Regorafenib is a multi-kinase inhibitor targeting VEGFR1–3, TIE2, PDGFR, FGFR, KIT, RET, and RAF. It was approved by the FDA in 2012 based on the CORRECT trial, which demonstrated a statistically significant improvement in overall survival (OS 6.4 vs. 5.0 months, HR 0.77) in heavily pretreated mCRC patients. Real-world data confirm activity, though tolerability — particularly hand-foot skin reaction and fatigue — remains a clinical challenge [4].

Fruquintinib is a highly selective oral inhibitor of VEGFR1, VEGFR2, and VEGFR3 with minimal off-target activity. It received FDA approval in November 2023 based on the global phase III FRESCO-2 trial (n=691), which enrolled patients refractory to all standard therapies including prior anti-VEGF and anti-EGFR treatment. Fruquintinib significantly improved OS compared to placebo (7.4 vs. 4.8 months; HR 0.66; p<0.0001) [5].

Real-world comparisons suggest fruquintinib and regorafenib have broadly similar efficacy profiles, with the regorafenib → fruquintinib sequence associated with longer OS than the reverse [7]. Ongoing trials are exploring fruquintinib + PD-1 inhibitor combinations to overcome the immunosuppressive microenvironment of MSS CRC.

The approved strategy combines BRAF inhibition with EGFR blockade. Encorafenib plus cetuximab received FDA approval in 2020 based on the BEACON CRC trial, which demonstrated superior OS (9.0 vs. 5.4 months; HR 0.52) and ORR (26.8% vs. 1.8%) compared to standard chemotherapy in previously treated BRAF V600E–mutant mCRC.

A network meta-analysis of 60 studies (n=4,633 patients) confirmed that doublet chemotherapy combined with anti-EGFR/BRAF regimens provides the best first-line OS benefit (HR 0.49 vs. doublet chemotherapy + anti-VEGF) [9].

Triplet regimens incorporating MEK inhibitors (dabrafenib + trametinib + cetuximab) have shown ORRs of ~21% in real-world cohorts, with ongoing investigation into optimal sequencing [10]. Preclinical work combining BET inhibitors with MEK inhibitors has demonstrated synergistic MAPK pathway suppression, providing rationale for future clinical evaluation [11].

Sotorasib and adagrasib are both FDA-approved for KRAS G12C–mutant NSCLC, and both have demonstrated activity in CRC, though with notably lower single-agent ORRs (7–19%) than in lung cancer. This organ-specific resistance is driven by rapid EGFR-mediated feedback reactivation of RAS-MAPK signaling in CRC [14].

Divarasib (GDC-6036), a next-generation KRAS G12C inhibitor, demonstrated an ORR of 62.5% and median PFS of 8.1 months in combination with cetuximab in a phase 1b trial [16]. Garsorasib (D-1553) similarly achieved 45.2% ORR with cetuximab in a phase II study [17].

Acquired resistance in CRC is dominated by RAS/MAPK pathway reactivation: 69% of CRC patients develop acquired RAS/MAPK alterations at progression (vs. 26% in NSCLC), including new KRAS mutations, amplifications, and RAF/MAPK fusions [18]. Emerging strategies include RAS(ON) multi-selective inhibitors (RMC-6236), pan-KRAS inhibitors (BBO-11818), and KRAS G12D–selective agents (MRTX1133, RMC-9805) targeting the dominant non-G12C variants in CRC [19].

Tucatinib, a highly selective oral HER2 tyrosine kinase inhibitor with minimal EGFR inhibition, in combination with trastuzumab received FDA accelerated approval in January 2023 for chemotherapy-refractory, HER2-positive, RAS wild-type mCRC.

Alternative HER2-directed TKI strategies include pyrotinib + trastuzumab (ORR 50% in RAS wild-type patients; HER2-FUSCC-G study) [23] and the dual antibody combination pertuzumab + trastuzumab (clinical benefit rate 46%; DRUP trial) [24]. A meta-analysis of six HER2-targeted trials in mCRC reported a pooled ORR of 31.3% and median PFS of 6.2 months, confirming the class effect [25].

KRAS G12D inhibitors (MRTX1133, RMC-9805) target the most prevalent KRAS mutation in CRC (~12%). Pan-RAS inhibitors (BBO-11818) and RAS(ON) multi-selective inhibitors (RMC-6236) demonstrate activity across multiple KRAS mutant isoforms in both GDP- and GTP-bound states, potentially addressing the full spectrum of KRAS-mutant CRC.

SOS1 and SHP2 inhibitors — upstream RAS regulators — represent rational combination partners to deepen and prolong KRAS G12C inhibitor responses.

WEE1 and EZH2 inhibitors — PDX-based drug screening has identified genotype-specific vulnerabilities in KRAS G12C–mutant CRC models, supporting rational combination development [11]. Werner helicase (WRN) inhibitors exploit the synthetic lethal dependency of MSI-H tumors on WRN for replication fork stability, with early clinical trials ongoing.