Ado-Trastuzumab Emtansine Plus Pertuzumab Shows Activity and No Unexpected Toxicity in HER2-Positive Locally Advanced or Metastatic Breast Cancer


Key Points

  • The combination of ado-trastuzumab emtansine and pertuzumab produced promising response rates in first-line and second- or later-line treatment of metastatic HER2-positive disease.
  • The response rate was higher in patients with HER2 mRNA above the median value.

In a phase IIa trial reported in the Journal of Clinical Oncology, Miller et al assessed combined HER2-targeted therapy with the antibody-drug conjugate ado-trastuzumab emtansine (Kadcyla) and pertuzumab (Perjeta) in women with HER2-positive locally advanced or metastatic breast cancer. Pertuzumab binds HER2 at a different site than trastuzumab and prevents heterodimerization of HER2 with other human epidermal growth factor receptors. The combination showed activity in both first-line and second- or later-line metastatic settings and was not associated with any new safety signals.

Study Details

In the study, 64 patients with HER2-positive locally advanced or metastatic breast cancer received ado-trastuzumab emtansine at 3.6 mg/kg plus pertuzumab as a 840-mg loading dose followed by 420 mg once every 3 weeks, with 43 patients treated in the second- or later-line and 21 in the first-line metastatic setting. The primary efficacy endpoint was investigator-assessed objective response rate.

Patients receiving first-line treatment had received trastuzumab (Herceptin) (86%), a taxane (76%), and an anthracycline (62%) in the neoadjuvant or adjuvant setting. Patients receiving second- or later-line treatment had received a median of nine prior nonhormonal systemic agents in any setting (six for metastatic disease), including trastuzumab (100%), a taxane (95%), an anthracycline (79%), capecitabine (79%), and lapatinib (Tykerb) (72%).


The objective response rate was 41% overall, 33% in patients receiving second- or later-line treatment, and 57% in those receiving first-line treatment. Median progression-free survival was 6.6, 5.5, and 7.7 months, respectively, and median duration of response was 13.9, 11.8, and 13.9 months, respectively. Overall, complete response was observed in 5% of patients, partial response in 36%, and clinical benefit in 50%. An exploratory biomarker analysis showed that patients with HER2 mRNA levels above the median had a higher object response rate (44% vs 33%).

Adverse Events

The most common adverse events were fatigue (61%), nausea (50%), and diarrhea (39%). The most common grade 3 or higher adverse events were thrombocytopenia (13%), fatigue (11%), increased ALT (9%), and increased AST (9%). One patient had left-ventricular ejection fraction < 40% after study drug discontinuation.

The investigators concluded, “[Ado-trastuzumab emtansine] and pertuzumab can be combined at full doses with no unexpected toxicities. The preliminary efficacy in patients in the first-line and advanced [metastatic breast cancer] settings warrants further investigation.”

Kathy D. Miller, MD, of University of Indiana Simon Cancer Center, is the corresponding author for the Journal of Clinical Oncology article.

The study was supported by Genentech and F. Hoffmann-La Roche. For full disclosures of the study authors, visit

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