Trastuzumab deruxtecan extends survival in HER2-low metastatic breast cancer
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CHICAGO — Trastuzumab deruxtecan significantly extended PFS and OS among patients with HER2-low metastatic breast cancer, regardless of hormone receptor status, compared with standard of care therapy.
Results of the phase 3 DESTINY-Breast04 trial, presented at ASCO Annual Meeting and published simultaneously in The New England Journal of Medicine, additionally showed fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo) exhibited a manageable safety profile.
Rationale and methods
“We currently define the HER2 status of breast cancers in a binary model where HER2 breast cancers driven by the oncogene are treatable with currently available HER2-targeted therapies. HER2-negative breast cancers are not,” Shanu Modi, MD, medical oncologist at Memorial Sloan Kettering Cancer Center, said during a press briefing.
“Within the HER2 population, there are tumors with low levels of tumor expression for which this HER2 receptor may still be targetable," she added. "However, our currently available HER2-targeted therapies have not been effective in patients within this subgroup. We currently have a significant unmet need for effective therapies for this patient population.”
Trastuzumab deruxtecan previously showed promising efficacy in HER2-low metastatic breast cancer in a phase 1 study, which set the stage for the randomized, open-label DESTINY-Breast04 trial, Modi added.
Modi and colleagues compared the safety and efficacy of trastuzumab deruxtecan with treatment of physician’s choice among 557 patients with HER2-low metastatic breast cancer who previously received between one and two prior lines of chemotherapy for metastatic disease.
Researchers randomly assigned patients 2:1 to 5.4 mg/kg trastuzumab deruxtecan (n = 373) or physician’s choice of chemotherapy (n = 184), including capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel.
PFS by blinded independent central review among those with hormone receptor-positive disease served as the primary endpoint. PFS by blinded independent central review among all randomly assigned patients, OS among those with hormone receptor-positive disease and OS among all randomly assigned patients served as secondary outcomes. Other endpoints included objective response rate, duration of response, safety and an exploratory analysis of patients with hormone receptor-negative metastatic breast cancer.
Median follow-up was 18.4 months.
Key findings
Median duration of treatment was 8.2 months with trastuzumab deruxtecan and 3.5 months with physician’s choice treatment.
Results showed median PFS of 9.9 months (95% CI, 9-11.3) among patients assigned trastuzumab deruxtecan compared with 5.1 months (95% CI, 4.2-6.8) among those assigned physician’s treatment choice (HR = 0.5; 95% CI, 0.4-0.63).
Researchers also reported longer median OS with trastuzumab deruxtecan (23.4 months; 95% CI, 20-24.8) compared with physician’s choice (16.8 months; 95% CI, 14.5-20) for an HR of 0.64 (95% CI, 0.49-0.84).
In terms of safety, researchers observed grade 3 or higher treatment-emergent adverse events among 52.6% of patients assigned trastuzumab deruxtecan vs. 67.4% of those assigned physician’s treatment choice. Specifically, 12% of patients assigned trastuzumab deruxtecan experienced lung toxicity, including a 0.8% incidence of grade 5 adverse events and three reported deaths.
Of note, 45 patients assigned trastuzumab deruxtecan had independently adjudicated treatment-associated interstitial lung disease/pneumonitis compared with one patient assigned physician’s treatment choice.
Looking ahead
“Trastuzumab deruxtecan is the first HER2-targeted therapy to demonstrate statistically significant and clinically meaningful improvement in PFS and OS in this patient population, with benefits of this treatment observed across subgroups,” Modi said. “The safety and toxicity profile of this treatment was consistent with what we have seen in other trials. Overall, these results establish that HER2-low metastatic breast cancer is a targetable population of breast cancer with trastuzumab deruxtecan as a new standard of care in this setting.”
Perspective
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Tatini Datta, MD
Overall, these clinical trial results showed promising activity for HER2-directed therapy in metastatic breast cancer with low HER2 expression in terms of both PFS and OS. This opens another potential avenue of treatment options in this pretreated population that has traditionally not been thought to derive benefit from HER2-directed therapy.
More study is needed to determine how to optimally sequence HER2-directed therapy with other lines of treatment in the overall therapeutic paradigm for metastatic HER2-low breast cancer.
Perspective
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Jane Lowe Meisel, MD
The results of this trial are practice changing. As breast oncologists, we have seen trastuzumab deruxtecan rapidly incorporated as early as the second line in patients traditionally defined as HER2-positive. Everyone who has used this treatment in my clinic undoubtedly has seen some patients even with significant burdens of disease have their cancer melt away with this agent. What this trial does is extend the benefit of this agent to an entire new group of patients who traditionally are quite difficult to treat. These patients can now potentially benefit from this drug, which improves both PFS and OS in clinically and statistically meaningful ways.
This will offer a wonderful new treatment option for patients and also will fundamentally change the way we think about HER2 status and how we classify this for our metastatic patients. This is a huge win for our patients and for the oncology community.
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Modi S, et al. Abstract LBA3. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
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