Long-term Benefit of Sotorasib for Survival of Patients with Pre-treated Advanced/Metastatic NSCLC with G12C Mutation of KRAS Oncogene

COMMERCIAL ANNOUNCEMENT

Introduction

Lung cancer is the leading cause of cancer-related deaths worldwide, claiming more lives than colorectal cancer, breast cancer, and prostate cancer combined.² While the survival rates for NSCLC patients have been increasing, outcomes remain unsatisfactory for those with advanced disease. The 5-year survival rate for patients with metastatic lung cancer is on average only 7%.³

KRAS^G12C is the most common mutation of the KRAS oncogene in NSCLC⁴, affecting approximately 13% of patients with non-squamous NSCLC.⁵ For patients with NSCLC harboring the KRAS^G12C mutation who have failed or ceased to respond to first-line therapy, treatment options are limited.

Amgen has taken on one of the toughest challenges in clinical cancer research over the past 40 years by developing the KRAS^G12C inhibitor known as sotorasib (marketed under the name Lumakras/Lumykras).

Fresh Analysis of Data from the CodeBreaK 100 Study

Sotorasib is a KRAS^G12C inhibitor administered once per day per os. In phase II of the CodeBreaK 100 study involving patients with advanced NSCLC with KRAS^G12C mutation, sotorasib demonstrated an objective response rate (ORR) of 37%, median duration of response (DOR) of 11.1 months, median PFS of 6.8 months, and median OS of 12.5 months, with a manageable safety profile.⁶ The newly published 2-year pooled results from phase I/II of the CodeBreaK 100 study, summarized here, represent what is likely the longest evaluation of treatment with a KRAS^G12C inhibitor to date.¹

Investigated Parameters

CodeBreaK 100 was a multicenter, open-label, single-arm study. The primary endpoint in phase I was safety and tolerability, while the primary endpoint in phase II was ORR. Secondary endpoints included DOR, PFS, OS, and safety. Late adverse effects emerging after one year of treatment were also monitored. An exploratory analysis evaluated tumor molecular characteristics that might be associated with better efficacy of sotorasib.¹

Evaluated Population

A total of 174 patients were enrolled (48 in phase I and 126 in phase II), with a median age of 65 and comprising 52% females. Metastases were present in 97% of patients. The median number of prior lines of therapy was 2, with 83% of patients treated with anti-PD-L1 or PD-1 monoclonal antibodies and platinum-based chemotherapy. About a quarter of the patients had PD-L1 expression < 1%, a quarter ≥ 1%, a quarter ≥ 50%, and a quarter were of unknown status. The median duration of sotorasib treatment was 5.6 months (range 0.2–35.9 months).¹

Pooled 2-Year Results

Efficacy

Sotorasib led to an ORR of 41%, a median DOR of 12.3 months, PFS of 6.3 months, a median OS of 12.5 months, and 2-year OS reached 33%. Long-term clinical benefit (PFS ≥ 12 months) was observed in 23% of patients, while early progression (PFS ≤ 3 months) occurred in 36%. Patients with early progression had slightly higher incidences of visceral metastases, disease progression on prior therapy, and had previously received both platinum-based chemotherapy and immunotherapy. Long-term benefit of sotorasib was noted across all levels of PD-L1 expression, all levels of G12C variant allele frequency, and in some patients with somatic alterations in STK11 or KEAP1. It was also associated with a lower baseline level of circulating tumor DNA.¹

Safety

Adverse events were observed in 70% of patients, with grade 3 adverse events in 20% and grade 4 in 1%. No fatal adverse events occurred. Adverse events led to discontinuation in 6% of patients, temporary interruption, or dose reduction in 22%.¹

Diarrhea (30%) and increased levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) (both 18%) were the most common adverse events. More than one year of sotorasib use was observed in 45 patients, with 24% experiencing new adverse events after one year of treatment, all grade 1–2 except for one case of grade 3 hemolytic anemia (2%). Dose reduction was required for one patient after one year of therapy.¹

Conclusion

This long-term analysis demonstrated that once-daily sotorasib at a dose of 960 mg has a favorable safety profile and shows sustained efficacy in patients with NSCLC with KRAS^G12C mutation.

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Sources:
1. Dy G. K., Govindan R., Velcheti V. et al. Long-term outcomes and molecular correlates of sotorasib efficacy in patients with pretreated KRAS G12C-mutated non-small-cell lung cancer: 2-year analysis of CodeBreaK 100. J Clin Oncol 2023 Jun 20; 41 (18): 3311−3317, doi: 10.1200/JCO.22.02524.
2. Sung H., Ferlay J., Siegel R. L. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021; 71 (3): 209−249, doi: 10.3322/caac.21660.
3. Lung Cancer Survival Rates. American Cancer Society, 2021. Available at: www.cancer.org/cancer/lung-cancer/detection-diagnosis-staging/survival-rates.html 
4. Arbour K. C., Jordan E., Kim H. R. et al. Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clin Cancer Res 2018; 24 (2): 334−340, doi: 10.1158/1078-0432.CCR-17-1841.
5. Sebastian M., Eberhardt W. E. E., Hoffknecht P. et al.; CRISP Registry Group. KRAS G12C-mutated advanced non-small cell lung cancer: a real-world cohort from the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315). Lung Cancer 2021; 154: 51−61, doi: 10.1016/j.lungcan.2021.02.005.
6. Skoulidis F., Li B. T., Dy G. K. et al. Sotorasib for lung cancers with KRAS p.G12C mutation. N Engl J Med 2021; 384: 2371−2381, doi: 10.1056/NEJMoa2103695.
7. Canon J., Rex K., Saiki A. Y. et al. The clinical KRAS^G12C inhibitor AMG 510 drives anti-tumour immunity. Nature 2019; 575 (7781): 217−223, doi: 10.1038/s41586-019-1694-1.