Table 4.
Tyrosine kinase inhibitors (TKIs) for pretreated metastatic colorectal cancer treatment.
| TKI | Targets | Phase of the Study | Setting | Results | References |
|---|---|---|---|---|---|
| Regorafenib | VEGFR-11, VEGFR-22 VEGFR-33, TIE24, PDGFR, FGFR6, KIT7, RET8, RAF-19, BRAF10 |
III, double-blind, placebo-controlled. CORRECT11 trial: regorafenib vs12. placebo | mCRC13 patients progressing after all approved standard therapies | mOS14: 6.4 months with regorafenib vs. 5.0 months with placebo (HR15 = 0.77; 95% CI16: 0.64–0.94; one-sided p = 0·0052) | [68,69] |
| III, double-blind, placebo-controlled. CONCUR17 trial: regorafenib + BSC18 vs. placebo + BSC | mCRC Asian patients with progressive disease after at least two previous treatment lines or who were unable to tolerate standard treatments | mOS: 8.8 months in the regorafenib + BSC group vs. 6.3 months in the placebo group (HR=0.55, 95% CI: 0.40–0.77, one-sided p = 0·00016 | [70] | ||
| IIIb, open-label. CONSIGN19 Study: regorafenib | mCRC patients who progressed after approved standard therapies |
Safety profile (primary endpoint) consistent with data from CORRECT and CONCUR trials -mPFS20: 2.7 months (95% CI: 2.6–2.7) |
[71] | ||
| Ib, open-label, dose-escalation study. Regorafenib + cetuximab | Advanced refractory solid tumors | -Regorafenib 160 mg/day (3 weeks on/1 week off) was declared MTD21 in combination with cetuximab -All-grade treatment-emergent adverse events: fatigue (52%), hypophosphatemia (48%), and diarrhea (40%) - PR22: 21% |
[72] | ||
| Ib, open-label, dose-finding and dose-expansion. REGONIVO/EPOC160323:Regorafenib + nivolumab | Previously treated, advanced gastric cancer or mCRC | - Regorafenib 80 mg + nivolumab had a manageable safety profile -OR24 in 38% of patients (including 11 MSS25 gastric cancers, 7 MSS mCRC, and 1 MSI-H26 mCRC): RR27 of 44% in gastric cancer and 29% in MSS mCRC |
[73] | ||
| Fruquintinib | VEGFR-1,VEGFR-2, VEGFR-3 | Ib | Chinese mCRC patients with ≥2 lines of prior therapies | -mPFS:5. 80 months -mOS:8.88 months |
[74] |
| II, double-blind, placebo-controlled: Fruquintinib + BSC vs. placebo + BSC |
Chinese mCRC patients with ≥2 lines of prior therapies | -mPFS: 4.73 months fruquintinib + BSC (95% CI: 2.86–5.59) vs. 0.99 months placebo + BSC; 95% CI: 0.95–1.58); (HR = 0.30; 95% CI:0.15–0.59; p < 0.001) -mOS 7.72 vs. 5.52 months (HR = 0.71; 95% CI: 0.38–1.34) |
[74] | ||
| III, FRESCO28 trial: randomized, double-blind, placebo-controlled, fruquintinib vs. placebo |
Chinese mCRC patients progressing after at least 2 prior chemotherapy regimens. Prior anti-VEGFR29 therapy not allowed | -mOS: 9.3 months (95% CI, 8.2–10.5) vs. 6.6 months (95% CI, 5.9–8.1; HR = 0.65; 95% CI, 0.51–0.83; p < 0.001) -mPFS: 3.7 months (95% CI, 3.7–4.6) vs. 1.8 months [95% CI, 1.8–1.8] months); HR = 0.26 (95% CI, 0.21 to 0.34; p < 0.001) |
[75] | ||
| Axitinib | VEGFR-1, VEGFR-2, VEGFR-3, KIT, PDGFR | II, randomized, double-blinded, placebo-controlled. Maintenance axitinib vs. placebo |
mCRC patients that had not progressed after 6–8 months of first-line chemotherapy | mPFS: 4.96 vs. 3.16 months; HR = 0.46; 95% CI: 0.25–0.86; p = 0.0116 -mOS = 27.61 vs. 19.99 months; HR = 0.68; 95% CI: 0.31–1.48; p = 0.3279) |
[76] |
| II, single arm Maintenance axitinib |
mCRC patients that had not progressed after 4 cycles of first-line mFOLFOX30/bevacizumab | mPFS:8.3 months | [77] | ||
| Apatinib | VEGFR-2 | II | ≥Third line | mPFS:3.9 months (95% CI: 2.1–5.9) -mOS:7.9 months (95% CI: 4.6–10.1+) |
[78] |
| Nintedanib | VEGFR, PDGFR, FGFR | I/II; nintedanib+ mFOLFOX-631 vs. bevacizumab + mFOLFOX6 | First line | mPFS:10.5 months vs. 15.4 months | [79] |
| III; LUME-Colon 132; efficacy and safety of nintedanib + BSC vs. placebo + BSC |
mCRC patients after failure of standard therapies (37% pretreated with regorafenib) | -mPFS:1.5 months vs. 1.4 months (HR = 0.58; p < 0.0001) -no difference in mOS (6.4 vs. 6.1 months (HR = 1.01; p = 0.8659) |
[80] |
Note: 1VEGFR-1 = vascular endothelial growth factor receptor 1; 2VEGFR-2 = vascular endothelial growth factor receptor 2; 3VEGFR-3 = vascular endothelial growth factor receptor 3; 4TIE-2 = tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2; 45PDGFR = platelet-derived growth factor receptor; 6FGFR = fibroblast growth factor; 7KIT = v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog; 8RET = rearranged during transfection; 9RAF-1 = rearranged during transfection; 10BRAF = v-raf murine sarcoma viral oncogene homolog B1; 11CORRECT = patients with metastatic COloRectal cancer treated with REgorafenib or plaCebo after failure of standard Therapy; 12vs. = versus; 13mCRC = metastatic colorectal cancer; 14mOS = median overall survival; 15HR = hazard ratio; 16CI: = confidence interval; 17CONCUR = Asian Subjects With Metastatic Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy; 18BSC = best supportive care; 19CONSIGN = Regorafenib for Patients With Metastatic Colorectal Cancer Who Progressed After Standard Therapy; 20mPFS = median progression-free survival; 21MTD = maximum tolerated dose; 22PR = partial response; 23REGONIVO/EPOC1603 = Regorafenib + Nivolumab in gastric and colorectal cancer; 24OR = objective response; 25MSS = microsatellite-stable; 26MSI-H = microsatellite instability-high; 27RR = response rate; 28FRESCO = Fruquintinib Efficacy and Safety in 3+ Line Colorectal Cancer Patients; 29VEGFR = vascular endothelial growth factor; 30mFOLFOX = modified oxaliplatin, 5-fluorouracil, leucovorin; 31mFOLFOX6 = modified oxaliplatin, 5-fluorouracil, leucovorin - 6; 32LUME-Colon 1 = A Randomized, Double-blind, Placebo-controlled Phase III Trial of Nintedanib plus Best Supportive Care (BSC) versus Placebo plus BSC in Patients with Advanced Colorectal Cancer Refractory to Standard Treatment.