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Trastuzumab Deruxtecan Ushers in New Treatment Era for HER2-Low Breast Cancer

— DESTINY-Breast04 extends agent's benefits to historically tough-to-treat disease

Last Updated June 6, 2022
MedpageToday

CHICAGO -- Patients with HER2-low metastatic breast cancer treated with trastuzumab deruxtecan (Enhertu) achieved significant improvements in survival compared with those treated with chemotherapy alone, according to results from the .

In the phase III international study, among a population of 494 patients with both HR-positive disease (88.7%) and HR-negative disease (11.3%), the risk of disease progression or death was approximately 50% lower, and the risk of death was 36% lower, with trastuzumab deruxtecan (T-DXd) than with the treatment of physician's choice of chemotherapy (TPC) at a median follow-up of 18.4 months.

The benefit was seen regardless of hormone receptor status, reported Shanu Modi, MD, Memorial Sloan Kettering Cancer Center in New York City, at the American Society of Clinical Oncology (ASCO) annual meeting. Results were published simultaneously in the .

Also, patients treated with T-DXd had a median progression-free survival (PFS) of 9.9 months versus 5.1 months in patients treated with TPC (HR 0.50, P<0.001). The results were similar for patients who were HR-positive (10.1 months with T-DXd vs 5.4 months in the chemotherapy group, HR 0.51, P<0.001), and patients in the HR-negative cohort (8.5 months vs 2.9 months, HR 0.46).

As for overall survival (OS), patients treated with T-DXd experienced a 6.6-month improvement verus patients who received TPC, with a median OS of 23.4 months versus 16.8 months, respectively (HR 0.64, P=0.001). OS results were comparable when broken down into HR-positive (HR 0.64, P=0.0028) and HR-negative (HR 0.48) subgroups.

"Overall these results establish HER2-low metastatic breast cancer as a targetable population of breast cancer, with trastuzumab deruxtecan as a new standard of care in this setting," Modi said at an ASCO press conference.

T-DXd is a next-generation, HER2-targeted antibody drug conjugate. "By virtue of its unique properties and mechanism of action -- particularly, the bystander effect -- it has activity across a broad range of HER2 expression in tumors," Modi explained, adding that a demonstrated promising efficacy of the drug in patients with heavily pretreated HER2-low breast cancer.

Extended Benefits

"I think the results of this trial, clearly, will be practice changing," said ASCO discussant Jane Lowe Meisel, MD, of the Winship Cancer Center at Emory University in Atlanta. "What this trial does is really extend the benefits of this agent to a whole new group of patients that is traditionally quite difficult to treat -- [they] are endocrine refractory, ER-positive, triple-negative patients who have progressed on one or two lines of therapy and are HER2-low. Now they can potentially benefit from this drug, which we've seen improves both progression-free and overall survival in clinically and statistically meaningful ways."

"This offers a wonderful new option for patients, and also really fundamentally change the way we think about HER2 status, and how we classify this in our metastatic patients," Meisel observed. "This is really just a huge win for our patients and the oncology community."

Press conference moderator Julie Gralow, MD, ASCO chief medical officer and executive vice president, noted that "We're going to have to change the way we report pathology for breast cancer, now, as a result of this study."

Study Details

DESTINY-Breast04 included patients with centrally-confirmed HER2-low unresectable and/or metastatic breast cancer who had previously been treated with one or two lines of chemotherapy in the metastatic setting. Additionally, patients with HR-positive breast cancer were required to have endocrine refractory disease. Low expression of HER2 was defined as a score of 1+ on immunohistochemical (IHC) analysis or as an IHC score of 2+.

The authors pointed out that a "key consideration in the DESTINY-Breast04 trial was the use of conventional HER2 IHC testing (and HER2 ISH testing when applicable) to identify cancers with HER2-low status...The data from this trial will...be used to update labeling of the assay [VENTANA HER2/neu [4B5] IUO Assay system] to include a predictive claim for patients with HER2-low breast cancer. However, given reported limitations, alternative quantitative methods to better select patients for this new therapy may be warranted."

Median patient age was around 56, and the vast majority were female. Around 45% of the patients were in Europe or Israel and almost half were white.

Patients were randomly assigned in a 2:1 ratio to receive T-DXd or TPC, which included capecitabine (Xeloda), eribulin (Halaven), gemcitabine (Gemzar), paclitaxel, or nab-paclitaxel.

Regarding safety, adverse events grade ≥3 occurred in 52.6% of the patients who received T-DXd and 67.4% of those who received TPC. Furthermore, interstitial lung disease/pneumonia was observed in a substantial proportion of patients who received T-DXd.

"Lung toxicity is an important toxicity of T-DXd," Modi acknowledged. "We saw lung toxicity in 12% of patients, including an 0.8% incidence of grade 5 events, with three reported deaths, highlighting the importance of awareness and close monitoring of patients to prevent this serious toxicity."

Modi noted that HER2 status is currently defined in a binary model, where HER2-positive breast cancers driven by the oncogene are currently treatable with HER2-targeted therapies, while HER2-negative breast cancers are not.

"However, within the HER2 population there are tumors that have low levels of HER2 expression, which we have termed HER2-low breast cancer, for which this HER2 receptor may still be targetable," she said. "Our currently available therapies are HER2-targeted therapies that have not proven effective in patients in this subgroup."

These HER2-low cancers are currently treated as HER2-negative cancers, where therapy is guided by hormone receptor status, Modi stated. "And ultimately, once we've exhausted endocrine therapies and a few lines of targeted agents, we really have limited late-line options for these patients. We really have a big unmet need for more effective therapies," she said.

A Standing Ovation

Modi later unveiled the results of DESTINY-Breast04 during a late-breaking abstract plenary session, and to say that the study was well-received would be an understatement, as she received a 40-second standing ovation at the conclusion of her presentation.

"I see from the standing ovation you're as excited about this data as I am," ASCO discussant Patricia LoRusso, DO, PhD, FASCO, of the Yale School of Medicine in New Haven, Connecticut, told the audience.

"Should the standard of care for patients with HER2-low breast cancer change as a result of the data that Dr. Modi presented today from Destiny4-Breast?” she asked. "My answer to you is ‘absolutely."

"And I believe we need more appropriate tools to define the most appropriate patient population," LoRusso added. "Drug development has outpaced biologic determination of tumor types. And we need to identify additional populations with different tumor types to determine the true and global effect and benefit of T-DXd for our oncology community."

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    Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.

Disclosures

The study was funded by Daiichi Sankyo and AstraZeneca.

Modi disclosed relationships with, and/or support from, Daiichi Sankyo/AstraZeneca, Seattle Genetics, AstraZeneca, Daiichi Sankyo, Genentech, GlaxoSmithKline, Lilly, Macrogenics, Puma Biotechnology, and Zymeworks, as well as support from AstraZeneca, Daiichi Sankyo, Roche/Genentech, Seattle Genetics (all institutional). Co-authors disclosed multiple relationships with industry.

Meisel reported relationships with AstraZeneca, Curio Science, Genentech, GlaxoSmithKline, Novartis, SeaGen, Pfizer, Seattle Genetics, Puma Biotechnology, Total Health Conferencing, Medscape.

Primary Source

American Society of Clinical Oncology

Modi S, et al "Trastuzumab deruxtecan (T-DXd) versus treatment of physician's choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): Results of DESTINY-Breast04, a randomized, phase 3 study" ASCO 2022; Abstract LBA 3.

Secondary Source

New England Journal of Medicine

Modi S, et al "Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer" N Engl J Med 2022; DOI: 10.1056/NEJMoa2203690