Trastuzumab deruxtecan shows ‘terrific activity’ in second line for breast cancer subset
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Trastuzumab deruxtecan reduced risk for disease progression or death compared with trastuzumab emtansine among patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and a taxane.
Results of the multicenter, open-label, randomized phase 3 DESTINY-Breast03 trial, published in The New England Journal of Medicine, also showed an association of trastuzumab deruxtecan (Enhertu; AstraZeneca, Daiichi Sankyo) with adjudicated interstitial lung disease and pneumonitis, although researchers reported numerically lower incidence than in previous trials.
“The activity we observed with trastuzumab deruxtecan in the late-line setting was so great that we wanted to explore it in earlier lines,” Javier Cortés, MD, PhD, director of International Breast Cancer Center in Barcelona, Spain, told Healio. “Trastuzumab deruxtecan should replace trastuzumab emtansine as the preferred option in the second-line setting.”
Background and methodology
Cortés and colleagues pursued the research to compare the efficacy and safety of trastuzumab deruxtecan, a HER2 antibody-drug conjugate, against trastuzumab emtansine — also known as ado-trastuzumab emtansine (Kadcyla, Genentech) and T-DM1 — the current standard of care for patients with HER2-positive metastatic breast cancer whose disease has progressed after treatment with a combination of anti-HER2 antibodies and a taxane.
The analysis included 524 patients randomly assigned to trastuzumab deruxtecan (n = 261; median age, 54.3 years; 58.2% Asian; 27.2% white) or trastuzumab emtansine (n = 263; median age, 54.2 years; 61.6% Asian; 27.4% white). PFS as determined by blinded independent central review served as the primary endpoint; secondary endpoints included OS, objective response and safety.
Key findings
At 12 months, 75.8% (95% CI, 69.8-80.7) of patients who received trastuzumab deruxtecan remained alive without disease progression vs. 34.1% (95% CI, 27.7 to 40.5) of those who received trastuzumab emtansine (HR for progression or death due to any cause = 0.28; 95% CI, 0.22-0.37). Moreover, 94.1% (95% CI, 90.3-96.4) of patients in the trastuzumab deruxtecan group remained alive at 12 months vs. 85.9% (95% CI, 80.9-89.7) of the trastuzumab emtansine group (HR for death = 0.55; 95% CI, 0.36-0.86; prespecified significance boundary not reached).
More than twice as many patients who received trastuzumab deruxtecan had an overall (complete or partial) response (79.7%; 95% CI, 74.3-84.4) vs. those who received trastuzumab emtansine (34.2%; 95% CI, 28.5-40.3), including a higher percentage with a complete response (16.1% vs. 8.7%).
Cortés told Healio he was surprised by what he deemed “the impressive HR of PFS and the great number of patients with a complete response.”
In toxicity analysis, researchers reported drug-related adverse events of any grade among 98.1% of the trastuzumab deruxtecan group (45.1% grade 3 or grade 4) and 86.6% of the trastuzumab emtansine group (39.8% grade 3 or grade 4). They noted 10.5% of patients in the trastuzumab deruxtecan group experienced adjudicated drug-related interstitial lung disease or pneumonitis vs. 1.9% in the trastuzumab emtansine group — none grade 4 or grade 5.
Implications
Cortés said trastuzumab deruxtecan exhibited “terrific activity” in patients with HER2-positive metastatic breast cancer previously treated with taxanes and trastuzumab.
“Although the interstitial lung disease and pneumonitis were less frequent and severe compared with trastuzumab emtansine, we should carefully follow our patients and treat this event as soon as possible if it happens,” Cortés said. “We also should not forget that the great majority of patients with HER2-positive metastatic breast cancer still die as a consequence of this disease, so more treatment options are clearly needed.”
He said further research should focus on strategies to decrease interstitial lung disease and pneumonitis, obtain more data in patients with brain metastases and explore trastuzumab deruxtecan’s activity in the early breast cancer setting.
For more information:
Javier Cortés, MD, PhD, can be reached at International Breast Cancer Center, Marquesa de Vilallonga 12, 08017, Barcelona, Spain; email: jacortes@vhio.net.
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