In heavily pretreated patients with HER2-positive metastatic breast cancer [fam-]trastuzumab deruxtecan-nxki (T-DXd), a novel antibody-drug conjugate, achieved high response rates and durable responses, according to results of the phase II DESTINY-Breast01 trial presented at the 2019 San Antonio Breast Cancer Symposium.1 All patients enrolled in the trial had been treated with other HER2-targeted agents. The results of DESTINY-Breast01 were published simultaneously in The New England Journal of Medicine.2
Ian Krop, MD, PhD
Lead author Ian Krop, MD, PhD, Associate Chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, Boston, said, “Although HER2-directed therapies such as trastuzumab, pertuzumab, and [ado-trastuzumab emtansine] (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.”
In these heavily pretreated patients with metastatic breast cancer, the objective response rate was 60.9%, the median duration of response was 14.8 months, and the median progression-free survival was 16.4 months. The disease control rate was 97%.
“Interstitial lung disease was observed in 25 patients and requires attention to pulmonary symptoms and careful monitoring,” Dr. Krop cautioned.
The open-label multicenter phase II DESTINY-Breast01 study enrolled patients with unresectable and/or metastatic HER2-positive breast cancer, all of whom received prior T-DM1 and prior trastuzumab; 65.8% received prior pertuzumab, and 54.3% received other anti-HER2 therapies. Nearly 100% of patients also received other systemic therapy, and 48.9% received prior hormone therapy. The median number of lines of prior therapy for metastatic disease was six (range, 2–27). The median age was 55, and about 24% were 65 years of age or older. About 50% had hormone receptor–positive tumors.
“It is exciting to have a potential new therapy that is active in this heavily pretreated population.”— Ian Krop, MD, PhD
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Patients with prior interstitial lung disease—a concern with T-DM1 and this novel agent—were excluded from the study. Stable, treated brain metastases were allowed.
Participants were treated with the phase II recommended dose of T-DXd (5.4 mg/kg). And the study included 249 patients who were resistant or refractory to T-DM1 and 4 who were intolerant to it.
The primary endpoint of objective response rate confirmed by an independent review committee was 60.9%. The complete response rate was 6%, the partial response rate was 54.9%, stable disease was observed in 3.64%, and progressive disease was noted in 1.6% (1.1% of patients were not evaluable for response).
Of interest, among 168 patients, a waterfall plot for best change in tumor size revealed some degree of tumor shrinkage in all but 4 patients. However, about 40% did not shrink by more than 30% from baseline (prespecified for response). Objective responses were seen among all prespecified subgroups, including those treated with prior pertuzumab, those with hormone receptor–positive and –negative disease, and those with and without brain metastasis.
The median progression-free survival was 16.4 months. In patients with baseline brain metastasis, the median progression-free survival was 18 months. However, Dr. Krop cautioned that this was a small subgroup with a wide confidence interval. With a median follow-up of 11 months, the median overall survival has not been reached.
The median duration of treatment with T-DXd was 10 months (range, 0.7–20.5 months). Almost all patients (99.5%) experienced a treatment-related adverse event. The most common treatment-related adverse events of any grade were nausea, fatigue, alopecia, vomiting, constipation, and neutropenia (mostly grade 1 or 2). Grade 3 or higher treatment-related adverse events were reported in 57.1%, and those considered to be drug-related occurred in 48.4%. Serious adverse events occurred in 22.8%. Treatment-related adverse events leading to treatment discontinuation occurred in 11 patients with pneumonitis and in 5 patients with interstitial lung disease.
Interstitial lung disease, an adverse event of special concern, was reported in 25 patients (13.6%: 5 grade 1, 15 grade 2, 0 grade 3, and 4 grade 5). The median time to onset of interstitial lung disease was 6.5 months. Thirteen of 20 patients with grade ≥ 2 received steroids. Of the 25, 7 recovered, 2 were recovering, 4 died, and data on the other 12 were unknown. Four deaths occurred (between 63 and 148 days).
“We knew interstitial lung disease was a serious concern in patients treated with T-DXd,” Dr. Krop said. “Although these events were primarily grade 1 and 2, after reviewing these data, close monitoring for signs and symptoms of interstitial lung disease is recommended in future studies of T-DXd, for early detection and prompt treatment. If interstitial lung disease is suspected, hold the drug and start steroids immediately,” he told the audience.
Cardiac toxicity, such as cardiomyopathy and left ventricular dysfunction, have been reported with other anti-HER2 therapies, in particular trastuzumab and pertuzumab. Clinically significant cardiac toxicity was not observed with T-DXd in DESTINY-Breast01.
“The data we have seen previously with first-line anti-HER2-directed therapy [trastuzumab and pertuzumab] in CLEOPATRA were groundbreaking—the median survival was 57 months, but that was first-line therapy in metastatic disease. In this trial, patients received multiple therapies after first-line treatment. These measures of response were substantially higher than have been seen in any other studies of patients with metastatic HER2-positive breast cancer,” Dr. Krop noted.
Dr. Krop continued: “Response rates are roughly double what we see in the third-line setting or beyond. The median progression-free survival has been in the 4- to 5-month range, but it was 16 months in this trial. It is exciting to have a potential new therapy that is active in this heavily pretreated population.”
Recommended first-line therapy for HER2-positive metastatic breast cancer is the combination of two anti-HER2 drugs—trastuzumab and pertuzumab—plus a taxane. Second-line therapy is the antibody-drug conjugate T-DM1. There is no established standard of care after T-DM1, and currently available options are of limited benefit.
T-DXd is an antibody-drug conjugate with the same amino acid sequence as trastuzumab, linked to a payload of topoisomerase 1 inhibitor. This new agent has a much higher ratio of cytotoxic drug to antibody (8:1) than T-DM1, making it more potent against cancer cells. T-DXd is membrane-permeable, “thus it can kill neighboring tumor cells regardless of HER2 expression,” Dr. Krop explained.
A caveat in interpreting these results is that DESTINY-Breast01 is a single-arm trial, and it did not compare T-DXd with established therapies.
Three phase III studies are ongoing: DESTINY-Breast02 (vs the standard of care after T-DM1 in patients with HER2-positive disease); DESTINY-Breast03 (vs T-DM1 in patients with HER2-positive disease); and DESTINY-Breast04 (vs chemotherapy in patients with low expression of HER2).
“These promising data show the potential to establish a new standard of care for previously treated patients with HER2-positive advanced breast cancer,” Dr. Krop stated.
DISCLOSURE: Dr. Krop has an immediate family member who has been employed by AMAG Pharmaceuticals; has an immediate family member who has served in a leadership role for AMAG Pharmaceuticals; has an immediate family member who owns stock or other ownership interests in AMAG Pharmaceuticals; has received honoraria from AstraZeneca and Genentech/Roche; has served as a consultant or advisor to Merck, Novartis, Seattle Genetics, and Taiho Pharmaceutical; and has received institutional research funding from Genentech and Pfizer.
1. Krop IE, Saura C, Yamashita T, et al: [Fam-] trastuzumab deruxtecan in subjects with HER2-positive metastatic breast cancer previously treated with T-DM1: DESTINY-Breast01. SABCS. Abstract GS1-03. Presented December 11, 2019.
2. Modi S, Saura C, Yamashita T, et al: Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. December 11, 2019 (early release online).
Steven J. Isakoff, MD, PhD, a medical oncologist at Massachusetts General Hospital, Boston, commented on the results of the DESTINY-Breast01 trial.
Steven J. Isakoff, MD, PhD
“These data are extraordinarily encouraging, suggesting we will have another new option for patients with metastatic...