medwireNews: Trastuzumab deruxtecan (T-DXd) significantly improves the survival outcomes of previously treated patients with HER2-low metastatic breast cancer relative to standard chemotherapy, show DESTINY-Breast04 data presented at the 2022 ASCO Annual Meeting in Chicago, Illinois, USA.
“By effectively creating a new category of breast cancer, HER2-low, this trial will redefine how we classify breast cancer and will significantly expand the population of patients who can benefit from HER2-targeted therapy,” said ASCO expert Jane Lowe Meisel (Winship Cancer Institute of Emory University, Atlanta, Georgia, USA) in a comment to the press.
Outlining the rationale for the trial, study investigator Shanu Modi (Memorial Sloan Kettering Cancer Center, New York, USA) explained that HER2-low metastatic breast cancer – defined as a HER2 immunohistochemistry (IHC) score of 1+ or IHC 2+ and a negative in situ hybridization result – is treated as HER2-negative disease, “where therapy is guided by hormone receptor status.”
She continued: “Ultimately, all patients with HER2-low metastatic breast cancer, both hormone [receptor]-positive and negative, have limited options in the late-line setting and are typically treated with palliative single-agent chemotherapy,” which “offers only modest benefits.”
The researchers therefore evaluated T-DXd – a next-generation, HER2-directed antibody–drug conjugate with a unique mechanism of action, including the bystander effect – in this patient population, recruiting 557 patients who had received one or two lines of chemotherapy prior to inclusion in the phase 3 trial. The majority were hormone receptor-positive (89.6%) and had received three or more lines of systemic therapy in the metastatic setting (62.1%).
The primary endpoint was independently assessed progression-free survival (PFS) in the hormone receptor-positive population, and this was significantly longer for the 331 participants who were randomly assigned to receive T-DXd 5.4 mg/kg every 3 weeks than for their 163 counterparts who instead received physician’s choice of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel.
The median PFS durations were 10.1 and 5.4 months, respectively, equating to a hazard ratio (HR) for progression or death of 0.51 in favor of T-DXd.
PFS was similarly significantly prolonged with T-DXd in the total trial population, at a median of 9.9 months compared with 5.1 months for chemotherapy, and an HR of 0.50.
T-DXd treatment also significantly improved overall survival (OS) relative to chemotherapy, both in the hormone receptor-positive and total populations, at medians of 23.9 versus 17.5 months and 23.4 versus 16.8 months, respectively. The HR for death was an identical 0.64 in both populations.
Modi also presented an exploratory analysis of PFS and OS in the hormone receptor-negative population, the findings of which were “consistent with the primary study results,” with respective HRs of 0.46 and 0.48 that both significantly favored T-DXd over chemotherapy.
Turning to the safety data, she said that “in general, there were no new safety signals for T-DXd in this HER2-low population and the overall safety profile was consistent with other studies.”
Moreover, “the profiles for the two arms were generally similar,” noted the presenter, although she pointed out that the incidence of drug-related nausea was “disproportionately” higher in the T-DXd group (73 vs 24%), but it was “mostly grades 1 and 2, and clinical experience suggests this can be managed with the use of prophylactic antiemetics.”
On the other hand, drug-related neutropenia occurred much more frequently in the chemotherapy than T-DXd arm, with events of at least grade 3 observed in 41% versus 14%.
The investigator highlighted that “lung toxicity is an important toxicity of T-DXd and requires awareness, vigilance, and early intervention.”
She reported that interstitial lung disease or pneumonitis of any grade occurred in 45 (12.1%) patients receiving T-DXd, compared with just one patient (0.6%) given chemotherapy. In the T-DXd group, 3.5% of the events were of grade 1, 6.5% were grade 2, 1.3% were grade 3, and the remaining 0.8% were grade 5.
“T-DXd is the first HER2-targeted therapy to demonstrate statistically significant and clinically meaningful improvement in [PFS] and [OS] compared to standard chemotherapy in patients with HER2-low metastatic breast cancer,” summarized Modi.
And she concluded: “These results establish HER2-low metastatic breast cancer as a targetable population of breast cancer, with [T-DXd] as a new standard of care in this setting.
“We anticipate these results to be practice changing.”
Patricia LoRusso (Yale University, New Haven, Connecticut, USA), who discussed the presentation, believes that the standard of care for patients with HER2-low breast cancer should “absolutely” change in view of these data.
But she stressed that “we need more sensitive tools to better define the most appropriate patient population,” and “we need to identify additional populations with different tumor types to determine the true and global effect and benefit of T-DXd for our oncology community.”
The results of the DESTINY-Breast04 trial are published simultaneously in The New England Journal of Medicine.
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2022 ASCO Annual Meeting; Chicago, Illinois, USA: 3–7 June
N Engl J Med 2022; doi:10.1056/NEJMoa2203690