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Late-Line HER2 Drug Impresses in Metastatic Breast Cancer

— Median PFS over three times better than what is typically seen in this setting, says investigator

MedpageToday

SAN ANTONIO -- An investigational antibody-drug conjugate targeting the HER2 receptor showed impressive response rates that proved durable for women with heavily pretreated metastatic breast cancer in a single-arm phase II trial.

Among 184 HER-positive patients in DESTINY-Breast01, 60.9% had an objective response to trastuzumab deruxtecan, and the median duration of response was 14.8 months, reported Ian Krop, MD, PhD, of the Dana-Farber Cancer Institute in Boston.

About 55% of patients had partial responses and 6% were complete responders, according to the findings presented at the San Antonio Breast Cancer Symposium (SABCS) and simultaneously published in the .

An additional 36.4% achieved stable disease with the drug, for a disease control rate of 97.3%. All subgroups appeared to show benefit, and at first follow-up, nearly every patient had some form of tumor shrinkage.

Median progression-free survival (PFS) was 16.4 months in the overall group, which reached 18.1 months for the small subset of 24 patients that had treated, stable asymptomatic brain lesions at enrollment.

"These data demonstrate the potential of trastuzumab deruxtecan to establish a new standard of care for patients with advanced HER-positive breast cancer," said Krop during an SABCS press briefing.

He noted that other drugs used in a similar setting (third- and later-line) haven't been nearly as effective as the current findings, with most studies showing a median PFS in the 4-to-5 month range.

Trastuzumab deruxtecan is an antibody drug conjugate with three key components: an anti-HER2 monoclonal antibody with the same amino acid as trastuzumab, a topoisomerase I inhibitor payload, and a tetra-peptide-based cleavable linker. Krop noted that the drug is 10 times more potent than topoisomerase I inhibitors such as irinotecan, one of the more typically-used drugs in this class.

"This is an agent that the cancers generally haven't been exposed to so there is the hope that this would be non cross-resistant," Krop said.

Past attempts with topoisomerase I inhibitors in breast cancer have been limited by toxicity.

"The idea here is by conjugating it to the antibody you're able to specifically deliver high concentrations of the drug directly to the tumor cell and that helps improve the therapeutic index," said Krop.

Median overall survival in the study was not reached -- an estimated 93.9% of patients remained alive at 6 months and 86.2% remained alive at 1 year.

Briefing moderator Carlos Arteaga, MD, of UT Southwestern Harold C. Simmons Comprehensive Cancer Center in Dallas, called the results "fantastic."

"This is in a heavily pretreated population," he emphasized. "As we move this treatment to earlier stages of disease, I think I would expect that this impact will be greater -- this is great news for patients with HER2-positive breast cancer."

Participants in the trial had a median of six prior systemic therapies, with 100% of the women having already received both trastuzumab and T-DM1. Another 65% had received pertuzumab (Perjeta), 54% had some other anti-HER2 agent, and 99.5% had received some other systemic anti-cancer therapy.

Patients with a significant history of interstitial lung disease (ILD) were excluded from the trial, but ILD still proved to be an issue, leading to treatment cessation in five patients. On independent adjudication, trastuzumab deruxtecan was found to be associated with grade 1/2 ILD in 10.9% of patients, as well as one case of grade 3/4 ILD, and four ILD-related deaths.

Krop said that ILD is an important risk of the agent and requires careful monitoring.

Low-grade hematologic and gastrointestinal adverse events (AEs) were the main source of treatment-related toxicity. The most common grade 3 AEs were decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). In contrast with other anti-HER2 agents, no clinically significant cardiotoxicity was observed in the study.

Disclosures

Krop disclosed serving on a data safety monitoring board for Merck and Novartis, support from Genentech/Roche and Pfizer, and relevant relationships with Genentech/Roche, Daiichi Sankyo, AstraZeneca, MacroGenics, and Context Therapeutics.

Primary Source

New England Journal of Medicine

Modi S, et al "Trastuzumab deruxtecan in previously treated HER2-positive breast cancer" N Engl J Med 2019; DOI: 10.1056/NEJMoa1914510.