Table 2.
Main trials of targeted therapy in CCA.
| Agent | Trial id and/or Name | Mechanism or Pathway | Phase | Study Population | Arms | Outcomes |
|---|---|---|---|---|---|---|
| IDH mutations | ||||||
| Ivosidenib | NCT02989857ClarIDHy trial | IDH-1 inhibitor (decreases oncometabolite 2-HG) | 3 | Previously treated, advanced, IDH1-mutant CCA. | Ivosidenib vs. Placebo | mPFS (months): 2.7 (95% CI, 1.6–4.2) vs. 1.4 (1.4–1.6); HR: 0.37; (95% CI, 0.25–0.54) p < 0.0001 mOS (months): 10.3 (95% CI, 7.8–12.4) vs. 7.5 (95% CI, 4.8–11.1) |
| FGFR alterations | ||||||
| Pemigatinib | NCT02924376 FIGHT-202 | FGFR 1, 2, and 3 reversible inhibitors; FGFR fusions or rearrangements | 2 | Advanced, previously treated CCA with and without FGFR2 fusions/rearrangements/alterations. | FGFR2 rearrangements or fusion CCA Other FGF/FGFR alterations No FGF/FGFR alterations |
ORR (%): 37 (95% CI, 27.9 –46.9) mOS (months): 17.5 (95% CI, 14.4–22.9) vs. 6.7 (95% CI, 2.1–10.5) vs. 4.0 (95% CI, 2.0–4.6) |
| Infigratinib (BGJ398) |
NCT02150967PROOF-201 | ATP-competitive FGFR 1, 2, and 3 tyrosine kinase reversible inhibitor |
2 | Locally advanced or metastatic CCA with FGFR2 fusions or rearrangements, previously treated with at least one gemcitabine-containing regimen. | Single arm | ORR (%): 23.1 (95% CI, 15.6–32.2) |
| Futibatinib (TAS-120) |
NCT02052778FOENIX-CCA2 | Highly selective, irreversible pan-FGFR antagonist |
2 | Advanced, previously treated iCCA with FGFR2 fusions/other rearrangements. |
Single arm | ORR (%): 41.7 mPFS (months): 9 mOS (months): 21.7 |
| Erdafitinib | NCT02699606LUC2001 | Pan-FGFR kinase inhibitor | 2 | Patients previously treated, aCCA with FGFR alterations. | Single arm | ORR (%): 50.0 |
| HER2 alterations | ||||||
| Pertuzumab and trastuzumab | NCT02091141MyPathway | Monoclonal ab targeting HER2 domain II; monoclonal ab binds to domain IV of HER2 | 2 | Previously treated, advanced BTC withHER2 amplification, overexpression, or both. |
Single arm | ORR (%): 23 (95% CI, 11–39) |
| Neratinib | NCT01953926(SUMMIT trial) | Pan-HER irreversible TKI, with clinical activity against HER2 |
2 | Previously treated, advanced BTC harboring HER2 somatic mutations. |
Single arm | ORR (%): 12 (95% CI, 3–31) mPFS (months): 1.8 (95% CI, 1.1–3.7) |
| BRAF V600E mutation | ||||||
| Dabrafenib and trametinib | NCT02034110ROAR trial | B-type Raf proto-oncogene, tyrosine kinase in the MAPK pathway |
2 | Previously treated, advanced BTC withBRAF V600E mutation. | Single arm | ORR (%): 47 (95% CI, 31 to 62) |
Abbreviations: aCCA, advanced cholangiocarcinoma; BTC, biliary tract cancer; CCA, cholangiocarcinoma; HER2, human epidermal growth factor receptor 2; iCCA, intrahepatic cholangiocar-cinoma; IDH, isocitrate dehydrogenase; FGFR, fibroblast growth factor receptor; ORR, overall re-sponse rate; mOS, median overall survival; mPFS, median progression-free survival; and TKI, ty-rosine kinase inhibitor.