DS-8201a Efficacious in Breast Cancer Across Varying HER2 Levels

KeepHealthCare.ORG – DS-8201a Efficacious in Breast Cancer Across Varying HER2 Levels

Hiroji Iwata, MD, PhD

Long-term findings from a phase I study of trastuzumab deruxtecan (DS-8201a) showed that the investigational HER2-targeting antibody-drug conjugate had antitumor activity in multiple tumor types that expressed HER2 at varying levels. Lead author Hiroji Iwata, MD, PhD, said that the activity observed with DS-8201a may shift the definition of HER2 expression in cancer.

In August 2017, the FDA granted a breakthrough designation to DS-8201a for the treatment of patients with HER2-positive, locally advanced, or metastatic breast cancer who have been treated with trastuzumab (Herceptin) and pertuzumab (Perjeta) and have disease progression after ado-trastuzumab emtansine (T-DM1; Kadcyla). Patients included on this portion of the phase I study were those with breast, gastric, colorectal, salivary, or non–small cell lung cancer.

The long-term findings of this study were presented at the 2018 ASCO Annual Meeting. Of 200 patients enrolled on the study, 121 remained on treatment after data cutoff. Patients included were those with HER2-positive breast cancer following treatment with T-DM1, HER2-positive gastric cancer following trastuzumab, breast cancer with HER2 expression, and other HER2-expressing solid tumors.

The overall response rate (ORR) was 50.6% (n = 81) by RECIST v1.1 criteria among 160 evaluable patients. The highest ORR reported was 64.2% in the HER2-positive breast cancer population. The median disease control rate among HER2-positive patients was 94.0%, the median progression-free survival (PFS) was 10.4 months, and the median overall survival (OS) was not reached at a median follow-up of 6.0 months.

DS-8201a was also active among HER2-low breast cancer patients, with an ORR of 38.5% (10/26). The disease control rate in this group was 88.5% (23/26), the median PFS was 13.6 months, and the median OS was not reached at a median follow-up of 4.9 months.

Treatment discontinuation was primarily attributed to progressive disease (25%; 50/200) or adverse events (9%; 18/200). Out of all 200 patients enrolled on the study, 93 experienced grade ≥3 adverse events, with the most common being nausea (3.5%), decreased appetite (4.5%), and vomiting (1.5%). Additionally, 2 patients died of interstitial lung disease.

In an interview with OncLive®, Iwata, vice director and chief of Breast Oncology at Aichi Cancer Center Hospital, discussed the promise of DS-8201a in breast cancer or other solid tumors with HER2 expression.

OncLive: Can you provide some background on DS-8201a?
Iwata: The HER2-positive population is sensitive to anti-HER2 therapies, and the activity is very promising in metastatic breast cancer. However, the HER2/neu breast cancer population does not show as promising of results when using these anti-HER2 therapies. DS-8201a is a very promising drug, and a competitor to anti-HER2 antibody with a similar molecular payload. The characteristic of DS-8201a that is very promising is the bystander effect. Bystander effect permeates on the membrane, so the result is not only beneficial for HER2-overexpressing patients, but patients who are HER2/neu. 

The bystander effect is a very promising characteristic. Therefore, it is promising in HER2/neu or HER2-low breast cancer and gastric cancer.

What are the significance of the findings?
These phase I data are not only important for breast and gastric cancer, but also for any other cancer with HER2 overexpression or with a HER2-mutant cohort. Those patients can achieve good results using DS-8201a. The breast and gastric cancer population is a very heavily pretreated one and there is a high response here, which is important. 

Data with DS-8201a are promising. Both the FDA and the Japan’s Pharmaceuticals and Medical Devices Agency consider it a breakthrough therapy. 

What would be the optimal sequencing for this agent?
The next step after standard frontline therapy would be where we use DS-8201a. In the future, it may enter the frontline [setting] as a standard of care as new data are obtained. I hope DS-8201a will become a new standard for HER2-positive metastatic breast cancer and for the HER2/neu population.  

Are there any next steps?
Based on the DS-8201a study, the definition of HER2 expression should be changed. Right now, the definition of HER2 expression is overexpression, but DS-8201a has good activity in HER2/neu patients, as well. Perhaps in the future, the definition of HER2 should be changed to include low, medium, and high [expressors]. The definition is very important. 

Iwata H, Tamura K, Doi T, et al. Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-expressing solid tumors: Long-term results of a large phase 1 study with multiple expansion cohorts. J Clin Oncol. 2018;36(suppl; abstr 2501).

Source: https://www.onclive.com/web-exclusives/ds8201a-efficacious-in-breast-cancer-across-varying-her2-levels

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