'Compelling' Data on Trastuzumab Deruxtecan in Heavily Pretreated Breast Cancer

Megan Brooks

December 11, 2019

SAN ANTONIO — The investigational agent trastuzumab deruxtecan (AstraZeneca/Daiichi Sankyo) showed strong antitumor activity in women with HER2-positive metastatic breast cancer previously treated with multiple agents including trastuzumab emtansine (Kadcyla, Genentech) in a phase 2 clinical trial.

The data are "compelling," said Ian Krop MD, PhD, associate chief, Division of Breast Oncology at Dana-Farber Cancer Institute, Boston.

The objective response rate was 61% and median progression-free survival was 16 months. "Those are roughly double or triple what we've typically seen in other studies of this third- and later-line [treatment] population, where the median progression-free survival has been in the 4- to 5-month range," said Krop.

While trastuzumab deruxtecan had a generally manageable safety profile, interstitial lung disease (ILD) is "an important risk" that requires "careful monitoring and prompt intervention," he noted.

Trastuzumab deruxtecan has the potential to be a "new standard of care" for patients with advanced HER2-positive breast cancer, he said.

Krop presented the results of the phase 2 DESTINY-Breast01 study during a press briefing here today at the San Antonio Breast Cancer Symposium (SABCS), which were simultaneously published in the New England Journal of Medicine.

"These are fantastic results in a heavily pretreated population," commented SABCS co-director and press briefing moderator Carlos Arteaga, MD.

"As we move this treatment to earlier stages of disease, I would expect that the impact would be even greater in these patients. This is great news for patients with HER2-positive breast cancer," said Arteaga, who directs the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center.

Validation of Phase 1 Results

Both trastuzumab emtansine and trastuzumab deruxtecan are antibody-drug conjugates composed of a HER2-specific monoclonal antibody. But unlike trastuzumab emtansine, which has a microtubule inhibitor as the cytotoxic payload, trastuzumab deruxtecan has a potent topoisomerase 1 inhibitor as the payload.

"This is a kind of chemotherapy that is not typically used in HER2-positive breast cancer, so it's less likely that cancers will have developed resistance to this agent," Krop explained.

Trastuzumab deruxtecan also has a higher drug-to-antibody ratio than trastuzumab emtansine (roughly 8 vs 3 to 4) while retaining a favorable pharmacokinetic profile.

Study Details

DESTINY-Breast01 was an open-label, single-group multicenter phase 2 study involving 184 women with metastatic HER2-positive breast cancer previously treated with a median of six prior lines of therapy, including trastuzumab, trastuzumab emtansine, pertuzumab, and other targeted therapies. They were treated with trastuzumab deruxtecan 5.4 mg/kg body weight given by intravenous infusion every 3 weeks.

In the intent-to-treat analysis, 112 of 184 patients responded to the drug (objective response rate, 60.9%; 95% confidence interval [CI], 53.4% to 68.0%). There were 11 (6.0%) complete responses and 101 (54.9%) partial responses. This validates earlier observations from the phase 1 study, which showed a response rate of 59.5% in a similar patient population.

The activity of trastuzumab deruxtecan was relatively consistent across all major subgroups, including those previously treated with pertuzumab where the response rate was about 65%.

The median time to response was 1.6 months (95% CI, 1.4 to 2.6 months), "essentially at the time of the first restaging," Krop noted. The median response duration was 14.8 months (95% CI, 13.8 to 16.9 months)

Median progression-free survival (PFS) was 16.4 months (95% CI, 12.7 months to not reached). In the subgroup of 24 patients with brain metastases, median PFS was 18.1 months (95% CI, 6.7 to 18.1 months).

The disease-control rate (response rate plus stable disease rate) was 97.3% (95% CI, 93.8% to 99.1%), and the clinical-benefit rate (disease-control rate with stable disease lasting at least 6 months) was 76.1% (95% CI, 69.3% to 82.1%). Fewer than 2% of patients had progressive disease at time of first restaging.

ILD a Confirmed Risk With Trastuzumab Deruxtecan

Treatment-emergent adverse events occurred in all but one patient (99.5%), with 57.1% experiencing an adverse event of grade 3 or higher, including decreased neutrophil count, nausea, anemia, decreased lymphocyte count, and fatigue. There was no clinically significant cardiac toxicity.

Adverse events led to a dose interruption in 65 patients (35.3%) and to a dose reduction in 43 patients (23.4%); 28 patients (15.2%) discontinued treatment due to an adverse event, most commonly pneumonitis or ILD.

ILD related to trastuzumab deruxtecan therapy, a risk that emerged in the phase 1 study, was observed in 25 (13.6%) patients. These events were primarily grade 1 or 2; however, there were four grade 5 ILD-related deaths (2.2%) in the study. Due to this potential toxicity, close monitoring for signs and symptoms of ILD is recommended in future studies, Krop said.

"Although data on treatment for trastuzumab deruxtecan-induced ILD are limited, if diagnosed, interruption of treatment and prompt intervention with glucocorticoids is recommended," Krop added in a conference statement.

Several phase 3 studies of trastuzumab deruxtecan are underway in various patient populations.

Trastuzumab deruxtecan for HER2-positive metastatic breast cancer has breakthrough therapy and fast track designations and priority review status from the US Food and Drug Administration. The agency is expected to review the application in the second quarter of 2020.

The study was sponsored by Daiichi Sankyo Inc and AstraZeneca. Krop reported grant and research support from Genentech/Roche and Pfizer; consulting fees/honoraria from Genentech/Roche, Daiichi Sankyo, AstraZeneca, Macrogenics, and Context Therapeutics; and is on a data safety monitoring board of Merck and Novartis. Arteaga has disclosed no relevant financial relationships.

San Antonio Breast Cancer Symposium 2019: Abstract GS1-03. Presented December 11, 2019.

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