We just moved 'a step in the right direction' for HER2+ BTC patients—here's why

The frontline treatment for most biliary tract cancers (BTC) is chemotherapy plus a checkpoint inhibitor. When this treatment option fails, however, we need options — and can now resort to drugs that target HER2 expression and amplification.

“I’m always cautious about saying anything is ‘game-changing’ but these drugs are a step in the right direction,” says Shubham Pant, MD, professor in department of gastrointestinal medical oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, in an interview with MDLinx. Most oncologists agree, as these options now offer a chance to do more for patients who would have otherwise had few options.

Innovative mechanisms in the spotlight

Trastuzumab deruxtecan and zanidatamab differ greatly in their mechanisms of action.

Trastuzumab deruxtecan is an HER2-directed monoclonal antibody that provides targeted delivery of cytotoxic agent. It harbors a highly potent topoisomerase I inhibitor, membrane-permeable payload that results in DNA damage and cell death of tumor cells. The tumor-selective cleavable linker hooks up to the antibody and is stable in plasma. This linker is selectively cleaved by enzymes upregulated in tumor cells.^[]

On the other hand, zanidatamab is a dual HER2-targeted bi-specific antibody that may induce anti-tumor activity. It is not a T-cell engager but binds to two extracellular sites on HER2. Tumor cell death may result from multiple mechanisms including HER2 internalization; the reduction of HER2 on the cell surface, and the induction of antibody-dependent cellular cytotoxicity.^[]

Dr. Pant notes that it results in trans binding which means “it gets a lot of these HER2 receptors to come together, thus leading to better receptor down regulation. It's almost like having two agents in one drug that can lead to increased efficacy of the drug against the cancer.”

The trials fueling the treatments

Trastuzumab deruxtecan was assessed in the DESTINY-Breast06^[], a randomized, multicenter, open-label trial involving 866 adult patients with advanced or metastatic HR-positive breast cancer with HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2-ultralow (IHC 0 with membrane staining) expression. This status was characterized by Ventana’s PATHWAY anti-HER-2 (4B5) Rabbit Monoclonal Primary Antibody assay.

The researchers randomized patients (1:1) to receive either fam-trastuzumab deruxtecan-Niki 5.4 mg/kg (N=436) by either intravenous infusion every three weeks or the clinician’s choice of single agent chemotherapy (N=430, capecitabine 60%, nab-paclitaxel 24%, or paclitaxel 16%).^[]

Progression-free survival (PFS) was the major efficacy outcome measured in patients with HER2-low breast cancer. The trial indicated a statistically significant improvement in PFS in patients with HER2-low breast cancer (n=713), with the median PFS being 13.2 months in the fam-trastuzumab deruxtecan-nxki arm and 8.1 months in the chemotherapy arm (HR: 0.62; p-value <0.0001). The trial also showed a a statistically significant improvement in PFS in the overall population, with a PFS of 13.2 in the fam-trastuzumab deruxtecan and 8.1 months in the chemotherapy arm. In total, 335 patients died in both trial arms in the overall population. ^[]

Some common adverse reactions of trastuzumab deruxtecan — occurring in 20% or more participants— included reduced white blood cell count, decreased neutrophil count, nausea, decreased hemoglobin, decreased lymphocyte count, and fatigue.^[]

The efficacy of zanidatamab was evaluated in HERIZON-BTC-01^[], an open-label multicenter, single-arm trial involving 62 patients with unresectable or metastatic HER2-positive (IHC3+) BTC. Patients must have have received at least one prior gemcitabine-containing regimens in the advanced disease setting to be eligible for the trial.

Importantly, the prescribing information for zanidatamab includes a boxed warning for embryo-fetal toxicity. Common adverse reactions include diarrhea, infusion-related reactions, abdominal pain, and fatigue.^[]

Staying realistic about limitations

Given the advanced nature of disease in these populations, Dr. Pant is hesitant to label "limitations" of drugs such as rastuzumab deruxtecan and zanidatamab.

"I would say patients do tend to progress after time, and they tend to develop resistance mechanisms with progression," he says. "So, we just need to find a way to make these therapies a little bit better. These are very good therapies, but we can do better.”

In patients who fail HER2 targeted treatment, Dr. Pant recommends looking into experimental clinical trials and further use of next-generation sequencing to identify other drug targets.