Trastuzumab Deruxtecan Shows Durable Antitumor Activity in HER2-Positive Metastatic Breast Cancer

JHOP - April 2020 Vol 10, No 2 - From the Literature, Breast Cancer
Commentary by Robert J. Ignoffo, PharmD, FASHP, FCSHP, FHOPA
Clinical Professor Emeritus, University of California, San Francisco;
Professor Emeritus, Touro University–California, Mare Island, Vallejo, CA
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BACKGROUND: The phase 1 results of trastuzumab deruxtecan were promising in patients with metastatic breast cancer and varying level s of HER2 expression. This finding led to the recently published phase 2 DESTINY-Breast01 study in patients with HER2-postive metastatic breast cancer. Based on the results of this study, on December 20, 2019, the US Food and Drug Administration granted accelerated approval to trastuzumab deruxtecan for the treatment of unresectable or metastatic HER2-positive breast cancer in adults who have received ≥2 previous anti–HER2-based regimens in the metastatic setting.

METHODS: DESTINY-Breast01 was a 2-part, open-label, single-group, phase 2 clinical trial that enrolled 184 patients with metastatic HER2-positive breast cancer who had received trastuzumab emtansine and a median of 6 treatments for advanced disease. In the first part of the study, the researchers evaluated 3 different doses of trastuzumab deruxtecan to establish the recommended dose of 5.4 mg/kg. In the second part of the study, the efficacy and safety of trastuzumab deruxtecan were assessed. The primary end point was confirmed objective response rate (ORR). The secondary end points included disease control rate, duration of response, and progression-free survival (PFS).

RESULTS: Trastuzumab deruxtecan induced a confirmed ORR of 60.9%; of the responding patients, 6% had a complete response and 54.9% had a partial response. The median time to response was 1.6 months, and the median duration of response was 14.8 months, with a disease control rate of 97.3%. The clinical benefit rate was 76.1% at 6 months. After a median follow-up of 11.1 months, the median PFS was 16.4 months, with a PFS of 18.4 months in 24 patients with brain metastases. The overall survival rates were 93.9% at 6 months and 86.2% at 12 months; the median overall survival was not reached.

Treatment-emergent adverse events occurred in 99% of patients, and 57.1% of the patients had ≥3 events. The most common any-grade events were nausea (77.7%), fatigue (49.5%), alopecia (48.4%), vomiting (45.7%), constipation (35.9%), decreased neutrophil count (34.8%), decreased appetite (31%), anemia (29.9%), and diarrhea (29.3%).

Although most adverse events were low grade, 25 (13.6%) patients had interstitial lung disease related to trastuzumab deruxtecan treatment. At the data cutoff, 7 patients recovered, 2 were recovering, 10 had ongoing interstitial lung disease, and 4 patients died; the status of 2 patients was unknown.

“In this global, phase 2 study, trastuzumab deruxtecan had a high level of clinical activity in patients with HER2-positive metastatic breast cancer who had undergone extensive previous therapies,” the researchers observed. “Such therapy was associated with a substantial risk of interstitial lung disease, a toxic effect that requires attention to pulmonary symptoms and careful monitoring.”

Source: Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610-621.

Commentary by Robert J. Ignoffo

This phase 2 clinical trial showed a remarkable response rate with trastuzumab deruxtecan treatment in heavily pretreated patients with HER2-positive metastatic breast cancer. A 60% response rate after an average of 6 treatments indicates that this antibody–drug conjugate is a truly effective agent. Trastuzumab deruxtecan is designed to have a higher drug-to-antibody ratio (8:4 vs 3:4) than trastuzumab emtansine. In addition, the released cytotoxic payload with trastuzumab deruxtecan crosses cell membranes more easily than with trastuzumab emtansine. Because trastuzumab emtansine is very effective in the second-line setting, it would be of interest to compare this drug in a clinical trial with trastuzumab deruxtecan.

The National Comprehensive Cancer Network (NCCN) has included trastuzumab deruxtecan as an option in its guidelines for patients with HER2-positive metastatic breast cancer who have received ≥2 lines of HER2-targeted therapy. However, the NCCN cautions that trastuzumab deruxtecan is contraindicated in patients with interstitial lung disease.

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