Trastuzumab deruxtecan outperforms chemotherapy-based regimens for breast cancer subset
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SAN ANTONIO — Fam-trastuzumab deruxtecan-nxki improved outcomes compared with capecitabine-based regimens as third-line treatment for certain patients with HER2-positive metastatic breast cancer, according to study findings.
Results of the phase 3 DESTINY-Breast02 trial — presented at San Antonio Breast Cancer Symposium — showed longer survival and higher response rates with fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo) among patients previously treated with ado-trastuzumab emtansine (Kadcyla, Genentech).
“In addition to confirming the favorable benefit-to-risk profile of [fam-trastuzumab deruxtecan-nxki] in this population, this research was also important to evaluate the efficacy of one antibody-drug conjugate ... in patients whose cancer has already progressed on another antibody-drug conjugate,” Ian Krop, MD, PhD, associate cancer center director for clinical research and chief clinical research officer at Yale Cancer Center, said in a press release. “This is the first randomized trial to ask this important question.”
Background and methods
Fam-trastuzumab deruxtecan-nxki — often simply called trastuzumab deruxtecan — is a novel antibody-drug conjugate with three components: a humanized anti-HER2 immunoglobulin G1 monoclonal antibody with the same amino acid sequence as trastuzumab (Herceptin, Genentech); a topoisomerase 1 inhibitor payload; and a tetrapeptide-based cleavable linker.
The agent is approved in the United States for treatment of HER2-positive or HER2-low metastatic breast cancer.
Ado-trastuzumab emtansine is an antibody-drug conjugate composed of two anticancer agents using a stable linker — the HER2-targeting agent trastuzumab and the chemotherapy agent DM1. It is engineered to deliver chemotherapy directly to HER2-positive cancer cells, thereby limiting damage to healthy tissue.
Results of the single-arm, phase 2 DESTINY-Breast01 trial showed third-line trastuzumab deruxtecan had clinical activity for patients with HER2-positive metastatic breast cancer previously treated with ado-trastuzumab emtansine.
Based on these findings, the FDA granted accelerated approval to trastuzumab deruxtecan as third-line treatment for patients with metastatic or unresectable breast cancer who previously received two or more HER2-targeted therapies.
Researchers designed DESTINY-Breast02 as a confirmatory study to assess trastuzumab deruxtecan vs. physician’s choice of treatment for 608 patients whose metastatic breast cancer progressed during or after ado-trastuzumab emtansine treatment.
The majority of patients in the trastuzumab deruxtecan and physician’s choice groups had received at least two prior lines of therapy in the metastatic setting (95% vs. 94.1%).
Investigators randomly assigned patients 2:1 to trastuzumab deruxtecan dosed a 5.4 mg/kg every 3 weeks or physician’s choice, which included capecitabine plus either trastuzumab or lapatinib (Tykerb, Novartis).
PFS by blinded independent central review served as the primary endpoint. Secondary endpoints included OS, objective response rate, duration of response, investigator-assessed PFS and safety.
Results
Results showed improved median PFS (17.8 months vs. 6.9 months; HR = 0.35; 95% CI, 0.28-0.45) and a higher rate of 2-year PFS (42.2% vs. 13.9%) among trastuzumab deruxtecan-treated patients.
Researchers also reported longer median OS (39.2 months vs. 26.5 months; HR = 0.65; 95% CI, 0.5-0.86) and a higher 2-year OS rate (65.9% vs. 54.3%) with trastuzumab deruxtecan.
A higher percentage of patients assigned trastuzumab deruxtecan achieved confirmed objective response (69.7% vs. 29.2%; P < .0001).
Adverse events among patients assigned trastuzumab deruxtecan appeared consistent with prior reports, Krop said.
Researchers reported comparable rates of any-grade drug-related adverse events (97.5% vs. 92.3%), grade 3 or higher drug-related adverse events (41.3% vs. 30.8%) and serious drug-related adverse events (11.4% vs. 7.7%) between the trastuzumab deruxtecan and physician’s choice groups.
A higher percentage of patients in the trastuzumab deruxtecan group discontinued therapy due to drug-related treatment-emergent adverse events (14.4% vs. 5.1%).
Trastuzumab deruxtecan includes a boxed warning for interstitial lung disease and embryo-fetal toxicity.
In DESTINY-Breast02, 10.4% of patients assigned the therapy developed interstitial lung disease; most were grade 1 or grade 2, but investigators reported two grade 5 cases (0.5%).
“The results of DESTINY-Breast02 confirm the findings of DESTINY-Breast01, demonstrating high levels of efficacy of [trastuzumab deruxtecan] in patients with HER2-positive metastatic breast cancer previously treated with [ado-trastuzumab emtansine],” Krop said. “Furthermore, they extend these findings, demonstrating that [trastuzumab deruxtecan] is not only highly active, but also superior to conventional chemotherapy-based regimens in this patient population.”
Researchers acknowledged study limitations, including the exclusion of patients with progressive metastases to the central nervous system from this trial. In addition, the control arm was limited to capecitabine-based therapies, so investigators could not make a direct comparison between trastuzumab deruxtecan and regimens that contain other chemotherapeutic agents.
Next steps and implications
Investigators may perform follow-up analyses to evaluate patient-reported outcomes. Future studies could examine efficacy and safety of the agent among patients with central nervous system metastases, Krop said.
In addition, studies are underway to assess trastuzumab deruxtecan as first-line treatment for patients with HER2-positive metastatic breast cancer, as well as those with early-stage disease.
Earlier this year, the FDA expanded the approval of trastuzumab deruxtecan to include second-line treatment of patients with HER2-positive metastatic breast cancer who received a prior anti-HER2-based regimen.
During a press conference, Krop addressed how the DESTINY-Breast02 findings from the third-line setting align with current widespread use of the agent as second-line therapy.
“In general, we in oncology tend to use our best therapies earlier. We don’t hold them back,” Krop said. “The main reason for that is because, unfortunately, there is significant attrition of patients from one line to another. ...
“Given the unprecedented efficacy of [trastuzumab deruxtecan] in this trial and in previous trials, it really would be a shame for a patient not to receive the drug because you’re waiting to use it in a later line of therapy that they may not get to,” Krop added. “This study, while confirmatory, does not change our practice. [Trastuzumab deruxtecan] should still be used in the second-line setting in virtually all patients.”
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Krop I, et al. Abstract GS2-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 6-10, 2022; San Antonio.
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