Predictive Impact of Mutations in Patients With Proficient Mismatch Repair/Microsatellite Stable -Mutated Metastatic Colorectal Cancer Treated With Target Therapy or Chemotherapy.

PURPOSE

Target therapy (TT) with encorafenib plus cetuximab is a standard option in patients with -mutated (mut) pretreated metastatic colorectal cancer (mCRC). Recently, mutations in , encoding a negative regulator of the WNT pathway, were associated with longer progression-free survival (PFS) and overall survival (OS) in patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) -mut mCRC treated with TT. Here, we explored the effect of mutations on the efficacy of second-line TT versus standard chemotherapy (CT).

METHODS

A retrospective cohort of patients with pMMR/MSS -mut tumors, available mutational status, and treated with second-line TT or oxaliplatin- and/or irinotecan-based CT was analyzed.

RESULTS

One hundred thirty-two patients with pMMR/MSS -mut mCRC were included. was found mut in 34 (26%) cases. Among mutants, TT was associated with longer PFS (7.7 3.0 months; = .002) and higher overall response rate (ORR; 45% 0%; = .009) compared with CT. Conversely, among wild-type (wt) patients, only a trend for longer PFS (4.5 3.7 months; = .064) favoring TT, with no differences in ORR ( = .14), was observed. After excluding 36 patients receiving TT in third line or beyond, a longer OS (19.4 10.1 months; = .022) and a numerically OS advantage (10.6 6.6 months; = .068) were reported for TT both in the -mut and in the wt groups. However, no interaction effect was reported between mutational status and treatment in ORR ( = .96), PFS ( = .13), and OS ( = .44).

CONCLUSION

Patients with pMMR/MSS -mut mCRC achieve benefit from TT versus CT independently of mutational status, although a higher magnitude of benefit from TT is observed in -mut tumors. These findings deserve confirmation in concluded and ongoing randomized trials.