Back Back
CCA: Targeted Therapy
What’s New With Targeted Therapy for Advanced Cholangiocarcinoma: Reports From ASCO 2022

Released: August 03, 2022

Expiration: August 02, 2023

Nina Beri
Nina Beri, MD
Activity Information

Activity

Progress
1
Course Completed
Continue

Key Takeaways:

  • The treatment landscape for biliary tract cancers is evolving, and ongoing clinical trials are investigating the efficacy of targeted therapies in the first-line setting and beyond.
  • In the phase II HERB trial, the antibody–drug conjugate trastuzumab deruxtecan has shown efficacy in a small population of patients with advanced biliary tract cancer whose tumors express HER2.
  • In the phase II FOENIX-CCA2 trial, the FGFR inhibitor futibatinib has shown efficacy in patients with advanced and metastatic intrahepatic cholangiocarcinoma harboring FGFR2 fusions and rearrangements with disease progression after 1 or more lines of systemic treatment, with the most common adverse event being hyperphosphatemia.

Gemcitabine plus cisplatin (GemCis) has been the standard of care for advanced biliary tract cancer (BTC) since the phase III ABC‑02 study (NCT00262769). More recently, the phase III TOPAZ‑1 study showed a survival benefit for the addition of the PD-L1 inhibitor durvalumab to GemCis when compared with GemCis alone. However, second‑line options for BTCs have been limited in terms of efficacy. In the second‑line setting, folinic acid plus 5-fluorouracil (5-FU) and oxaliplatin (FOLFOX) was tested in the phase III ABC‑06 study (NCT01926236), with an objective response rate (ORR) of 5%. The phase II NIFTY study (NCT03524508) looked at liposomal irinotecan plus 5‑FU and leucovorin, with an ORR of 14.8% by blinded independent central review. This highlights the need for additional treatment options for patients with BTC who have progressed on frontline therapy. In this commentary, I discuss recent advances in targeted therapy for the treatment of patients with advanced BTC, particularly those whose tumors express human epidermal growth factor receptor 2 (HER2) or harbor fibroblast growth factor receptor (FGFR) fusions or rearrangements.

Targeting HER2-Positive BTC
HER2 positivity rates in BTC range from approximately 5% in intrahepatic cholangiocarcinoma (CCA) and 10% to 20% in extrahepatic CCA to 20% to 30% in gallbladder cancer. Trastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate containing a humanized anti‑HER2 antibody; a cleavable, tetrapeptide‑based linker; and a topoisomerase 1 inhibitor. The multicenter phase II HERB trial is investigating the use of T-DXd in patients with HER2‑expressing advanced BTC who are refractory or intolerant to gemcitabine‑containing regimens, and data from this trial were reported at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting.

In this trial, patients were categorized as having tumors that were HER2-positive or HER2-low expressing based on immunohistochemistry and in situ hybridization scores. In total, 24 patients with HER2-positive BTC and 8 patients with HER2-low BTC were enrolled and received 5.4 mg/kg T-DXd every 3 weeks. The primary endpoint of this study was confirmed ORR, with secondary endpoints including disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of treatment-emergent adverse events (TEAEs).

T-DXd showed efficacy in patients regardless of tumor HER2 expression levels. The response rate in the 22 patients with HER2-positive BTC was 36.4%, with a DCR of 81.8%. The median PFS was 5.1 months, the median OS was 7.1 months, and the duration of response (DoR) was 7.4 months. The efficacy in the HER2‑low group was lower, with a response rate of 12.5%.

The incidence of grade ≥3 TEAEs was 81.3%, with the most commonly reported events being anemia (53.1%), neutropenia (31.3%), and leukopenia (31.3%). In total, 8 patients (25%) discontinued their treatment because of adverse events (AEs), and 8 patients (25%) developed interstitial lung disease (3 with grade 1, 1 with grade 2, 2 with grade 3, and 2 with grade 5). Interstitial lung disease is a very important potential AE, so it is critical to carefully monitor and remain vigilant to detect and intervene at an early stage.

The HERB trial was a small study, with only 32 patients, and I think larger studies are warranted. However, given the fairly low efficacy of current second‑line therapies, T-DXd could have a role in the second line. If I have a patient with HER2-overexpressing BTC, it is something I would potentially consider for them. Whether T-DXd will move into the front line will depend on the result of further studies that are needed to compare it with GemCis and the combination of GemCis plus durvalumab.

Targeting CCA Harboring FGFR Alterations

Reversible, ATP-Competitive FGFR Inhibitors
Approximately 9% to 14% of intrahepatic CCAs harbor FGFR fusions or rearrangements. The 2 FDA-approved FGFR inhibitors—pemigatinib and infigratinib—are ATP-competitive, reversible FGFR1‑3 inhibitors. Both pemigatinib and infigratinib are approved by the FDA for the treatment of adults with previously treated, unresectable, locally advanced or metastatic CCA with an FGFR2 fusion or other rearrangement.

Two notable ongoing trials are investigating pemigatinib or infigratinib in patients with CCA. The ongoing phase III FIGHT‑302 study (NCT03656536) is evaluating the efficacy of pemigatinib vs GemCis in the first‑line setting for advanced CCA harboring an FGFR2 rearrangement.

