This study, the CodeBreaK100 clinical trial, assesses the efficacy and safety of sotorasib, the first in class, selective and potent inhibitor of KRAS G12C. This is important because up until now there have been no regulatory approved targeted therapies for KRAS G12C mutant non-small cell lung cancer which represents approximately 13% of all patients with non-squamous non-small cell lung cancer.
What was the methodology used in this study?
The CodeBreaK100 clinical trial was a global single arm phase II clinical trial that evaluated treatment with sotorasib at a dose of 960mg once a day in patients with locally advanced or metastatic KRAS G12C mutated non-small cell lung cancer as assessed by central pathology review that had previously received at least one line of standard of care systemic therapy and up to three total lines of prior therapy. Patients were treated with sotorasib monotherapy at a dose of 960mg once a day and were followed radiographically every six weeks for the first 48 weeks, and twelve weeks thereafter. The primary endpoint of the study was objective response rate, as determined by central independent review. Secondary endpoints were typical for a phase II clinical trial and included duration of response, progression free survival, overall survival, and disease control rate. We also evaluated exploratory endpoints including the efficacy of sotorasib in molecularly defined patient subgroups.
What were your findings?
The key findings from the CodeBreaK100 clinical trial were that at the median follow-up of 15.3 months, sotorasib yielded a confirmed objective response rate of 37.1%, with a median duration of response of 11.1 months, a median progression-free survival of 6.8 months and a median overall survival of 12.5 months. Furthermore, the activity of sotorasib was evaluated across a range of patient subgroups determined by baseline characteristics or molecular profiles. One of the most interesting findings was that sotorasib exhibited broad activity across patient subgroups, including molecular subgroups defined by co-occurring mutations in TP53, STK11, and TIP1. Particularly in patients with a co-occurring mutation in STK11 that were wildtype for TIP1, treatment with sotorasib yielded an objective response rate of 50% with a median progression free survival of 11 months, and a median overall survival of 15.3 months. This is important because STK11 mutations have been associated with inferior clinical outcomes with standard of care systemic therapies including chemoimmunotherapy, PD-1 inhibitor and monotherapy, platinum doublet chemotherapy, as well as second line chemotherapy with docetaxel.
How can these results impact the future treatment of NSCLC?
The results of the CodeBreaK100 clinical trial are practice changing and have formed the backbone for the regulatory approval by the US FDA of sotorasib for the treatment of KRAS G12C mutated locally advanced or metastatic non-small cell lung cancer after failure of at least one prior line of therapy. Based on these results I believe that sotorasib represents the new standard of care for this patient population. Furthermore, I would say that the results of the CodeBreaK100 clinical trial reiterate the need to obtain broad, comprehensive molecular profiling in every patient with locally advanced or metastatic non-small cell lung cancer that we see in our clinics.
Is there anything else important that you would like to mention?
I would also like to add that treatment with sotorasib was overall safe and tolerable. The majority of treatment related adverse events were low-grade, grade 1 or grade 2, and were in the majority of cases manageable either with dose interruption or dose reduction, as well as supportive care medication. Overall in the study, those interruptions or those reductions were required in 22.2% of patients due to a treatment related adverse event, and treatment discontinuation occurred in 7.1% of patients. This represents also an important advantage of treatment with sotorasib.