Sotorasib approved as the first targeted therapy for KRAS-Mutant Lung Cancer – Medical News Asia

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Lung cancer is one of the leading cancers in Hong Kong, accounting for 26.4% of cancer mortality in 2018.¹ Approximately 80%-85% of the lung cancers are non-small cell lung cancer (NSCLC).² A common oncogenic driver in NSCLC are the Kirsten Rat Sarcoma (KRAS) mutations present in roughly one-fourth of cases.³ Of this, the G12C point mutation (KRAS p.G12C or KRAS^G12C) is one of the common KRAS aberrations in NSCLC.⁴ Although more prevalent in Western populations, KRAS mutations still occur in 4.3% of Chinese patients with NSCLC.⁵ Attempts at targeting KRAS mutations in the past have not been successful until recently, when sotorasib, the first KRAS^G12C-inhibitor received accelerated approval from the United States Food and Drug Administration on May 28, 2021.⁶

Sotorasib is a small molecule that exerts specific and irreversible inhibition on KRAS^G12C. The phase 1/2 CodeBreaK100 trial evaluated the efficacy of sotorasib in NSCLC patients harbouring a KRAS^G12C mutation. Sotorasib demonstrated promising anticancer activity in the phase 1 study and showed an objective rate (ORR) of 37.1% and a median progression-free survival (PFS) of 6.8 months in the phase 2 study.^7,8 Treatment-related adverse events (TRAEs) were reported in 69.8% of patients.⁸

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A post-hoc analysis of the CodeBreaK100 trial of sotorasib in KRAS^G12C-mutated advanced NSCLC patients with stable brain metastases (BM) was recently reported during the World Conference on Lung Cancer 2021.⁹ The study excluded patients with active untreated BM, but those with stable BM were allowed on trial as long as surgery or radiotherapy was completed at least 4 weeks before enrolling in the study.⁹ The primary endpoint of the study was ORR per RECIST 1.1 by independent central review, and other key secondary endpoints included duration of response, disease control rate (DCR), PFS, overall survival (OS), and safety. Investigators determined the presence of neurologically stable/asymptomatic BM at baseline.⁹

A total of 174 patients were included: 23.0% had stable BM while 77% had no BM at baseline.⁹ In patients with baseline BM, most received prior radiotherapy or surgery. In this group, a 25.0% ORR and 77.5% DCR was observed. Median PFS and OS was 5.3 and 8.3 months, suggesting systemic durable anticancer activity.⁹ More encouraging results were observed in patients without baseline BM, with an ORR of 41.7%, a DCR of 84.1%, a median PFS of 6.7 months, and a median OS of 13.6 months.⁹ Response assessment in neuro-oncology (RANO) analysis demonstrated that 87.5% of patients with evaluable BM (n=16) achieved intracranial disease control.⁹ Safety in the BM group was in line with prior findings, with a favourable safety profile and majority of TRAEs of low grade.⁹

Reference

Hong Kong Cancer Registry. Overview of Hong Kong Cancer Statistics of 2018. Hong Kong Hospital Authority. Available at: https://www3.ha.org.hk/cancereg/pdf/overview/Overview%20of%20HK%20Cancer%20Stat%202018.pdf. Last accessed: 10 September 2021.

American Cancer Society. Available online. https://www.cancer.org/cancer/lung-cancer/about/what-is.html. Last accessed: 10 September 2021

Addeo A et al. Cancers (Basel). 2021;13(11):2541.

Biernacka A et al. Cancer Genet. 2016;209(5):195-198.

Loong HHF et al. Translational Lung Cancer Research. 2020;9(5).

FDA. Available online. https://www.fda.gov/news-events/press-announcements/fda-approves-first-targeted-therapy-lung-cancer-mutation-previously-considered-resistant-drug. Last accessed: 10 September 2021.

Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.

Skoulidis F et al. New England Journal of Medicine. Published online June 4, 2021.

Ramalingam SS et al. Presented at: 2021 World Conference on Lung Cancer. Available at: https://library.iaslc.org/conference-program?product_id=24&author=&category=&date=&session_type=&session=&presentation=&keyword=CodeBreaK%20100&cme=undefined&. (Accessed 13 September 2021)

Disclaimer

This article is not medical advice. Patients should seek personal assessment by a licenced specialist. Physicians are recommended to read the full publication(s) as cited in the article before making medical decisions. This article does not supersede nor replace the published article(s).