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Novel HER2 Antibody-Drug Conjugate Shows Promise in Heavily Pretreated Breast Cancer Patients

SAN ANTONIO – The investigational HER2-targeted antibody-drug conjugate trastuzumab deruxtecan (T-DXd) resulted in durable objective responses in a majority of patients with HER2-positive breast cancer who were heavily pretreated, including with T-DM1 (Genentech's Kadcyla) and other existing HER2-targeted treatments, new results from a Phase II clinical trial, DESTINY-Breast01, have shown.

The data were presented today at the San Antonio Breast Cancer Symposium and published simultaneously in the New England Journal of Medicine

Although HER-2 directed therapies like trastuzumab (Genentech's Herceptin), pertuzumab (Genentech's Perjeta), and T-DM1 have led to improved outcomes for patients with HER2-positive advanced breast cancer, resistance to these drugs develops "almost inevitably," Ian Krop, associate chief of the Division of Breast Oncology at Dana-Farber Cancer Institute, said in a statement accompanying the presented results. "We do not have a clear standard of care for these patients once resistance occurs," he added, which creates a clear unmet need for new options.

Similar to T-DM1, T-DXd is a monoclonal antibody targeting HER2, but unlike T-DM1, which has a microtubule inhibitor as the cytotoxic payload, T-DXd uses a topoisomerase 1 inhibitor — a class of drugs Krop said is uncommonly used in breast cancer, hopefully meaning patients are less likely to be resistant to it. T-DXd also has eight molecules of payload, which is twice as many as T-DM1, according to Krop. 

In a prior Phase I study, investigators were able to show an objective response rate of 59 percent for T-DXd in patients with advanced HER-2 positive breast cancer previously treated with T-DM1. The US Food and Drug Administration granted priority review to the therapy this October.

In the new Daiichi Sankyo- and AstraZeneca-sponsored Phase II study, Krop and colleagues enrolled 253 patients who had been previously treated with T-DM1, and many of whom had had other HER2 drugs, with an average of six lines of prior therapy in the cohort overall. 

In all 184 patients received the recommended phase II dose of 5.4 mg/kg and the overall response rate in this group was 60.9 percent: 6 percent complete responses and 54.9 percent partial responses. Median progression-free survival was 16.4 months. 

"This is one reason why these data are so compelling," Krop said discussing the trial during the conference. "This is a heavily pre-treated population, so to put in context … a PFS of 16 months [and a] response rate of 60 percent, those are roughly double and triple of what we usually see in a third-line and later population."

The disease control rate in the 184 patients was also 97 percent, which Krop said "suggests that the vast majority of cancers in this population seem to have at least some sensitivity to this agent. 

Overall, he argued, the high rate of durable responses observed "demonstrate the potential of trastuzumab deruxtecan to establish a new standard of care for patients with advanced HER2-positive breast cancer. 

Importantly, the Phase II study also collected new safety information for the ADC. Almost all the patients in the trial had some sort of treatment-emergent adverse events, with 57 percent having side effects of grade 3 or higher, including decreased neutrophil count, nausea, anemia, decreased lymphocyte count, and fatigue. Overall, 15 percent of patients discontinued treatment because of some adverse event, mainly lung issues.

Interstitial lung disease, something Krop said is a serious concern, was observed in 25 patients. "While these events were primarily grade 1 or 2, there were unfortunately four grade 5 ILD-related deaths" (roughly 2.2 percent of the cohort).

"Because of this potential toxicity, close monitoring for signs and symptoms … is recommended for early detection. If ILD is suspected, evaluations should include high-resolution CT, pulmonologist consultation, pulmonary function tests, and other tests," he said.

Although data on treatment for T-DXd-induced ILD are limited, if diagnosed, interruption of treatment and prompt intervention with glucocorticoids is recommended," Krop added.  During his presentation he said that of the 20 patients who experienced moderate ILD and didn't pass away, seven are known to have recovered, two are recovering, but the rest were not available for followup.

"Why we [are seeing] this particular risk is unclear, and we need to do more to research this and to identify which patients are at risk for getting most severe cases ... and how to mitigate that risk," Krop said, discussing the toxicity results. That said, he added, it is encouraging that the breast cancer community was able to make progress in dealing with the cardiac toxicities associated with non-conjugate HER2 drugs like trastuzumab and how it is rising to the challenge of new immune-related toxicities in the context of immune checkpoint inhibitors.

"I think we can learn how to better deal with this, but clearly more research is needed," he reiterated.

The current study was a single-arm trial and as such did not pitch T-DXd against other therapies, so drawing conclusions about the treatment's performance relative to others is impossible. But, Krop said that there are already several Phase III trials ongoing in both HER2-overexpressing and HER2-low patients.

"This is great news for patients with breast cancer," UT Southwestern professor Carlos Arteaga added during a press preview of the results. "As Dr. Krop stated, these are heavily pretreated patients, and as we move this treatment to earlier stages of disease, I would expect [the] impact to be even greater," he said.