The phase II CBGJ398X2204 study (NCT02150967) evaluated infigratinib in patients with previously treated CCA harboring FGFR2 fusions or rearrangements. There was an ORR of 23.1%, a DCR of 84.3%, and a DoR of 5 months, which led to FDA approval of the drug last year. That study was the basis of the current ongoing phase III PROOF-301 trial (NCT03773302), which is evaluating infigratinib vs GemCis in the first‑line setting in patients with advanced/metastatic CCA harboring FGFR2 fusions and rearrangements. Patients are being randomized 2:1 to receive either infigratinib 125 mg daily for 21 days of a 28‑day cycle or GemCis, with PFS as the primary endpoint. Key secondary endpoints include OS, investigator-assessed PFS, ORR, DoR, and safety. The study team is planning to enroll approximately 300 patients, and crossover is allowed if progression of disease is confirmed. Of importance, this study is going to collect cell-free DNA at baseline, during treatment, and upon disease progression, which will contribute to our understanding of primary and secondary resistance.

Irreversible, Selective FGFR Inhibitors
There has been great interest in futibatinib, a potent selective FGFR1-4 inhibitor, because it demonstrates irreversible covalent binding to a conserved cysteine in the FGFR kinase domain P loop, and it has strong activity against several mutants of the FGFR2 kinase domain that are resistant to reversible FGFR inhibitors, such as pemigatinib and infigratinib.

At ASCO 2022, we saw results of the phase II FOENIX‑CCA2 trial (NCT02052778). This is a single‑arm study looking at futibatinib in patients with advanced and metastatic intrahepatic CCA harboring FGFR2 fusions and rearrangements. All enrolled patients had prior progression of disease after 1 or more lines of systemic treatment including GemCis; of note, patients who had previously received an FGFR inhibitor were excluded. The primary endpoint was ORR, and secondary endpoints were DoR, DCR, PFS, OS, safety, and patient‑reported outcomes. In total, 103 patients received futibatinib 20 mg daily, and at the time of data cutoff, 93% of patients had discontinued treatment, with a median follow-up of 25 months. The response rate was 41.7%, with a DCR of 82.5%. The median DoR was 9.5 months, and 74% of responses were 6 months or longer. The median PFS was 8.9 months, and the 12‑month PFS rate was 35%. The median OS was 20 months, with a 12‑month OS of 73%.

No new safety signals were identified with this report from the FOENIX-CCA2 trial. Hyperphosphatemia is common with FGFR inhibitors. In the FOENIX-CCA2 trial, 91% of patients experienced any-grade hyperphosphatemia, and 31% of patients had grade 3 hyperphosphatemia, with no grade 4 or grade 5 events. Hyperphosphatemia was managed by phosphate‑lowering therapy and dose modification, with a median time to resolution of 7 days. Other AEs of special interest included nail toxicity (52% of patients), transaminitis (27%), palmar–plantar erythrodysesthesia (22%), rash (9%), and retinal disorders (8%). Of importance, quality of life outcomes also were tracked, showing that patients maintained their quality of life during the course of their treatment.

In the FOENIX-CCA2 trial, an exploratory analysis of FGFR2 status in circulating tumor DNA (ctDNA) showed that 83 of 95 patients with an available ctDNA sample were positive for FGFR2 fusion or rearrangement, for a positive percent agreement of 87%. The investigators suggested that exploratory ctDNA analysis is a potential new method for FGFR2 fusion detection in patients with intrahepatic CCA. This is important, especially for patients with intrahepatic CCA, because it can be difficult to obtain enough tissue to send for next-generation sequencing, particularly if it is a small tumor that perhaps was diagnosed based on brushings. In such cases, it may be reasonable to send a liquid biopsy for detection of genetic alterations. This could also allow us to better understand intratumoral heterogeneity, because it is difficult to perform biopsies of multiple lesions. The detection of FGFR alterations in liquid biopsy also could contribute to our understanding of resistance mutations. In cases in which patients develop resistance after treatment with an FGFR inhibitor, it would be a good idea to perform ctDNA analysis not only at the point of progression, but also potentially during the course of therapy, which may help us to understand the development of resistance mutations.

Futibatinib is also being investigated as first-line treatment for patients with intrahepatic CCA with FGFR2 rearrangements in the ongoing phase III FOENIX‑CCA3 study (NCT04093362). This trial is evaluating the efficacy and safety of futibatinib vs GemCis. Both FOENIX-CCA2 and FOENIX-CCA3 are important studies, as positive results may present an additional option for patients with CCA, potentially even for those who have disease progression on another FGFR inhibitor.

Conclusion
The use of targeted therapies for BTCs is evolving, and it will be interesting to see the results of the ongoing studies mentioned here. I am particularly excited about the first-line studies, as these will help us understand how we should sequence treatments for patients with BTC. Increased use of liquid biopsy also may help us identify actionable mutations more easily and understand when and how resistance to targeted therapies occurs. There is a lot to look forward to in the realm of precision medicine for the treatment of BTCs.

For more insights into the care of patients with CCA, listen to our recent podcast episode and read our CME-certified text module, “Precision Medicine Approaches in the Management of Cholangiocarcinoma.”

Your Thoughts?
Have you been using FGFR inhibitors in your clinical practice? What have been your biggest challenges? Answer the polling question and join the conversation by posting a comment in the discussion box below.

Continue

Poll

1.
How often do you assess patients with BTC for potentially actionable biomarkers?
Submit