The National Medical Products Administration of China has approved the use of single-agent fam-trastuzumab deruxtecan-nxki in adult patients with unresectable or metastatic HER2-positive breast cancer who previously received 1 or more anti–HER2-based regimens.
The National Medical Products Administration of China has approved the use of single-agent fam-trastuzumab deruxtecan-nxki (Enhertu) in adult patients with unresectable or metastatic HER2-positive breast cancer who previously received 1 or more anti–HER2-based regimens.1
The regulatory decision is supported by findings from the phase 3 DESTINY-Breast03 trial (NCT03529110), in which trastuzumab deruxtecan (n = 261) significantly improved progression-free survival (PFS) over ado-trastuzumab emtansine (T-DM1; Kadcyla; n = 263) in those with HER2-positive unresectable and/or metastatic breast cancer who previously received trastuzumab (Herceptin) or a taxane.
In the investigative arm, the median PFS had not yet been reached (95% CI, 18.5-not evaluable) per blinded independent central review (BICR) vs 6.8 months (95% CI, 5.6-8.2) in the control arm, translating to a 72% relative reduction in the risk of disease progression or death (HR, 0.28; 95% CI, 0.22-0.37; P < .000001).
“This approval marks an important day for the breast cancer community in China as patients with HER2-positive metastatic breast cancer continue to need additional treatment options,” Binghe Xu, MD, professor and director of the Department of Medical Oncology of Cancer Hospital and Institute Cancer Center, Chinese Academy of Medical Sciences, stated in a press release. “Despite initial treatment, patients with HER2-positive metastatic breast cancer will often experience disease progression, demonstrating the importance of early systemic disease control and the potential for [trastuzumab deruxtecan] to help eligible patients.”
The global, head-to-head, randomized, open-label trial enrolled patients with HER2-positive, unresectable or metastatic breast cancer who had experienced disease progression during or after trastuzumab and a taxane in the context of advanced or metastatic disease, or who had progressed within 6 months following neoadjuvant or adjuvant treatment involving trastuzumab or a taxane.2 Those with clinically stable, previously treated brain metastases were eligible for inclusion.
Key exclusion criteria included having symptomatic brain metastases; prior treatment with a HER2-targeted antibody-drug conjugate (ADC) in the context of metastatic disease; a history of noninfectious interstitial lung disease (ILD) for which they were given glucocorticoids; or suspected ILD that could not be ruled out via imaging at the time of screening.
Participants were randomly assigned 1:1 to receive trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks intravenously (IV) or IV trastuzumab emtansine at 3.6 mg/kg every 3 weeks. The primary end point of the trial was PFS by BICR, and an important secondary end point is overall survival (OS). Other end points include overall response, investigator-assessed PFS, and safety.
A total of 524 patients were enrolled to the trial at 169 centers spanning 15 countries. Demographic and baseline disease characteristics were comparable between the treatment arms and were noted to be largely representative of the overall population of patients with HER2-positive breast cancer.
The median age in the trastuzumab deruxtecan arm was 54.3 years (range, 27.9-83.1) vs 54.2 years (range, 20.2-83.0) in the trastuzumab emtansine arm. Most patients across the arms were from Asia (57.1% vs 60.8%, respectively), were Asian (58.2% vs 61.6%), had HER2 3+ status (89.7% vs 88.2%), an ECOG performance status of 0 (59.0% vs 66.5%), had visceral disease (70.5% vs 70.3%), and received prior treatment for metastatic disease (92.0% vs 89.0%).
The median number of prior lines of treatment received in the investigative arm was 1 (range, 0-16) vs 2 lines (range, 0-14) in the control arm. Specifically, 49.8% vs 46.8% of patients, respectively, received 1 prior line; 21.5% vs 24.6% received 2 prior lines; 13.4% vs 13.3% received 3 prior lines; 5.7% vs 7.2% received 4 prior lines; and 8.8% vs 6.8% received 5 or more prior lines.
