The plethora of actionable targets in intrahepatic cholangiocarcinoma has created opportunities for these patients to be treated with targeted therapy.
Biliary tract cancers are an aggressive group of malignancies that historically have been very challenging to treat because of their anatomical location and limited responsiveness to systemic therapy.1-3 Biliary cancers arise from the epithelial lining of the intrahepatic bile ducts known as intrahepatic cholangiocarcinoma (IHCC), extrahepatic bile ducts known as extrahepatic cholangiocarcinoma (EHCC), and the gallbladder (GBC).3 Risk factors associated with the development of biliary tract cancers include liver flukes (Opisthorchis viverrini and Clonorchis sinensis), hepatitis B and C, nonalcoholic steatohepatitis, alcoholism, cholelithiasis, primary sclerosing cholangitis, and choledochal cysts.3,4 Although biliary tract cancers are rare, recent studies suggest that the incidence of IHCC is rising in the United States and that the mortality from IHCC is increasing worldwide.5,6
For patients with biliary tract cancers, as with most solid tumors, surgical resection is the only therapeutic modality that offers a chance at a cure. However, because of the challenging anatomical location and the tendency of patients to present with advanced disease, only approximately 35% of patients with biliary tract cancer have resectable disease.1 For patients with advanced disease, the landmark ABC-02 trial (NCT00262769) established first-line cisplatin and gemcitabine chemotherapy as the standard of care.7 This trial, which randomized 410 patients to gemcitabine alone or cisplatin/gemcitabine, demonstrated that cisplatin/gemcitabine, compared with gemcitabine monotherapy prolongs overall survival (OS) by 3.6 months (11.7 months vs 8.1 months, respectively).7
After progression on first-line chemotherapy, the benefit of second-line treatment has been unclear because it had not been explored by large randomized trials until recently. The phase 3 ABC06 trial (NCT01926236) randomized 162 patients with advanced biliary tract cancer who progressed on first-line cisplatin/gemcitabine chemotherapy to either leucovorin, fluorouracil, and oxaliplatin (FOLFOX) or best supportive care.8 Results of the trial showed a modest 0.9 month survival benefit in patients treated with FOLFOX, highlighting the need for more effective systemic therapies.
In recent years, molecular profiling has demonstrated that approximately 45% of patients with IHCC have actionable alterations.9-13 The plethora of actionable targets in IHCC has created opportunities for these patients to be treated with targeted therapy. However, actionable alterations in EHCC and GBC are rarer, and targeted therapies for patients with these malignancies are urgently needed.12,13 For the remainder of this review, we focus on the targetable alterations found in IHCC.
Approximately 15% of patients with IHCC have tumors with FGFR2 rearrangements.2,9,12,13 Several reversible FGFR inhibitors in clinical development, such as Debio 1347, erdafitinib (Balversa), infigratinib, and derazantinib, have shown encouraging activity against IHCCs with FGFR2 rearrangments.14-17 Recently, a reversible adenosine triphosphate–competitive FGFR kinase inhibitor, pemigatinib (Pemazyre), became the first FDA-approved targeted therapy for cholangiocarcinoma based on the results of the FIGHT-202 trial (NCT02924376). In that trial, 107 patients with cholangiocarcinoma harboring FGFR2 rearrangements who were previously treated with chemotherapy were treated with 13.5 mg of oral pemigatinib once daily (21-day cycle; 2 weeks on, 1 week off).18 The trial demonstrated an impressive 36% objective response rate and a median progression-free survival (PFS) of 6.9 months in patients with IHCC tumors with FGFR2 rearrangements.
An irreversible FGFR inhibitor, futibatinib, has also shown impressive activity in FGFR2-rearranged IHCC. In results from the single-arm phase 1/2 FOENIX-CCA2 trial (NCT02052778), the agent elicited an objective response rate of 34% and a median PFS of 7.2 months.19 Notably, investigators have reported several cases in which futibatinib has overcome acquired resistance to reversible FGFR inhibitors.20 For example, Goyal et al described an extraordinary case of a patient with IHCC harboring an FGFR2 translocation who responded to the FGFR inhibitor infigratinib for 12.6 months and then, after developing acquired resistance to infigratinib, responded for 15.8 months to futibatinib.20 This finding has generated great optimism because of the potential of sequential FGFR inhibitor therapy to offer prolonged benefit, such as the 28.4-month improvement in the case above.
