Pertuzumab Plus Trastuzumab Surpasses Prespecified Activity Threshold in ERBB2/3-Altered Biliary Tract Cancer

Pertuzumab plus trastuzumab produced antitumor activity and a mild adverse effect profile in patients with pretreated biliary tract cancer with ERBB2/3 alterations.

Timothy L. Cannon, MD

Timothy L. Cannon, MD

The addition of pertuzumab (Perjeta) to trastuzumab (Herceptin) led to a disease control rate (DCR) of 40% (95% CI, 27%-100%) in patients with previously treated biliary tract cancer (BTC) harboring ERBB2/3 amplification, overexpression, or mutation, according to findings from the BTC-specific disease cohort of the phase 2 TAPUR trial (NCT02693535) published in the Journal of Clinical Oncology.1,2

Regarding responses in evaluable patients (n = 28), there was 1 complete response, 8 partial responses, and 2 cases of prolonged stable disease ([SD] >16 weeks), for an overall response rate (ORR) of 32% (95% CI, 16%-52%), allowing investigators to reject the null hypothesis of a 15% DCR (P = .0015). Additionally, the median progression-free survival (PFS) and overall survival (OS) were 11 weeks (95% CI, 8-16) and 30 weeks (95% CI, 17-49), respectively.

“Larger studies are necessary to further validate these findings but accruing the requisite number of patients to large, randomized trials for ERBB2-positive BTCs may be challenging, given the relatively low incidence and the fact that ERBB2-directed therapies, including pertuzumab and trastuzumab, are already included in the National Comprehensive Cancer Network Guidelines as a category 2A recommendation,” lead study author Timothy L. Cannon, MD, codirector of the Gastrointestinal Cancer Program at Inova, and coauthors wrote in the publication.

TAPUR is an ongoing, phase 2 basket trial evaluating the efficacy of FDA-approved and commercially available targeted agents in patients with advanced cancer harboring genomic alterations that are known to be drug targets.

To qualify for the pertuzumab and trastuzumab cohort, patients at least 18 years of age needed to have tumors with ERBB2/3 amplification or overexpression of 1 of the following mutations, insertions, or deletions: G309A, G309E, S310F, D769H, D769Y, L755S, V777L,

V842I, E321G, R896C, P780ins, del L755-T759, or R678Q. Patients with advanced BTC needed to have measurable disease per RECIST 1.1 criteria, an ECOG performance status of 0 to 2, and adequate organ function.

Patients were excluded if they had received prior treatment with ERBB2 inhibitors or had an abnormal left ventricular ejection fraction by multiple-gated acquisition scan or echocardiogram or dyspnea at rest because of disease or comorbidities.

Eligible patients received an initial intravenous dose of 840 mg of pertuzumab over 60 minutes plus 8 mg/kg of trastuzumab over 90 minutes for the first 3-week cycle followed by pertuzumab 420 mg and trastuzumab 6 mg/kg over 30 to 60 minutes every 3 weeks thereafter. Treatment was continued until clinical and/or radiographic evidence of progressive disease or withdrawal because of unacceptable toxicity, patient preference, or physician recommendation.

The primary end point was investigator-assessed disease control per RECIST 1.1 criteria, which was defined as an objective response or SD for at least 16 weeks from the start of study therapy. Secondary end points included ORR, PFS, OS, duration of response (DOR), duration of SD, and safety.

A total of 29 patients were enrolled from February 2017 to January 2022 at 22 clinical sites, 28 of whom were evaluable for safety and efficacy. Regarding baseline characteristics, 14 (48%) patients had gallbladder cancer, 12 (41%) had cholangiocarcinoma, and three (10%) had ampullary cancer. Of the 12 patients with cholangiocarcinoma, 6 had intrahepatic disease, 2 had extrahepatic disease, and 4 were not specified.

Overall, 21% of patients identified as Black or African American, and 10% identified as Asian or Asian American. A total of 17% of patients had an ECOG performance status of 2, and 31% were 70 years of age or older. Most patients (n = 26) had only ERBB2 alterations; the other three patients had tumors with ERBB2 and ERBB3 alterations. Twenty patients (69%) had tumors with ERBB2 amplifications, which included seven with additional ERBB2/3 alterations and four with an ERBB2 mutation. Coalterations in the following genes were also identified: TP53 (n = 17), CDKN2A (n = 10), CDKN2B (n = 9), SMAD4 (n = 8), ARID1A (n = 5), KRAS (n = 4), PIK3CA (n = 2), ALK (n = 1), and BRAF (n = 1).

Regarding safety, grade 3 adverse effects (AEs) and serious AEs that were possibly treatment related occurred in 4 (14%) of the 29 patients. One patient (3%) had a drug-related serious AE (infusion-related reaction). Grade 3 AEs included anemia (n = 1), diarrhea (n = 1), and fatigue (n = 1), and no grade 4 or 5 AEs occurred.

“The results from this TAPUR study cohort indicate that pertuzumab plus trastuzumab has meaningful clinical activity in heavily pretreated patients with BTC with ERBB2 alterations,” study authors concluded. JCO Associate Editor Eileen M. O’Reilly, MD, a gastrointestinal medical oncologist at Memorial Sloan Kettering Cancer Center in New York, New York, wrote regarding the study’s relevance, “The TAPUR phase 2 basket trial, evaluating combination therapy targeting the HER2 pathway, adds to the body of evidence supporting the relevance of this target in extrahepatic cholangiocarcinoma and gallbladder cancer.”

Providing additional perspective, Cathy Eng, MD, FACP, FASCO, of Vanderbilt-Ingram Cancer Center said, “The findings from the ASCO-sponsored TAPUR basket trial further validates the very promising role of the ERBB2/3 pathway in the treatment of advanced biliary tract carcinoma, with the combination of pertuzumab plus trastuzumab as a possible treatment option. These findings demonstrate the need for HER2 testing in this patient population.”3


  1. Cannon TL, Rothe M, Mangat PK, et al. Pertuzumab plus trastuzumab in patients with biliary tract cancer with ERBB2/3 alterations: results from the targeted agent and profiling utilization registry study. J Clin Oncol. Published online May 15, 2024. doi:10.1200/JCO.23.02078
  2. TAPUR: testing the use of Food and Drug Administration (FDA) approved drugs that target a specific abnormality in a tumor gene in people with advanced stage cancer (TAPUR). Updated April 26, 2024. Accessed May 15, 2024.
  3. Pertuzumab plus trastuzumab shows meaningful clinical activity in biliary tract cancer with ERBB2/3 alterations. News release. ASCO. May 15, 2024. Accessed May 15, 2024.
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