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Experts Consider Resistance, Combinations as Another HER2-Targeted Breast Cancer Drug Emerges

NEW YORK – In a Phase III trial of Byondis' (vic-)trastuzumab duocarmazine as a third-line treatment for advanced or metastatic HER2-positive breast cancer, the drug improved progression-free survival compared to physician's choice treatments.

While results from the so-called TULIP trial were positive, experts at the European Society for Medical Oncology Congress on Sunday reflected on the drug's activity in the context of other therapies for previously treated, metastatic HER2-positive breast cancer like trastuzumab deruxtecan (Daiichi Sankyo/AstraZeneca's Enhertu).

The market for HER2-positive metastatic breast cancer treatments is quite crowded. For previously treated patients, there are several targeted therapies already approved in the US, including trastuzumab deruxtecan, margetuximab-cmkb (MarcroGenics' Margenza), neratinib (Puma Biotechnology's Nerlynx), trastuzumab emtansine (Genentech's Kadcyla), and trastuzumab (Genentech's Herceptin).

Following the results from the TULIP trial, Byondis will submit a biologics license application for its drug to the US Food and Drug Administration before the end of 2021, potentially providing yet another option for metastatic HER2-positive breast cancer patients. In 2018, the FDA granted trastuzumab duocarmazine fast track designation.

The TULIP study enrolled 437 patients with advanced or metastatic HER2-positive breast cancer who had received two or more previous lines of treatment. Patients were randomized to either trastuzumab duocarmazine treatment or physician's choice treatment, which included combinations of chemotherapies and trastuzumab.

The median progression-free survival for patients in the trastuzumab duocarmazine arm was seven months compared to 4.9 months in the physician's choice arm. Median overall survival was numerically higher in the trastuzumab duocarmazine group versus the physician's choice group, 20.4 months and 16.3 months, respectively, but the difference wasn't statistically significant. Health-related quality of life parameters also weren't significantly different between the arms, noted trial investigator Cristina Saura Manich, head of the breast cancer unit at Vall d’Hebron University Hospital in Barcelona.

The response rates between the two treatment arms were also similar, 28 percent for the trastuzumab duocarmazine group and 30 percent for the physician's choice group. But 70 percent of patients treated with trastuzumab duocarmazine had a reduction in target lesion measurements compared to 58 percent in the other group.

Manich noted that the 30 percent response rate was expected for these heavily pretreated patients, but she had hoped to see a better response rate among trastuzumab duocarmazine-treated patients.

"In the clinic, the patients are doing well," she explained. "The main toxicity is eye-related conjunctivitis and keratitis, and that sometimes complicates treatment, with some discontinuations and some dose reductions, but most patients with those toxicities are recovered."

Separately at the ESMO Congress, researchers presented positive results from the Phase III DESTINY-Breast03 trial of AstraZeneca and Daiichi Sankyo's trastuzumab deruxtecan in previously treated, metastatic HER2-positive breast cancer. That study found that after a year of follow-up, median progression-free survival was not reached, and the progression-free survival rate at one year was 75.8 percent for patients treated with trastuzumab deruxtecan.

"The main issue here, and especially taking into account the results with trastuzumab deruxtecan [from DESTINY-Breast03], is that it's difficult to balance the benefit," Manich said. "Some patients may have resistance to these drugs, and we may continue working on new drugs for those patients."

Barbara Pistilli, a medical oncologist at Gustave Roussy Cancer Institute in France, said in reviewing the data that with so many options available in this setting, more research is needed to identify biomarkers for determining if patients will respond or become resistant to the different drugs. She urged more research into the various drugs' mechanisms of action, the interplay between different components of the drugs, and how they interact with the tumor and tumor microenvironment.

"One antibody-drug conjugate doesn't fit all, and we need more granular biomarkers, beyond the immunohistochemical [HER2] target expression," said Pistilli, who was not involved with the TULIP trial, at the meeting. "We need complex technologies, a multiomics approach to finally identify the biomarkers of response or resistance to the different [antibody-drug conjugates] that cannot be only the target expression but can be also the signaling pathways or even some non-tumor cells in the tumor microenvironment."

Pistilli also considered whether Byondis' trastuzumab duocarmazine could be an option for patients who are resistant to trastuzumab deruxtecan. The drugs have certain differences in their payload that could make Byondis' drug an option for patients who are progressing on trastuzumab deruxtecan, she suggested, adding that her hypothesis would need to be tested in a clinical trial.

For instance, if resistance to trastuzumab deruxtecan is related to the monogenic properties of the drug or the activity of its payload, which includes a topoisomerase-I inhibitor, then it is "more likely that trastuzumab duocarmazine is active after trastuzumab deruxtecan" because the first drug relies on a different payload with alkylating agents, she explained.

If researchers can determine what causes resistance to certain breast cancer treatments, that could also help guide oncologists' treatment decisions in this crowded treatment setting. Manich hopes researchers from the DESTINY Breast clinical trials program will continue to explore trastuzumab deruxtecan's mechanisms of action and resistance and help figure out how to sequence available therapy options for patients.

"In one year, the number of approved antibody-drug conjugates by FDA [in HER2-positive breast cancer] has doubled with an impressive improvement in the therapeutic index of [trastuzumab duocarmazine]," Pistilli said, "I would also like to think that, in the next 10 years, we will be able to define the best combination strategies of the antibody-drug conjugates. We can even imagine combining different [drugs] in concomitant or [with an] alternating schedule to overcome resistance and to expand their therapeutic index."