Amgen has bravely embraced one of the most daunting obstacles in the field of cancer research over the past four decades by creating LUMAKRAS/LUMYKRAS, an inhibitor designed specifically for KRASG12C. This accomplishment represents a significant breakthrough due to the immense challenges associated with targeting the KRAS G12C mutation. LUMAKRAS/LUMYKRAS has showcased a positive benefit-risk profile, demonstrating remarkable and lasting anticancer activity in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) who possess the KRAS G12C mutation. This groundbreaking therapy comes in the form of a once-daily oral formulation, providing convenience and ease of administration for patients. In May 2021, US FDA granted accelerated approval to LUMAKRAS for the treatment of KRAS G12C mutated NSCLC.
Amgen's LUMAKRAS has proven to be superior to chemotherapy in preventing tumor progression in patients with previously treated KRAS G12C-mutated NSCLC. Central nervous system (CNS) metastases, a regrettable common complication in advanced NSCLC with KRAS G12C mutations, affect approximately 30-40% of patients. The Phase III CodeBreaK 200 trial, which is the only randomized study for any KRASG12C inhibitor, included a post-hoc analysis focusing on patients with advanced NSCLC and stable CNS lesions at the start of the trial, as determined by a blinded independent central review (BICR).
Using a modified exploratory response assessment called RANO-BM, this analysis revealed that LUMAKRAS exhibited a delayed time to CNS progression and longer CNS progression-free survival (PFS) compared to the chemotherapy drug docetaxel. The post-hoc analysis of CodeBreaK 200 demonstrated that LUMAKRAS delayed CNS progression-free survival by more than five months, providing a potentially meaningful clinical benefit for second-line NSCLC patients with KRAS G12C mutations.
Furthermore, in the analysis, LUMAKRAS exhibited a more than twofold increase in the CNS objective response rate (ORR), which measures the shrinkage of CNS tumors after treatment, compared to docetaxel (33.3% vs. 15.4%). Importantly, the safety profile of LUMAKRAS in this analysis was similar to that observed in the overall population of the CodeBreaK 200 trial. Additionally, the concordance between disease control in systemic and intracranial was higher with LUMAKRAS (88%) compared to docetaxel (54%).
LUMAKRAS demonstrated improved progression-free survival (PFS) compared to docetaxel, regardless of the level of PD-L1 expression, and maintained a PFS benefit over docetaxel across key co-alteration subgroups, including STK11, KEAP1, and TP53. Notably, the time to CNS recurrence was 9.6 months with LUMAKRAS compared to 5.4 months with docetaxel. These biomarker data collectively provide valuable insights for treatment decision-making and guide the ongoing development of the CodeBreaK 200 clinical trial, which explores LUMAKRAS in innovative combination therapies.
Regarding adverse events, treatment-related side effects of any grade were observed in 77.5% of patients receiving LUMAKRAS, while 89.7% of patients treated with docetaxel experienced such events.
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KOL insights
“Randomized evaluation of IC activity of any KRASG12C in sotorasib: reduced risk of progression in CNS recurrence vs. docetaxel in patients with pretreated KRAS G12C mutation advanced NSCLC. Time to CNS recurrence was 9.6 months with sotorasib vs. 5.4 months in docetaxel” –Expert Opinion.
Conclusion
The data highlights the significant efficacy of LUMAKRAS in treating not only the primary tumor but also the associated CNS metastases in patients with KRAS G12C-mutated NSCLC. The findings hold promise for improving outcomes and quality of life for individuals facing this specific form of advanced lung cancer. These findings highlight the efficacy of LUMAKRAS in targeting CNS lesions, with a notable improvement in CNS tumor response compared to traditional chemotherapy. Moreover, the biomarker data support the potential of LUMAKRAS in treating specific genetic subgroups, providing a foundation for personalized treatment strategies. The safety profile of LUMAKRAS further reinforces its potential as a valuable therapeutic option for patients with KRAS G12C-mutated NSCLC.
