T-DM1 is Active and Well Tolerated in Patients with HER2-positive Metastatic Breast Cancer and Brain Metastases

The exploratory subgroup analysis of the KAMILLA trial represents the largest reported cohort of patients with HER2-positive metastatic breast cancer and brain metastases treated with T-DM1 in a prospective setting. The study team observed clinically meaningful antitumor activity in patients with and without prior radiotherapy, suggesting that T-DM1 is active, well tolerated in this difficult to treat population and warrants further exploration. The findings are published by Dr Filippo Montemurro of the Candiolo Cancer Institute, FPO-IRCCS in Candiolo, Torino, Italy and colleagues on 4 July 2020 in the Annals of Oncology.

Systemic treatment with HER2-targeted agents may improve clinical outcomes in patients with HER2-positive metastatic breast cancer and brain metastases. Activity of the HER2-targeted tyrosine kinase inhibitors (TKIs) lapatinib and neratinib alone or in combination with capecitabine and the HER2-specific TKI tucatinib in combination with trastuzumab and capecitabine has been reported in patients with HER2-positive metastatic breast cancer and brain metastases.

The authors wrote in the study background that among other potentially active drugs in these patients, the antibody-drug conjugate T-DM1 has been shown to improve overall survival (OS) in patients with trastuzumab-resistant advanced metastatic breast cancer and asymptomatic brain metastases previously treated with radiotherapy, compared with lapatinib plus capecitabine. Two small additional studies also provided signals of T-DM1 clinical activity in this difficult to treat population.

KAMILLA (NCT01702571) is an ongoing, international, single-arm, open-label, phase IIIb study that evaluates the safety and efficacy of T-DM1 in patients previously treated with HER2-targeted therapy and chemotherapy for HER2-positive locally advanced/metastatic breast cancer. The primary analysis found that T-DM1 was well-tolerated and showed efficacy consistent with that reported in previous studies. In the Annals of Oncology, the study team now reports the results of a post-hoc exploratory analysis describing T-DM1 safety and efficacy in patients with and without baseline brain metastases based on final cohort 1 data.

Patients received T-DM1 until unacceptable toxicity, withdrawal of consent, or disease progression. The main outcome measures were best overall response rate (BOR defined as complete response plus partial response) and clinical benefit rate (CBR defined as complete response plus partial response plus stable disease lasting ≥6 months) by RECIST v1.1, progression-free survival (PFS), OS and safety.

Of 2002 treated patients, 398 had baseline brain metastases. In 126 patients with measurable brain metastases, the BOR was 21.4% (95% confidence interval [CI] 14.6–29.6) and CBR was 42.9% (95% CI 34.1–52.0), respectively.

A reduction in the sum of the major diameters of brain metastases ≥30% occurred in 42.9% (95% CI 34.1–52.0), including 49.3% (95% CI 36.9–61.8) of 67 patients without prior radiotherapy for brain metastases.

In the 398 patients with baseline brain metastases, median PFS was 5.5 months (95% CI 5.3–5.6) and OS was 18.9 months (95% CI 17.1–21.3), respectively.

Adverse events profile was similar in patients with and without baseline brain metastases, although nervous system adverse events were more common in patients with baseline metastases, 208 [52.3%]) versus 701 in those without baseline brain metastases (43.7%).

In summary this exploratory analysis of patients with HER2-positive metastatic breast cancer and brain metastases enrolled in a prospective clinical trial shows that T-DM1 is active and well tolerated in this population. Overall response rate was 21.4% across all organs in patients with HER2-positive metastatic breast cancer and measurable brain metastases. Brain target lesion responses were observed in patients with and without prior radiotherapy. In patients with baseline brain metastases treated with T-DM1, median PFS was 5.5 months. Safety was generally similar in patients with versus without baseline brain metastases, except for nervous system adverse events. The study team concluded that T-DM1 should be explored further in this setting.

The authors thanked the team at Covance Clinical-Biotech for managing this global study. It was supported by F. Hoffmann-La Roche, which participated in the design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, and approval of the manuscript, and decision to submit the manuscript for publication.


Montemurro F, Delaloge S, Barrios CH, et al. Trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer and brain metastases: exploratory final analysis of cohort 1 from KAMILLA, a single-arm phase IIIb clinical trial. Annals of Oncology; Published online 4 July 2020. DOI: https://doi.org/10.1016/j.annonc.2020.06.020