KRAS G12C inhibitors as monotherapy or in combination for metastatic colorectal cancer: A proportion and comparative meta-analysis of efficacy and toxicity from phase I-II-III trials.

BACKGROUND

1-2 % of metastatic colorectal cancers (mCRC) harbor an activating KRAS-G12C mutation. This study aims to pool the results of available clinical trials of KRAS-G12C inhibitors, comparing monotherapy and combinations.

METHODS

A systematic literature search was conducted in the MEDLINE database and ESMO/ASCO meeting abstracts. Phase I-II-III trials that investigated a KRAS-G12C inhibitor in patients with mCRC were included. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). Pooled proportions and comparative subgroup analyses for monotherapy and combinations were presented with the random effects model.

RESULTS

596 patients with previously treated mCRC in 14 study cohorts treated with one of sotorasib, adagrasib, divarasib, or olomorasib as monotherapy or in combination with cetuximab/panitumumab were included. Combination treatment revealed an ORR of 33.9 % (95 %CI: 20.7-48.4) (I: 87.1), which is significantly higher than monotherapy [16.7 %, (95 %CI: 8.3-27.3) (I: 73.2)] (p = 0.045). Median PFS was significantly longer with the combination [5.7 months (95 %CI: 4.4-7.1) (I: 80.8) vs. 4.2 months (95 %CI: 3.6-4.7) (I:0.0), p = 0.027]. Grade 3-4 treatment-related adverse events (TRAEs) were significantly more frequent with the combination [32.8 % (95 %CI: 26.4-39.6) (I:42.5) vs.16.5 % (95 %CI: 4.9-33.1) (I: 84.2), p = 0.047]. Common adverse events specific to the combinations were skin toxicities, paronychia, and hypomagnesemia.

CONCLUSION

This analysis suggests that KRAS-G12C inhibitors in combination with anti-EGFR agents may provide a doubled ORR and 1.5-month PFS benefit compared to monotherapy in previously treated mCRC patients, but with a doubled grade 3-4 TRAEs, including skin toxicities, paronychia, and hypomagnesemia. Treatment preferences should be individualized in these highly pretreated patients.