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Sotorasib-for-the-treatment-of-KRASG12C-mutated-lung-cancer
Medical writer: Kirsty LEE | Last updated: 15 October 2020 | In: Gastrointestinal Cancer, Lung Cancer, Oncology, Targeted Therapies
Article Keywords
NSCLC, CRC, KRAS, AMG 510, KRAS G12C, RAS, solid tumours, sotorasib
RAS is the most frequently mutated gene family in cancers, with KRAS mutations being involved as a driver in three of the most lethal cancers – lung cancer, colorectal cancer, and pancreatic cancer.1Moore AR et al. Nat Rev Drug Discov. 2020;19(8):533-552. Incidence of KRAS mutations vary between ethnicity with Caucasians having a higher incidence than African-Americans or Asians.2Loong HH-F et al. Transl Lung Cancer Res. 2020;0(0). In non-small lung cancer (NSCLC), the most common KRAS mutation is G12C.2Loong HH-F et al. Transl Lung Cancer Res. 2020;0(0). In Asia, G12C mutations in particular account for 14.5% of KRAS mutations in the Chinese population.2Loong HH-F et al. Transl Lung Cancer Res. 2020;0(0). KRAS G12C was identified in 4.3% of lung cancer samples and 2.5% of colorectal cancer samples.2Loong HH-F et al. Transl Lung Cancer Res. 2020;0(0).
Attempts for developing inhibitors of RAS-driven oncogenesis has failed over the last three decades, until an allele-specific covalent inhibitor, sotorasib (previously known as AMG 510), was granted fast track designation by the United States Food and Drug Administration (US FDA).1Moore AR et al. Nat Rev Drug Discov. 2020;19(8):533-552. Sotorasib is a small molecule that specifically and irreversibly inhibits KRAS G12C.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Results of a phase 1 trial of sotorasib in patients with advanced solid tumours harbouring KRAS G12C mutation were recently published in the New England Journal of Medicine.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.
The phase 1, multicentre, open-label trial aimed to evaluate the safety, pharmacokinetics, and efficacy of sotorasib in advanced solid tumours with mutated KRAS G12C.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Patients were aged ≥18, with histologically confirmed locally advanced or metastatic cancer that was confirmed to have a KRAS G12C mutation by local molecular testing on tumour tissues.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Patients with NSCLC were allowed previous platinum-based combination therapy, targeted therapies, or both, and patients with colorectal cancer (CRC) were allowed two previous lines of systemic therapy for metastatic disease.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Patients with solid tumours other than NSCLC or CRC had to have received at least one previous line of systemic therapy.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.
The trial had dose escalation and expansion cohorts, and sotorasib was administered orally once daily.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The planned dose levels for escalation cohorts were 180, 360, 720, and 960mg.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The primary endpoint was safety.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Secondary endpoints included maximum plasma concentration, time to achieve maximum plasma concentration, objective response, duration of response, disease control, and progression-free survival (PFS).3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.
A total of 129 patients, of which 59 had NSCLC and 42 had CRC, were enrolled in this trial.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The median follow-up was 11.7 months, and treatment discontinuation occurred in 82.9% of patients.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The most common reason for discontinuation was disease progression.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The median age of the study population was 62 years, with a median of 3 previous lines of anticancer therapy for metastatic disease.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. No dose-limiting toxic effects were observed with sotorasib.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Adverse events of any cause were reported in 96.9% of patients, with the most common events being diarrhoea (29.5%), fatigue (23.3%), and nausea (20.9%).3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Grade ≥3 TEAEs included an increase in alanine aminotransferase (ALT) levels, diarrhoea, and anaemia.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. One patient reported a grade 4 TEAE of elevated ALT, which returned to baseline after reducing the sotorasib dose and tapering glucocorticoids.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.
The maximum plasma concentration of sotorasib was 7.50μg/mL, with a median time to maximum plasma concentration of 2.0 hours.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The mean elimination half-life was 5.5 hours.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The 960mg dose once daily was identified as the dose for the dose expansion cohort.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.
Of the 59 NSCLC patients, 19 had a confirmed partial response, and 33 had stable disease.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Responses were seen across all dose levels.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Tumour shrinking of any magnitude was observed in 71.2% of patients at the first assessment in week 6.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The median time to response was 1.4 months, and median duration of response 10.9 months.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Median duration of stable disease was 4.0 months.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. In the CRC patients, a confirmed partial response was observed in 7.1% of patients, and 66.7% had stable disease.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The median duration of stable disease was 5.4 months.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The median PFS was 4.0 months for all CRC patients.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.
These results show that sotorasib demonstrated promising activity in patients with heavily pre-treated KRAS G12C mutated solid tumours, although the differences in response between NSCLC and CRC patients indicate that KRAS G12C may not be the dominant oncogenic driver in CRC.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. Majority of patients receiving sotorasib experienced adverse events, although majority were of low grade.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217. The study authors indicate that other trials evaluating sotorasib as monotherapy or in combination for NSCLC or other solid tumours are underway.3Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.
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Reference
- Moore AR et al. Nat Rev Drug Discov. 2020;19(8):533-552.
- Loong HH-F et al. Transl Lung Cancer Res. 2020;0(0).
- Hong DS et al. N Engl J Med. 2020;383(13):1207-1217.
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).
© Copyright 2020 MediPaper Medical Communications Ltd. – Sotorasib for the treatment of KRASG12C mutated lung cancer
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© Copyright 2020 MediPaper Medical Communications Ltd. – Sotorasib for the treatment of KRASG12C mutated lung cancer
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