Pertuzumab plus Trastuzumab a Promising Combination in Patients with HER2-Positive Metastatic Biliary Tract Cancer

December 2021, Vol 2, No 4

The HER2-targeted therapies pertuzumab and trastuzumab have improved patient outcomes in several cancer types. However, studies of HER2-targeted treatments for biliary tract cancer have been limited to retrospective studies, case reports, and small clinical trials of patients who were not identified with HER2-positive cancer.

In a phase 2a, multiple basket study called MyPathway, Milind M. Javle, MD, and colleagues investigated the use of pertuzumab plus trastuzumab in patients with metastatic biliary tract cancers with HER2 amplification, overexpression, or both.1

“Results from MyPathway, previous clinical trials, and anecdotal reports support the consideration of HER2-targeted therapy in patients with previously treated HER2-positive advanced biliary tract cancer, a historically difficult-to-treat population,” Dr Javle and colleagues observed.

MyPathway is an ongoing, nonrandomized, multicenter, open-label, phase 2a multiple basket trial. The study enrolled patients aged 18 years and older with previously treated metastatic biliary tract cancers and HER2 amplification, overexpression, or both, and life expectancy of at least 12 weeks. Patients receive an 840-mg loading dose of intravenous (IV) pertuzumab, followed by a 420-mg dose every 3 weeks, plus an 8-mg/kg loading dose of IV trastuzumab, followed by a 6-mg/kg dose every 3 weeks. Both agents are taken until disease progression or unacceptable side effects.

The study’s primary end point is investigator-assessed objective response rate (ORR). Key secondary end points are disease control rate, duration of response, progression-free survival (PFS), median overall survival (OS), and safety and tolerability.

For this small-cohort analysis, as of March 20, 2020 (ie, the data cutoff date), 39 patients with HER2-positive biliary tract cancer were enrolled. The median follow-up was 8.1 months. The ORR of patients who received the combination regimen was 23% (95% confidence interval [CI], 11%-39%). In addition, 28% of patients had stable disease for more than 4 months, which translated to an overall disease control rate of 51%. The median duration of response was 10.8 months (95% CI, 0.7-25.4).

At the data cutoff, 92% of patients had disease progression and 29% had died. The estimated median PFS was 4 months (95% CI, 1.8-5.7) and the estimated median OS was 10.9 months (95% CI, 5.2-15.6). The estimated OS at 1 year was 50%.

Pertuzumab plus trastuzumab demonstrated good tolerability compared with traditional chemotherapy. The most common treatment-emergent adverse effects were diarrhea (33%), increased alanine aminotransferase (33%), and increased aspartate aminotransferase (31%). Grade 3 or 4 adverse events included increased alanine aminotransferase (13%) and increased aspartate aminotransferase (13%). Adverse events resulting from 1 or both treatments, were reported in 62% of patients, and the most common included diarrhea (26%), increased alanine aminotransferase (10%), increased aspartate aminotransferase (10%), and infusion-related reaction (10%). No treatment-related serious adverse events, treatment-related grade 4 events, or death were reported.

“We believe that our data support the consideration of pertuzumab plus trastuzumab as a treatment option in the second line and beyond, and are encouraging for the initiation of randomised, clinical trials to further explore the efficacy of this and other HER2-targeted regimens in this disease setting,” concluded Dr Javle and colleagues. “Additional studies should also assess the role of HER2 overexpression in HER2-amplified biliary tract cancer and co-alterations that potentially confer resistance to HER2-targeted therapy, including KRAS and PIK3CA, which might affect real-world treatment choice.”


  1. 1. Javle M, Borad MJ, Azad NS, et al. Pertuzumab and trastuzumab for HER2-positive, metastatic biliary tract cancer (MyPathway): a multicentre, open-label, phase 2a, multiple basket study. Lancet Oncol. 2021;22:1290-1300.

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