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ESMO Data in HER2-Positive Lung, Breast Cancer Bolster Daiichi Sankyo, AstraZeneca's Enhertu


NEW YORK – Daiichi Sankyo and AstraZeneca's antibody-drug conjugate trastuzumab deruxtecan (Enhertu) demonstrated clear benefits for breast and lung cancer patients with HER2-positive tumors in studies presented Saturday at the European Society for Medical Oncology Congress.

The therapy, known as T-DXd for short, includes a HER2-targeting monoclonal antibody (trastuzumab) joined by a cleavable linker to a topoisomerase I inhibitor. Once trastuzumab binds to HER2 receptors on cancer cells, it releases the topoisomerase I inhibitor, causing cell death. The drug has also been shown to produce what investigators call a "bystander" killing effect, meaning that it releases the payload into neighboring cancer cells, too.

In the Phase II DESTINY-Lung01 trial, T-DXd had encouraging activity in patients with advanced, HER2-mutated non-small cell lung cancer, for whom there are no approved HER2-targeted therapies as of now. Among 91 NSCLC patients whose tumors harbored activating HER2 mutations and who had experienced disease progression following standard treatment, 50 patients, or 55 percent, responded to the antibody-drug conjugate. One patient experienced a confirmed complete response, while the other 49 had confirmed partial responses. Over 90 percent experienced disease control and tumor shrinkage on T-DXd, and the median duration of response was 9.3 months.

Though the trial's primary endpoint was response rate as measured by a team of independent reviewers, Bob Li, a medical oncologist specializing in lung cancer at Memorial Sloan Kettering, also presented preliminary progression-free and overall survival results from DESTINY-Lung01 at the meeting. The median progression-free survival time for these T-DXd-treated patients was 8.2 months, and the median overall survival was 17.8 months.

According to Li, responses to T-DXd were observed among patients who had received prior chemotherapy and immunotherapy alike. Patients whose cancers had metastasized to their central nervous systems including the brain were also eligible for the trial, and among 33 such patients, the median progression-free survival was just over seven months and the overall survival was 13.8 months.

The results of the trial give further support to researchers' hypothesis that NSCLC tumor cells, unlike breast cancer cells, don't necessarily need to overexpress HER2 to be susceptible to T-DXd's cancer-killing effects. Instead, the presence of a HER2 mutation in NSCLC is sufficient for T-DXd to target cancer cells and kill them. In a New England Journal of Medicine paper published in concert with the ESMO presentation, Li and co-authors wrote, "It has been shown preclinically that activating HER2 mutations enhance receptor internalization and intracellular uptake of the HER2 receptor antibody-drug conjugate complex … [which] may explain why efficacy is observed even in HER2-mutant cancers with no detectable HER2 expression."

In previous studies, researchers have tried unsuccessfully to treat HER2-overexpressing NSCLC patients with the first-generation HER2-targeted drug trastuzumab (Genentech's Herceptin) and chemo. Since the approval of trastuzumab in 1998 for HER2-overexpressing metastatic breast cancer, HER2-targeted treatment has become the standard of care for this subset of tumors, as well as for HER2-overexpressing gastric cancer. However, Li and authors noted that HER2 protein expression or amplification is comparatively rare in NSCLC, and there were "difficulties in defining precise molecular criteria for the selection of patients who would benefit from HER2-targeted agents."

More research is needed, according to researchers, to determine the exact underlying biological mechanisms that enable NSCLC patients with HER2 mutations to respond to T-DXd without overexpressing the HER2 protein. Still, based on the DESTINY-Lung01 data, the US Food and Drug Administration granted breakthrough therapy designation to T-DXd.

AstraZeneca and Daiichi Sankyo will continue to study T-DXd in NSCLC to determine the optimal dosing strategy to maximize benefit and minimize toxicities and to explore potential combination treatment strategies to improve response durability. To give NSCLC patients the best chance to enroll in these ongoing studies, it will be increasingly important to test them for HER2 mutations. As Daniel Shao Weng Tan, a senior consultant medical oncologist at the National Cancer Centre Singapore, noted in his discussion of the DESTINY-Lung01 data, "We need to give due consideration to the strategies to improve HER2 testing rates in order to expand on clinical experience and [this trial] really argues for the importance of broad upfront NGS testing in NSCLC."

