Trastuzumab deruxtecan ‘new gold standard’ in second line for breast cancer subset
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SAN ANTONIO — Fam-trastuzumab deruxtecan-nxki significantly extended OS compared with ado-trastuzumab emtansine among previously treated patients with HER2-positive unresectable or metastatic breast cancer, according to study results.
The randomized phase 3 DESTINY-Breast03 trial compared the two antibody-drug conjugates for patients whose disease progressed after trastuzumab (Herceptin, Genentech) and a taxane.
Updated findings presented at San Antonio Breast Cancer Symposium — and simultaneously published in The Lancet — showed a 36% lower risk for death with fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo) vs. ado-trastuzumab emtansine (Kadcyla, Genentech).
“We have shown for the first time that there is a clinically and statistically significant improvement in OS with trastuzumab deruxtecan compared with ado-trastuzumab emtansine in a randomized trial in HER2-positive breast cancer,” Sara A. Hurvitz, MD, FACP, medical director of Jonsson Comprehensive Cancer Center Clinical Research Unit and director of the breast cancer clinical trials program at UCLA, told Healio.
Background and methods
Until recently, ado-trastuzumab emtansine was the standard of care for patients with HER2-positive metastatic breast cancer whose disease progressed after treatment with anti-HER2 antibodies and a taxane.
The multicenter, open-label DESTINY-Breast03 trial compared the efficacy and safety of ado-trastuzumab emtansine with the HER2 antibody-drug conjugate trastuzumab deruxtecan for this patient population.
The analysis included 524 patients randomly assigned to trastuzumab deruxtecan (n = 261) or ado-trastuzumab emtansine (n = 263).
PFS served as the primary endpoint.
As Healio previously reported, results published in March showed trastuzumab deruxtecan conferred a 72% reduction in risk for progression (HR = 0.28; 95% CI, 0.21-0.37).
Results of a safety analysis presented in June showed similar rates between the trastuzumab deruxtecan and ado-trastuzumab deruxtecan groups of any-grade (99.6% vs 95.4%), grade 3 or higher (53.3% vs. 49.8%), or serious (21% vs. 19.2%) adverse events.
At SABCS, Hurvitz presented data on OS and objective response rates, as well as updated data related to PFS and safety. The data were based on median follow-up of 28.4 months with trastuzumab deruxtecan and 26.5 months with ado-trastuzumab emtansine.
Results
Researchers observed a 36% lower risk for death with trastuzumab deruxtecan (HR = 0.64; 95% CI, 0.47-0.87).
Median OS had not been reached in either treatment group; however, results showed higher OS rates with trastuzumab deruxtecan at 1 year (94.1% vs. 86%) and 2 years (77.4% vs. 69.9%).
“It is notable that 35% of patients in the [trastuzumab deruxtecan] group that stopped treatment received [ado-trastuzumab emtansine] after coming off study,” Hurvitz said during a presentation. “For those in the [ado-trastuzumab emtansine] group, 17% went on to receive [trastuzumab deruxtecan].
“There was no crossover in this study, but the rate of crossover after coming off study was lower from [ado-trastuzumab emtansine to trastuzumab deruxtecan], which was most likely due to the higher population of patients from Asian countries where this drug is not available as standard of care,” Hurvitz added. “We have not examined rates of crossover by region, but that is a very important factor that we will pay attention to as we continue to follow these data.”
Results also continued to favor trastuzumab deruxtecan with regard to PFS (median, 28.8 months vs. 6. 8 months; HR = 0.33; 95% CI, 0.26-0.43), objective response rate (78.5% vs. 35%) and complete response rates (21.1% vs. 9.5%).
Researchers reported grade 3 or higher treatment-associated adverse events among 56.4% of those assigned trastuzumab deruxtecan and 51.7% of those assigned ado-trastuzumab emtansine.
A higher percentage of patients assigned trastuzumab deruxtecan experienced interstitial lung disease/pneumonitis (15.2% vs. 3.1%); however, cases were mild or moderate, Hurvitz said.
“One of the most important toxicities that we are following with [trastuzumab deruxtecan] is interstitial lung disease, but there were no grade 4 or grade 5 [cases] in this clinical trial, even with longer follow-up,” Hurvitz said.
Researchers acknowledged study limitations, including the disproportionate enrollment of Asian patients and the fact that median OS had not reached at the time of analysis.
Implications
The updated results more firmly place trastuzumab deruxtecan as the treatment of choice in the second-line treatment setting and beyond for patients with metastatic HER2-positive breast cancer, Hurvitz told Healio.
“The first results of this trial were presented at the end of 2021, at which time we detected a significant improvement in median PFS. The data were so compelling that it placed [trastuzumab deruxtecan] as a standard of care in the second-line setting,” Hurvitz said. “At the time, because the survival data were not yet mature, [ado-trastuzumab emtansine] remained a viable option for patients after treatment with trastuzumab and a taxane.
“The current results solidify the position of [trastuzumab deruxtecan]. In my opinion, in regions where [this agent] is available, this should be the gold standard therapy after disease progression with trastuzumab and a taxane.”
References :
- Cortés J, et al. N Engl J Med. 2022;doi:10.1056/NEJMoa2115022.
- Hurvitz SA, et al. Abstract GS2-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2022.
- Hurvitz SA, et al. Lancet. 2022;doi:10.1016/S014-6736(22)02420-5.
- T-DXd yields longer overall survival than T-DM1 in patients with HER2-positive metastatic breast cancer (press release). Available at: . Published Dec. 7, 2022. Accessed Dec. 7, 2022.
Perspective
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The DESTINY-Breast03 trial results firmly place fam-trastuzumab deruxtecan-nxki as a standard second-line option for patients after progression on first-line treatment for HER2-positive metastatic breast cancer. Controversy may exist among patients with untreated brain metastases, for whom we have prospectively randomized data from the HER2CLIMB trial using triplet therapy with capecitabine, tucatinib (Tukysa, Seagen) and trastuzumab (Herceptin, Genentech), although often brain metastases are amenable to local therapy with radiation or surgery. Future directions are exploring the specific implications for patients with brain metastases — although early data with trastuzumab deruxtecan are promising — and sequencing questions, including how best to utilize tucatinib, and exploring this newer generation of HER2-directed therapies in the first-line metastatic disease setting and for those with residual disease after neoadjuvant therapy. There is also ongoing work to try to determine biomarkers or clinical predictors for who may be at risk for interstitial lung disease.
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Hurvitz SA, et al. Abstract GS2-02. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2022.
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