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Antibody-Drug Conjugate Picks Up Another Win in HR+/HER2-low Breast Cancer

— Trastuzumab deruxtecan extended its superiority versus chemotherapy into HER2-ultralow

MedpageToday

CHICAGO -- The antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd, Enhertu) significantly improved progression-free survival (PFS) versus chemotherapy in previously treated metastatic hormone receptor-positive (HR+)/HER2-low/ultralow breast cancer, a randomized trial showed.

Median time to progression improved from 8 months with chemotherapy to 13 months with T-DXd. Objective response rate (ORR) and time on treatment also increased with the ADC.

The trial also provided evidence supporting a new breast cancer subgroup, HER2-ultralow, reported Giuseppe Curigliano, MD, PhD, of the University of Milan and European Institute of Oncology in Italy, at the American Society of Clinical Oncology (ASCO) meeting.

"What's new in this study is trastuzumab deruxtecan is approved all over the world for HER2-low disease. Here we have a new category that is HER2-ultralow [membrane staining ≤10% of tumor cells] in patients never receiving chemotherapy," Curigliano said during an ASCO press briefing. "In terms of safety, the most common side effects were gastrointestinal toxicity, nausea, and vomiting. Unfortunately, three patients died of interstitial lung disease [ILD], a side effect of using trastuzumab deruxtecan, three out of 850."

"What's next? We are going to better evaluate the minimum [treatment] threshold to derive benefit from trastuzumab deruxtecan," he added. "Of course, the most important thing is work needed to identify this new class of patients. We need to have that reported in the pathology report at the level of staining for it."

The results of the DESTINY-Breast06 trial represent an exciting development in breast cancer suggesting that T-DXd can be moved up earlier in the course of treatment and offered to a larger group of patients (HER2-ultralow), said ASCO expert Erica Mayer, MD, MPH, of Dana-Farber Cancer institute in Boston.

"However, as was outlined, there are specific toxicities associated with this agent that may be more significant compared to traditional chemotherapy in this setting," said Mayer. "This is a change that we will bring back to our clinics and discuss with patients. This will not be for every patient, but this is definitely exciting news for us that will have an impact on our practice."

Adding to Curigliano's comments, ASCO chief medical officer Julie Gralow, MD, said "I think we will need a lot of discussion with our pathology colleagues on HER2-ultralow in particular, the reliability of seeing a little bit of faint membrane staining versus not."

Adjusting to the new category of HER2-ultralow will take time and effort, as oncologists and pathologists have a history of determining HER2 status: 3+, 2+, 1+, and 0.

"HER2 low is 2+ that's FISH [fluorescence in situ hybridization] negative and the 1+," Gralow continued. "That is distinguished from 0, which we've been doing for a long time. I think the trick is going to be distinguishing within that HER2-0. Now we're going to have two classifications, the ultralow that is less than 10% of cells that have a little bit of staining and then what we're calling HER2-0."

"I don't know if our eyes are good enough to see that difference," she continued. "I don't know if our stains are good enough to see that difference. That's what we're going to have to think about with our pathology colleagues because we might not have a good discriminator when it's that low."

The landmark DESTINY-Breast04 randomized trial established HER2-low (1+ or 2+/FISH negative) as a recognized breast cancer subtype and T-DXd as the treatment of choice for chemotherapy-exposed metastatic HR+/HER2-low breast cancer. Oncologists and pathologists have recognized that a proportion of breast cancers have HER2 expression below the threshold of HER2 low but higher than HER2-0 or HER2-negative ().

Investigators in the randomized trial hypothesized that T-DXd would improve PFS versus chemotherapy in endocrine-resistant/refractory metastatic HR+/HER2-low or ultralow breast cancer not previously treated with chemotherapy. The primary endpoint was PFS by blinded independent central review in the HER2-low subgroup. Key secondary endpoints were PFS by intention-to-treat analysis in the HER2-low and ultralow subgroups and overall survival (OS).

Patients were randomized to T-DXd or investigator's choice of chemotherapy (capecitabine, nab-paclitaxel, or paclitaxel). Data analysis included 866 patients, including 152 with HER2-ultralow breast cancer.

The primary analysis showed that T-DXd reduced the PFS hazard ratio by 38% in the HER2-low subgroup (95% CI 0.51-0.74, P<0.0001). Results were similar in the overall population (median PFS 13.2 vs 8.1 months, HR 0.63, 95% CI 0.53-0.75, P<0.0001) and in the HER2-ultralow subgroup (median PFS 13.2 vs 8.3 months, HR 0.78, 95% CI 0.50-1.21).

At a first interim analysis after a median follow-up of 18.6 months, OS favored T-DXd in the HER2-low subgroup but the data remained immature (HR 0.83, 95% CI 0.66-1.05).

Grade ≥3 adverse events occurred in 40.6% of the T-DXd cohort versus 31.4% of the chemotherapy arm. Adjudicated rates of ILD/pneumonitis were 11.3% with T-DXd (0.7% grade 3/4, 0.7% grade 5), whereas a single case of grade 2 severity occurred in the chemotherapy arm.

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined 鶹ý in 2007.

Disclosures

The study was supported by AstraZeneca.

Curigliano disclosed relationships with Ellipses Pharma, AstraZeneca, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celcuity, Daiichi-Sankyo, Exact Sciences, Foundation Medicine, Gilead Sciences, GlaxoSmithKline, Guardant Health, Hengrui Therapeutics, Lilly, Menarini, Merck, Novartis, Roche/Genentech, Seagen, Samsung, Veracyte, and Pfizer.

Mayer disclosed relationships with Novartis, Puma Biotechnology, Eli Lilly, Gilead Sciences, and AstraZeneca.

Gralow reported no relevant financial disclosures.

Primary Source

American Society of Clinical Oncology

Curigliano G, et al "Trastuzumab deruxtecan (T-DXd) vs physician's choice of chemotherapy (TPC) in patients with hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-low or HER2-ultralow metastatic breast cancer with prior endocrine therapy: Primary results from DESTINY-Breast06" ASCO 2024. Abstract LBA1000.