Mutations in codon 12 of KRAS have been identified in 13% of non-small cell lung 
cancer patients. Developing targeted therapies against KRASG12C mutation has 
proven to be challenging due to the abundance of GTP in the cytoplasm, rapid 
hydrolysis of GTP, and difficulty designing small molecules to achieve 
sufficient concentration for KRAS inhibition. Based on promising results in both 
preclinical and clinical trials, sotorasib, a novel KRASG12C inhibitor, was 
given conditional approval by the FDA in May 2021. The Phase I portion of the 
clinical trial produced 32% confirmed response with 56% of patients with stable 
disease. About 91.2% of patients who received the highest dose of 960mg daily 
achieved disease control. The Phase II portion, which used 960mg daily dosing 
resulted in 37.1% of patients with confirmed response and 80.6% of patients with 
disease control. Both phase I and phase II had similar progression-free 
survival, in 6.3 months and 6.8 months, respectively. In both phases, grade 4 
adverse events occurred in only one patient. The most common adverse events were 
elevations in LFTs, which down-trended upon dose reduction and steroid 
treatment. While the conditional approval of sotorasib was a major breakthrough 
for those patients harboring KRASG12C mutations, resistance mutations to 
sotorasib are increasingly common. Many proposals have been made to address 
this, such as the use of combination therapy for synthetic lethality, which are 
producing encouraging results. Here, we explore in further detail the 
development of sotorasib, its efficacy, mechanism of resistance, and strategies 
to overcome these resistances.