Previous treatment in the investigative and control arms included trastuzumab (99.6% vs 99.6%), pertuzumab (Perjeta; 62.1% vs 60.1%), a taxane (99.6% vs 99.6%), an anti-HER2 TKI (16.1% vs 13.7%), an anti-HER2 antibody or ADC (0.8% vs 1.1%), hormone therapy (41.8% vs 42.6%), or another systemic treatment (99.6% vs 99.6%).
Longer follow-up data were more recently published in The Lancet and had a median follow-up of 28.4 months (interquartile range [IQR], 22.1-32.9) in the trastuzumab deruxtecan arm and 26.5 months (IQR, 14.5-31.3) in the trastuzumab emtansine arm.3
The median PFS by BICR in the investigative vs the control arm was 28.8 months (95% CI, 22.4-37.9) and 6.8 months (95% CI, 5.6-8.2), respectively (HR, 0.33; 95% CI, 0.26-0.43; nominal P < .0001). The 12-month PFS rates were 75.2% (95% CI, 69.3%-80.2%) and 33.9% (95% CI, 27.7%-40.2%), respectively; the 24-month rates were 53.7% (95% CI, 46.8%-60.1%) and 26.4% (95% CI, 20.5%-32.6%), respectively.
The median OS had not yet been reached with trastuzumab deruxtecan (95% CI, 40.5-not estimable [NE]) or with trastuzumab emtansine (95% CI, 34.0-NE; HR, 0.64; 95% CI, 0.47-0.87; P = .0037). The 12-month OS rates in the investigative and control arms, respectively, were 94.1% (95% CI, 90.4%-96.4%) and 86.0% (95% CI, 81.1%-89.8%); the 24-month OS rates were 77.4% (95% CI, 71.7%-82.1%) and 69.9% (95% CI, 63.7%-75.2%).
Moreover, trastuzumab deruxtecan elicited an objective response rate (ORR) of 79% (95% CI, 73.1%-83.4%) by BICR compared with 35% (95% CI, 29.2%-41.1%) with trastuzumab emtansine. Of those who responded to trastuzumab deruxtecan, 21% achieved a complete response and 57% had a partial response. The median duration of response was 36.6 months (95% CI, 22.4-NE) with trastuzumab deruxtecan by BICR vs 23.8 months (95% CI, 12.6-34.7) with trastuzumab emtansine.
The toxicity profile of trastuzumab deruxtecan was examined in a total of 257 patients. No new safety signals were observed with the agent.1 The most common toxicities reported in at least 20% of patients on the investigative arm included nausea (75.9%), fatigue (49.4%), vomiting (49.0%), neutropenia (42.8%), alopecia (37.0%), constipation (34.2%), anemia (32.7%), increased transaminases (31.5%), musculoskeletal pain (31.1%), leukopenia (30.4%), decreased appetite (29.2%), diarrhea (29.2%), thrombocytopenia (25.7%), headache (21.8%), and abdominal pain (21.0%).
The most common serious adverse effects (AEs) to be experienced by 1% or more of patients included ILD (2.3%) and vomiting (1.9%).
Moreover, 10.5% of patients who received trastuzumab deruxtecan ended up discontinuing treatment due to AEs.
In May 2022, the FDA approved trastuzumab deruxtecan for use in patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti–HER2-based regimen in the metastatic setting or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of therapy completion.4 The decision was based on earlier data from DESTINY-Breast03, which served as the confirmatory trial for the prior December 2019 accelerated approval of the agent in adult patients with unresectable or metastatic HER2-positive breast cancer who previously received 2 or more anti–HER2-based regimens in the metastatic setting.
In July 2022, the European Commission approved trastuzumab deruxtecan for use as a monotherapy in adult patients with unresectable or metastatic HER2-positive breast cancer who received at least 1 prior anti–HER2-based regimen.5