In the trial presented at the ESMO Congress, researchers used Thermo Fisher Scientific's Oncomine Dx Target Test to centrally confirm HER2 mutations in the DESTINY-Lung01 trial, and in April, Daiichi Sankyo said it was working with Guardant Health to develop Guardant360 CDx as a companion test to identify NSCLC patients eligible to receive T-DXd. Guardant's liquid biopsy test is designed to detect alterations in 55 genes and also has companion diagnostic approval for another targeted NSCLC drug in AstraZeneca's portfolio, osimertinib (Tagrisso). 

New standard of care in breast cancer?

In a separate ESMO presentation on Saturday, Daiichi Sankyo and AstraZeneca shared results from their planned interim analysis of the Phase III DESTINY-Breast03 trial, in which T-DXd was compared head to head against Genentech's antibody-drug conjugate ado-trastuzumab emtansine (Kadcyla; T-DM1). Breast cancer patients were enrolled based on HER2 expression on tumors, as determined by centrally confirmed immunohistochemistry staining.

Genentech's T-DM1 has been approved for metastatic, previously treated HER2-positive breast cancer since 2013. Daiichi Sankyo and AstraZeneca's T-DXd received accelerated approval from the FDA in late 2019 as a treatment for metastatic, HER2-positive breast cancer patients who have previously received at least two anti-HER2 therapies. The agency granted accelerated approval based on the results from the Phase II single-arm DESTINY-Breast01 trial. Regulators in Japan also followed suit in March 2020.

With two antibody-drug conjugates available for HER2-positive breast cancer, oncologists have wondered how T-DXd would stack up against T-DM1 in the second-line treatment setting. In the absence of a head-to-head trial, however, many oncologists have been prescribing T-DXd as a third- or later-line treatment, after patients progress on T-DM1. As such, oncologists have been eagerly awaiting the DESTINY-Breast03 randomized trial results to see if they can move T-DXd to the second-line setting.

They can, according to Javier Cortes, head of the International Breast Cancer Center in Barcelona, who presented the DESTINY-Breast03 data at the meeting. Shanu Modi, a breast cancer oncologist at Memorial Sloan Kettering who discussed the data, agreed.

DESTINY-Breast03 randomized 524 patients with HER2-positive metastatic breast cancer — all of whom had previously received first-line trastuzumab and a taxane-based chemotherapy — to receive either T-DM1 or T-DXd. After a year of follow-up, the progression-free survival rate in the T-DXd arm was 75.8 percent versus 34.1 percent in the T-DM1 arm. Median progression-free survival was not yet reached as of the data cutoff for patients treated with T-DXd and 6.8 months for patients treated with T-DM1.

While it's still too early to definitively judge how the treatments will impact overall survival, Cortes shared preliminary estimates. After one year, the overall survival rate for T-DXd-treated patients was over 94 percent, versus 85.9 percent for the T-DM1-treated patients. The confirmed overall response rates, moreover, were 79.7 percent and 34.2 percent in the T-DXd versus T-DM1 arms, respectively, and when the investigators homed in on complete responses specifically, these rates were 16.1 versus 8.7 percent, respectively.

Although T-DXd outperformed T-DM1 across all the measured efficacy endpoints, the newer antibody-drug conjugate was associated with marginally higher side-effect rates versus T-DM1, particularly with regard to nausea, hair loss, and decreased white blood cell counts. Lung inflammation occurred in both groups, but mostly with grade 1 or 2 severity. Two patients in the T-DXd arm did experience grade 3 lung toxicities, but none of the patients in either arm experienced grade 4 or 5 lung toxicities.

"As an oncology community, we've learned how to manage the serious side effects of important therapies like checkpoint inhibitors and CAR T-cell therapy in order to provide them safely to the patients who need them," Modi said. "But this implies, of course, that vigilance and early intervention is absolutely mandatory to deliver T-DXd safely."

Looking ahead, AstraZeneca and Daiichi Sankyo have indicated that they are gearing up for regulatory action based on the DESTINY-Breast03 results. Last month, the firms put out a statement saying that in light of T-DXd meeting its primary endpoint in this study, they were prepared to pursue regulatory submissions globally seeking approval of the drug as a second-line treatment in HER2-positive advanced breast cancer.

The firms doubled down on this message following the ESMO presentation Saturday. "[DESTINY-Breast03] is a positive indication of the potential of this medicine to transform the treatment of HER2-positive metastatic breast cancer," Ken Takeshita, Daiichi Sankyo's global head of R&D, said in a statement. "These landmark data will form the basis of our discussions with global health authorities to potentially bring [T-DXd] to patients with previously treated HER2-positive metastatic breast cancer as a more effective treatment option as soon as possible."