The Lynx Group

“Unheard of” Results with Trastuzumab Deruxtecan in Metastatic HER2-Positive Breast Cancer

April 2020, Vol 11, No 2

San Antonio, TX—The novel antibody– drug conjugate trastuzumab deruxtecan (Enhertu) achieved “unprecedented” objective response rates of 60.9%, a median duration of response of 14.8 months, and a median progression- free survival (PFS) of 16.4 months in heavily pretreated patients with HER2-positive metastatic breast cancer, according to the results of the phase 2 DESTINY-Breast01 trial. The disease control rate was 97% in these patients whose disease progressed while receiving HER2-targeted agents, such as trastuzumab (Herceptin), ado-trastuzumab emtansine (T-DM1; Kadcyla), or pertuzumab (Perjeta). These data were presented at the 2019 San Antonio Breast Cancer Symposium and published to coincide with the presentation (Modi S, et al. N Engl J Med. 2020;382:610-621).

Based on the study results, on December 20, 2019, the FDA granted accelerated approval of the drug 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.

“Although HER2-directed therapies, such as trastuzumab, pertuzumab, and T-DM1, have led to improved outcomes for patients with HER2-positive advanced breast cancer, resistance to these drugs develops almost inevitably, and we do not have a clear standard of care for these patients once resistance occurs,” said lead investigator Ian E. Krop, MD, PhD, Associate Chief, Division of Breast Oncology, Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute, Boston, MA.

The current first-line therapy for HER2-positive metastatic breast cancer is the combination of the anti-HER2 drugs trastuzumab and pertuzumab plus a taxane. Second-line therapy is the antibody–drug conjugate T-DM1. There are no good options for patients whose disease progresses after T-DM1.

Trastuzumab deruxtecan is an antibody– drug conjugate with the same amino acid sequence as trastuzumab linked to a payload of topoisomerase 1 inhibitor. Because trastuzumab deruxtecan has a much higher ratio (8:1) of cytotoxic drug to antibody than T-DM1, it is more potent against cancer cells.

DESTINY-Breast01

The open-label multicenter phase 2 DESTINY-Breast01 study enrolled 249 patients with unresectable and/or metastatic HER2-positive breast cancer who had received T-DM1 and trastuzumab; 65.8% of the patients received treatment with pertuzumab, and 54.3% received other anti-HER2 therapies, with a median of 6 previous lines of therapy for metastatic disease. Approximately 50% of the patients had hormone receptor (HR)-positive tumors.

Patients with previous interstitial lung disease (ILD), which is a concern with this novel agent, were excluded. Stable brain metastases in patients who received treatment were allowed. The participants received a 5.4-mcg/kg dose of trastuzumab deruxtecan.

The primary end point, objective response rate confirmed by an Independent Review Committee, was 60.9% (complete response, 6%; partial response, 54.9%); stable disease was observed in 3.64% of patients, and 1.6% of patients had progressive disease; 1.1% of patients were not evaluable for response.

Objective responses were seen among all the prespecified subgroups, including those who received previous treatment with pertuzumab, patients with HR-positive or HR-negative disease, and patients with and without brain metastasis.

The median PFS was 16.4 months. In patients with baseline brain metastasis, the median PFS was 18 months, but Dr Krop cautioned that this was a small subgroup and not a prespecified end point. The median overall survival had not been reached at a median follow-up of 11 months.

Safety Issues

The median duration of treatment with trastuzumab deruxtecan was 10 months (range, 0.7-20.5 months). Almost all (99.5%) patients had a treatment- related adverse event of any grade. The grade ≥3 adverse events rate was 57.1%. Serious events occurred in 22.8% of patients; 11 patients discontinued treatment because of pneumonitis and 5 patients because of ILD.

In all, 25 (13.6%) patients had ILD, including 5 patients with grade 1 disease, 15 with grade 2, and 1 with grade 3. The median time to the onset of ILD was 6.5 months.

“We knew ILD was a serious concern in patients treated with T-DXd [trastuzumab deruxtecan],” Dr Krop said. “While these events were primarily grade 1 and 2, after reviewing these data, close monitoring for signs and symptoms of ILD is recommended in future studies of T-DXd for early detection and prompt treatment. If ILD is suspected, hold the drug and start steroids immediately,” he said.

Although cardiac events are a concern with trastuzumab and pertuzumab, clinically significant cardiac toxicity was not observed with trastuzumab deruxtecan in this study.

Three phase 3 clinical trials with trastuzumab deruxtecan are ongoing.

“Fantastic Results”

“These are fantastic results,” said Carlos Arteaga, MD, Director, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, who moderated the press conference at the meeting.

“This is a heavily pretreated population of advanced HER2-positive disease. If this antibody–drug conjugate were moved into an earlier setting, we would expect the results to be even better,” he emphasized.

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