CodeBreaK 100 Trial Results Demonstrate Sotorasib Conveys Clinical Benefit Across NSCLC Patient Subgroups

The most common mutated oncogene in cancer is the rat sarcoma (RAS) oncogene with Kirsten rat sarcoma (KRAS) being the most frequently mutated RAS isoform.¹ In cells, the KRAS protein cycles between an active form and an inactive form.¹ The active form activates signaling pathways responsible for cell proliferation, cell cycle regulation, and cell survival among other cellular functions.¹ When KRAS becomes dysregulated, tumor growth occurs and cancer cell survival, invasion, and migration are promoted.¹ In lung cancer, KRAS accounts for 31% to 35% of mutations with G12C mutations being the most common mutation type.¹ Patients with non–small-cell lung cancer (NSCLC) with KRAS mutations generally have a poor treatment outcome as these mutations are often associated with treatment resistance.^1,2 Sotorasib is a small-molecule KRAS^G12C inhibitor that irreversibly traps KRAS^G12C in an inactive state.² In the phase 2 CodeBreaK 100 trial, sotorasib demonstrated favorable efficacy in pretreated patients with KRAS^G12C NSCLC with an objective response rate (ORR) of 37.1% and a median 6.8 months of progression-free survival (PFS).^3,4 Based on this response, in May 2021 the US Food and Drug Administration approved sotorasib for adult KRAS^G12C-mutant NSCLC patients with ≥1 prior lines of systemic therapy.³ In patients with STK11 co-mutations, tumor response was also observed.⁴ The STK11 mutation is associated with poor clinical outcomes with standard treatment.⁴ At the virtual 2021 American Society of Clinical Oncology annual meeting, researchers presented further overall survival (OS) and efficacy results across an extended set of patient subgroups from the phase 2 CodeBreaK 100 trial.

In this trial, 960 mg of sotorasib was given to 124 patients with advanced KRAS^G12C NSCLC who had disease progression despite prior treatment.^3,4 Patients aged <65 years accounted for 30.8% of the patient population, while 44.1% of patients were aged ≥65 years. Two or more prior lines of therapy were found in 35.2% of the patients. All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and the majority (120) had metastatic disease. Adverse reactions led to permanent discontinuation of sotorasib in 9% of patients.³ The primary end point was ORR, and secondary end points were OS, PFS, and safety. In patients with prior anti–PD-1 or PD-L1 treatment, the ORR was 36.3%; in those patients without these prior treatments, the response rate was 45.5%. In patients with TP53 co-mutation, the ORR was 40.0%; in patients with STK11 co-mutation, it was 39.3%; and in patients with KEAP1 co-mutation, it was 40.0%.

In this further analysis of the CodeBreaK 100 trial, sotorasib clinical benefit was observed across the patients with KRAS^G12C-mutated subgroups.

References

1. Reck M, Carbone DP, Garassino M, Barlesi F. Targeting KRAS in non-small cell lung cancer: recent progress and new approaches. Ann Oncol. 2021;S0923-7534:02045-02047.
2. Hong DS, Fakih MG, Strickler JH, et al. KRASG12C inhibition with sotorasib in advanced solid tumors. N Engl J Med. 2020;383:1207-1217.
3. The ASCO Post. Sotorasib: subgroup analysis of phase II trial shows activity with breakthrough KRAS inhibitor in lung cancer. Posted June 25, 2021. https://ascopost.com/issues/june-25-2021/fda-approves-sotorasib-for-kras-g12c-mutated-nsclc. Accessed June 26, 2021.
4. Skoulidis F, Li B, Govindan R, et al. Overall survival and exploratory subgroup analyses from the phase 2 CodeBreaK 100 trial evaluating sotorasib in pretreated KRAS p.G12C mutated non-small cell lung cancer. J Clin Oncol. 2021;39(suppl 15):9003.