Emerging Molecular Targets in Cholangiocarcinoma: IDH1, HER2, BRAF, and Beyond

Web Exclusives - Cholangiocarcinoma

Targeted therapy has improved survival for patients with cancer across a broad spectrum of disease sites, but until recently, progress has been slow in the treatment of patients with cholangiocarcinoma (CCA).

At the 2020 Annual Cholangiocarcinoma Summit, Imane El Dika, MD, Assistant Attending Physician, Gastrointestinal Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, discussed new data regarding targeting IDH1, HER2, BRAF, and other mutations as potential targets in the treatment of patients with CCA.

IDH1 Mutations

Although their prognostic role in CCA remains unclear, IDH1 mutations are reported in up to 25% of patients with CCA.

In the phase 3 clinical trial of patients with chemotherapy-refractory CCA and IDH1 mutation, the first-in-class ivosidenib (Tibsovo), an oral IDH1 inhibitor, increased progression-free survival (PFS) and overall survival by more than 1 month compared with placebo.

Other clinical trials targeting CCA and IDH mutation are focused on the evaluation of combination therapies. A new phase 2 clinical trial of ceralasertib, an ataxia telangiectasia and rad3–related kinase inhibitor, and olaparib (Lynparza), a PARP inhibitor, is currently enrolling patients. Investigators are also exploring the combination of PARP inhibition and immunotherapy, Dr El Dika said.

HER2 Mutations

Another potential molecular target is the HER2 mutation seen in several cancers.

HER2 mutations are more common in gallbladder cancer, but have been reported in 0.9% to 4.7% of patients with CCA,” said Dr El Dika.

Initial reports from the phase 2 MyPathway clinical trial showed an objective response rate (ORR) of 37.5% and a median PFS of 4.2 months among 11 pretreated patients who received the combination of pertuzumab (Perjeta) and trastuzumab (Herceptin).

A basket clinical trial of trastuzumab deruxtecan (Enhertu), a HER2-targeted antibody–drug conjugate, also reported 1 response among 6 patients with biliary tract cancers.

Neratinib (Nerlynx), a tyrosine kinase inhibitor of HER2 approved for the treatment of patients with HER2-positive breast cancer, yielded an ORR of 10% in a phase 2 basket study of patients with CCA, gallbladder cancer, or biliary cancer and HER2 mutation. The responses were primarily seen in patients with gallbladder cancer or with CCA, said Dr El Dika.

Zanidatamab, a bispecific antibody, is another targeted agent under investigation. An ORR of 67% with this drug in an early-phase clinical trial of heavily pretreated patients led to an ongoing phase 2 study.

“Zanidatamab was also well-tolerated, with no grade 3 side effects,” said Dr El Dika.

BRAF Mutations and Beyond

Although uncommon in biliary cancers, BRAF mutation is also being studied with interesting results, noted Dr El Dika. A study of 43 patients with CCA and BRAF V600E mutation who received the BRAF inhibitor dabrafenib (Tafinlar), and the MEK inhibitor trametinib (Mekinist), had an ORR of 51%, a median PFS of 9.1 months, and an overall survival of 13.5 months.

BRCA and HRD mutations have been identified in 3.6% of biliary cancers. “HRD mutations are potentially more common in extrahepatic and gallbladder cancer, but have been reported in intrahepatic CCA as well,” said Dr El Dika. “They also carry a potentially favorable prognosis,” she added.

In addition to patients with BRCA1 or BRCA2 mutations, those with ATM, CHEK2, PALB2, PTEN, and NBM mutations have had favorable responses to platinum therapy, Dr El Dika explained.

Immunotherapy Shows Mixed Results

PD-L1 overexpression has been reported in 8.6% of patients with CCA, who may therefore benefit from immunotherapy, Dr El Dika said. So far, however, immunotherapy has had mixed results in the treatment of biliary tract cancers.

In patients with CCA and PD-L1 expression, the phase 1 KEYNOTE-028 study of pembrolizumab (Keytruda) showed a response rate of 17.4% but the phase 2 KEYNOTE-158 only had 5.8% responses.

By contrast, early data reported at the 2020 ASCO meeting showed that the combination chemotherapy of gemcitabine and cisplatin plus immune checkpoint blockade with durvalumab (Imfinzi) and tremelimumab had a median PFS of 13 months, an overall survival of 15 months, and a response rate of 50% to 73%.

“The response rate is strikingly high, and the disease control rate and duration of response are much higher than the historical data,” said Dr El Dika. “However, more mature data and more information about the study population are still needed.”

In the meantime, clinicians should consider routine molecular testing in all patients with CCA, Dr El Dika concluded.

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