A phase ib-II study of dabrafenib, trametinib, cetuximab plus irinotecan in patients with BRAF mutant metastatic colorectal cancer: Subgroup analysis and biomarker identification.
Authors: Chen Yungchang , Hu Hai , Song Bo , Shang Jin , Man Yuxin , Guo Qian , Yuan Hongfan , Rui Yuanyi , Deng Zijian , Pan Tao , Yi Bo , Zhang Zhixuan , Chen Ping , Lu Jin , Zhong Deyuan , Lin Tongyu 
Published: August 2024

e15581

Background: About 5%-12% of patients with metastatic CRC (mCRC) have BRAF mutations in which BRAF V600E mutated was most common, accounts for approximately 90% of cases of BRAF mutation mCRC. Therefore, multi-drug combination therapy with BRAF inhibitor has been tried. The efficacy results of this study have been reported in 2023 ASCO GI (#156). The ORR was 30% (3/10), the DCR was 80% (8/10). After a median follow-up of 19.7 months, the median PFS was 7.5 months. Here, we reported the results of subsequent analyses. Methods: In this phase Ib-II trial, 15 patients with BRAF-mutant mCRC received Dabrafenib, trametinib, cetuximab plus irinotecan combination therapy. Whole exome sequencing was conducted in 8 proficient mismatch repair (pMMR) mCRC patients with BRAF V600E-mutant. Patients were followed up clinically and radiographically. Response was defined as Complete Response (CR), Partial Response (PR), Stable Disease (SD) and Progressive Disease (PD) were defined according to the response definitions of the RECIST criteria. Results: 3 mCRC patients (CR or PR) were divided into response group, 5 mCRC patients (SD or PD) were divided into non-response group. Age (59.6±4.22 vs 39.0±9.93), Gender (male 66.67% vs 80%), ECOG score (0.67 vs 0.60), ALT flare rate (66.67% vs 60%) were similar in the two group. Patients in response group have better 2-year survival rate (66.7% vs 0%, P < 0.05). Furthermore, response-related Differential Expression Genes (DEGs) (log2fc > 1, P < 0.05) were analyzed. Meanwhile, GO and KEGG pathway analysis was conducted based on DEGs. Results showed that MAPK signaling pathway related genes were down-regulated in response group such as EGF, FGF18, HGF, IGF1, MAPK10, NGF. While Apoptosis related genes were up-regulated in response group such as BCL2L1, AIFM1, DAXX. Moreover, Antigen processing and presentation related genes such as CALR, CANX, HSPA8 were enriched in response group, which indicated a more active immune microenvironment. On the contrary, Hedgehog signaling pathway related genes such as GLI1, HHIP, BOC were enriched in non-response group. Next, we verified the clinical significance of DEGS in TCGA CRC cohort database using Cox-regression analysis. Results showed that expression of IGF1, NGF, CAMK2B, CCNA1 were associated with poor prognosis and CANX, HSPA8 were associated with better prognosis, which is in accordance with our sequencing results. Conclusions: Inhibition of MAPK signaling and promoted Apoptosis was found in BRAF V600E-mutant mCRC patients who were response to Dabrafenib, trametinib, cetuximab plus irinotecan. It's worth noticing that immune activation occurred in responsive patients, indicated a potential benefit from immunotherapy combination therapy. Moreover, Hedgehog signaling pathway may be target in rescue therapy in mCRC patients. Clinical trial information: ChiCTR2200063316.