New targets, new hope: Oncologists talk 3 groundbreaking innovations reshaping BTC care
Key Takeaways
Industry Buzz
“The HERIZON-BTC-01 trial demonstrated that for patients with HER2 3+ expression by immunohistochemistry there is an opportunity for significant benefit with the use of zanidatamab.” — Douglas Rubinson, MD, PhD
“Targeting IDH1 mutations—that being point mutations in codon 132—have shown some excellent responses in terms of targeted therapy." — Aatur D. Singhi, MD, PhD
“Given the limited benefit of 2nd-line cytotoxic chemotherapy with FOLFOX after gemcitabine/cisplatin plus immunotherapy, there is substantial interest in any targeted therapy that can be offered to patients.” — Douglas Rubinson, MD, PhD
Biliary tract cancers (BTCs) are aggressive cancers with bleak outcomes. Historically, chemotherapy has been the mainstay of treatment plans for such cancers, but it yields limited survival benefits.
Now, there's a shift happening. Treatment options are zeroing in on new targets — fibroblast growth factor receptor (FGFR) fusion genes, isocitrate dehydrogenase (IDH) mutations, the human epidermal growth factor receptor (HER) family, DNA damage repair (DDR) pathways, and more. Current clinical trials involving these targeted therapies have yielded encouraging results—either as monotherapies or in combination with other agents.[]
The following are three novel targeted therapies (ie, second-line treatments) that are changing the landscape for BTC treatment and bringing new hope.
Targeting HER2
In November 2024, the FDA granted accelerated approval to zanidatamab-hrii (Ziihera), which is a bispecific HER2-directed antibody for previously treated, unresectable or metastatic HER2-positive (IHC 3+) biliary tract cancer.[]
FDA approval was based on results of the HERIZON-BTC-01 open-label multicenter, single-arm trial involving 62 patients with unresectable or metastatic HER2-positive (IHC3+) BTC. Patients must have received at least one previous gemcitabine-containing regimen in the advanced disease setting to be eligible for the trial. Patients were assigned to two cohorts based on HER2 immunohistochemistry (IHC) scores: cohort 1 (IHC 2+ or 3+; HER2-positive) and cohort 2 (IHC 0 or 1+). [NS2]
Results demonstrated a response rate (ORR) of 52% and a median duration of response (DOR) of 14.9 months.
“The HERIZON-BTC-01 trial demonstrated that for patients with HER2 3+ expression by immunohistochemistry there is an opportunity for significant benefit with the use of Ziihera (zanidatamab),” said Douglas Rubinson, MD, PhD, gastrointestinal oncologist at the Dana-Farber Cancer Institute.
“Another option for treatment for HER2 positive patients is Enhertu (trastuzumab deruxetecan), based upon the DESTINY-PanTumor02 Phase 2 trial, which led to a tumor agnostic FDA approval of Enhertu for HER2-positive malignancies,” he continued.
Targeting IDH1
Conserved missense IDH1 mutations yield an accumulation of the onco-metabolite 2hydroxygluterate, which mediates oncogenesis and suppresses cellular differentiation. Following results of the Phase III ClarIDHy trial (n=185), ivosidenib (Tibsovo) is now FDA approved along with the companion Oncomine Dx Target Test.[]
Some meaningful tumor stability and progression free time was seen with this agent as monotherapy, thus resulting in its FDA approval, noted Anwaar Saeed, MD, an associate professor of medicine and the Chief of the Gastrointestinal (GI) Medical Oncology Program at UPMC and UPMC Hillman Cancer Center.
The primary efficacy endpoint for Phase 3 trial was progression-free survival (PFS). PFS improved in patients randomized to ivosidenib, while improvements in OS were not significant. Specifically, PFS improved by 63% in patients randomized to the agent (HR=0.37). Overall, 70% of patients randomized to placebo crossed over to receive ivosidenib after radiographic disease progression.[]
“Targeting IDH1 mutations—that being point mutations in codon 132—have shown some excellent responses in terms of targeted therapy,” stated Aatur D. Singhi, MD, PhD, a surgical pathologist with subspecialty training in gastrointestinal, liver, and pancreatobiliary pathology and associate professor of pathology at University of Pittsburgh Medical Center (UPMC).
Targeting FGFR2
FGFR2 is another subgroup that is well known in patients with bile duct cancers.
“There are a number of patients in this subgroup. Pemigatinib is one of the agents approved for FGFR2 deranged bile duct cancer. It also leads to a good comprehensive tumor response rate and better survival and outcomes and typically would be a choice in the second-line setting,” stated Dr. Saeed.
In April 2020, the FDA granted accelerated approval to pemigatinib (Pemazyre) based on the results of FIGHT-202, a multicenter open-label single-arm trial. The trial involved 107 patients with locally advanced unresectable or metastatic cholangiocarcinoma whose disease progressed on or after at least one previous therapy and had an FGFR2 gene fusion or rearrangement.
Study results suggested that the estimated ORR was 35.5%, including 3 complete responses (2.8%) and 35 partial responses (32.7%). Furthermore, in 38 patients with confirmed tumor responses, the median DOR was 9.1 months, with 63% of responders exhibiting a DOR lasting at least 6 months, and 18% of responders exhibiting a DOR lasting at least 12 months.[]
“Given the limited benefit of 2nd-line cytotoxic chemotherapy with FOLFOX after gemcitabine/cisplatin plus immunotherapy, there is substantial interest in any targeted therapy that can be offered to patients,” summed up Dr. Rubinson.