FGFR inhibitors are well tolerated overall but do cause some significant toxicities.21 Hyperphosphatemia, caused by inhibition of FGFR1-mediated regulation of renal phosphate transport, is very common and can be managed with a low-phosphate diet, phosphate binders such as sevelamer (Renagel), and dose modifications.21,22 Cutaneous toxicities are the other major adverse effects caused by these agents.21 Patients frequently complain of dry skin and eyes. They may experience nail changes and discoloration. Ophthalmological toxicities, including corneal abrasions and central serous retinopathy, can also occur.21
Pathogenic mutations in IDH1, a metabolic enzyme involved in the conversion of isocitrate to α-ketoglutarate, are present in approximately 20% of patients with IHCC.2,9,12,13,23 Ivosidenib (Tibsovo), an oral IDH1 inhibitor approved by the FDA for the treatment of IDH1-mutated acute myeloid leukemia, was evaluated in the phase 3 ClarIDHy trial (NCT02989857).24 In that trial, 185 patients (91% IHCC) with IDH1-mutated cholangiocarcinoma who had received 1 or 2 lines of prior therapy were randomly assigned to ivosidenib or placebo.24 Similar to the results of the phase 1 trial of ivosidenib in patients with cholangiocarcinoma, results of the ClarIDHy trial showed that ivosidenib appears to be cytostatic because the objective response rate with ivosidenib was similar to that with the placebo control (2.4% vs 0%, respectively).24,25 However, ivosidenib showed a modest benefit, with a median PFS of 2.7 months compared with 1.4 months for patients treated with placebo. Formally, no OS benefit with ivosidenib compared with placebo was observed in the trial (median OS, 10.3 vs 7.5 months; P = .09).24
The ClarIDHy trial allowed for crossover from placebo to ivosidenib; a prespecified statistical analysis called rank-preserving structural failure time (RPSFT) was performed to statistically account for the crossover.26 The RPSFT statistical analysis suggested an OS benefit with ivosidenib compared with placebo (median OS, 10.3 vs 5.1 months; P < .0001).26 Notably, the toxicity profile of ivosidenib was very favorable, and no difference was observed in the number of patients who discontinued therapy for toxicity with ivosidenib vs placebo.26 Dose reductions for patients treated with ivosidenib were also rare (3%).
In light of the encouraging data from the ClarIDHy trial, the developer of the drug, Agios Pharmaceuticals, Inc, has submitted a supplemental new drug application to the FDA for patients with previously treated, IDH1-mutated cholangiocarcinoma.27
BRAF V600E mutations are relatively rare and are present in approximately 3% of IHCC.2,9,12,13 Because combined BRAF/MEK inhibition has been effective in treating some BRAF-mutated malignancies, such as non–small cell lung cancer and melanoma, but not colorectal cancer, an important question has been whether BRAF-targeted therapy might be effective in IHCC.28 Investigators of the single-arm, multicenter phase 2 ROAR trial (NCT02034110) sought to answer this question by evaluating the BRAF inhibitor dabrafenib (Tafinlar) combined with the MEK inhibitor trametinib (Mekinist).29 Impressively, results of the ROAR trial demonstrated that the dabrafenib/trametinib combination had a 47% objective response in patients with BRAF V600E–mutated cholangiocarcinoma29 (Table17-19,24,26,29). Patients with cholangiocarcinoma enrolled in this trial had a median PFS of 9.2 months and median OS of 11.7 months.29
Several other targetable molecular abnormalities occur with low prevalence in IHCC. PD-1–directed immunotherapy is an effective option for patients with microsatellite instability–high cholangiocarcinomas, but unfortunately mismatch repair deficiency is rare in cholangiocarcinoma and found only in approximately 1% of patients.30 Similarly, targetable translocations such as ALK, ROS1, and NTRK are also present at low frequencies in IHCC, but when these abnormalities are present, targeted therapy can be effective.1,31,32 HER2 amplification and mutation are also present.9,12,13 Data suggest that targetable HER2 amplification may occur more frequently in patients with liver fluke–associated cholangiocarcinoma.33
IHCC has several actionable genomic alterations, and molecular profiling is helpful in identifying systemic treatment options. The high prevalence (approximately 45%) of these actionable alterations underscores the importance of performing next-generation sequencing for patients with IHCC. However, even with the initial success of targeting several molecular subtypes of IHCC, identifying additional druggable alterations remains an important goal. Furthermore, in the coming years, increased emphasis must be placed on finding additional therapeutic options for patients with EHCC and GBC.
Disclosures: James M. Cleary, MD, PhD, received research funding to his institution from AbbVie, Merus NV, Roche, and Bristol Myers Squibb. He received research funding from Merck, AstraZeneca, Esperas Pharma, Bayer, and Tesaro; and travel funding and consulting fees from Bristol Myers Squibb.