PATIENTS AND METHODS: APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region. Patients (n = 289) received once-every-2-weeks cetuximab with investigator's choice of chemotherapy (FOLFOX or FOLFIRI). The primary end point was best confirmed overall response rate (BORR); progression-free survival (PFS) and overall survival (OS) were secondary end points. Early tumor shrinkage (ETS) and depth of response (DpR) were also evaluated.
RESULTS: In the KRAS wt population, BORR was 58.8%, median PFS 11.1 months, and median OS 26.8 months. Expanded RAS mutational analysis revealed that patients with RAS wt mCRC had better outcomes (BORR = 64.7%; median PFS = 13.0 months; median OS = 28.4 months). The data suggest that ETS and DpR may be associated with survival outcomes in the RAS wt population. Although this study was not designed to formally assess differences in outcome between treatment subgroups, efficacy results appeared similar for patients treated with FOLFOX and FOLFIRI. There were no new safety findings; in particular, grade 3/4 skin reactions were within clinical expectations.
CONCLUSION: The observed activity and safety profile is similar to that reported in prior first-line pivotal studies involving weekly cetuximab, suggesting once-every-2-weeks cetuximab is effective and tolerable as first-line therapy and may represent an alternative to weekly administration.
AREA COVERED: The presented review article mainly summarizes the developments of small molecule KRAS inhibitors as drug candidates and rational approaches that are being utilized for the selective targeting of KRAS signaling in the mutant cancer cells.
EXPERT OPINION: After the initial success in targeting the mutant KRAS G12C variants, the search has been shifted to address the challenges concerning the resistance and efficacy of small molecule KRAS inhibitors. However, the contribution of other KRAS mutations at G12V, G13C, and G13D variants causing cancers is much higher than the mutations at G12C. In view of this aspect, specific attention is required to target all other mutations as well. Accordingly, for the development of KRAS targeted therapies, the design of small molecule inhibitors that can inhibit KRAS signaling and as well as target inhibition of other signaling pathways like RAS-SOS and RAS-PI3K has to be explored extensively.