³ Adagrasib (MRTX-849) is a new treatment for the KRAS^G12C mutation. The mutant KRAS protein is irreversibly locked in an inactive state by this inhibitor, which targets KRAS^G12C.⁴ Adagrasib also has a long 24-hour half-life, resulting in longer anticancer activity.⁴

Adagrasib was evaluated in the KRYSTAL-1 study, a large, multicohort, phase 1/2 trial with a subpopulation of 79 patients with advanced NSCLC and a KRAS^G12C mutation. Chemotherapy and an anti–PD-L1 drug had previously been used to treat these patients. The study’s key end points were drug safety, pharmacokinetics, and clinical activity and efficacy. In March 2021, the findings of the study were presented at the European Lung Cancer Virtual Congress.

Adagrasib 600 mg was given twice daily to the participants.⁵ A total of 51 individuals were assessed for therapy response. In 45% of patients, there was a partial response, and 50% of patients had stable disease.⁵ Further investigation of pharmacodynamic indicators and mechanistic biomarkers revealed that adagrasib treatment elicited an immunologic response. Furthermore, adagrasib showed a 64% response rate in a subset of patients with NSCLC with an STK11 mutation and a KRAS^G12C mutation.⁵

Patients appeared to tolerate adagrasib treatment quite well. The most prevalent side effects of therapy were gastrointestinal, including nausea (54%), diarrhea (48%), and vomiting (34%).⁵ Fatigue (28%) and a rise in alanine aminotransferase (23%) were 2 other common side effects.⁵ Hyponatremia occurred in 3% of patients.⁵ The efficacy and tolerability of adagrasib in previously treated patients with NSCLC tumors containing the KRAS^G12C mutation were proven in this study.

References

1. American Cancer Society. Cancer facts & figures 2021. www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2021/cancer-facts-and-figures-2021.pdf. 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 S-Y, Sun H, Zhou J-Y, et al. Clinical characteristics and prognostic value of the KRAS G12C mutation in Chinese non-small cell lung cancer patients. Biomark Res. 2020;8:22.
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. 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.