December 15, 2020 - The European Medicines Agency’s Committee for Medicinal Products for Human Use has adopted a positive opinion for fam-trastuzumab deruxtecan-nxki for use as a single agent in adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received 2 or more anti-HER2–based regimens.
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a positive opinion for fam-trastuzumab deruxtecan-nxki (Enhertu) for use as a single agent in adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received 2 or more anti-HER2–based regimens.1
The CHMP recommendation is based on data from the phase 2 DESTINY-Breast01 trial (NCT03248492) and data from a phase 1 trial (NCT02564900) examining the antibody-drug conjugate (ADC). Collectively, these results showed that trastuzumab deruxtecan elicited clinically meaningful and durable activity with an acceptable safety profile in this patient population.
“We are encouraged by the CHMP positive opinion given the significant unmet need for patients with HER2-positive metastatic breast cancer,” Giles Gallant, BPharm, PhD, FOPQ, senior vice president and global head of Oncology Development and Oncology R&D at Daiichi Sanyko, said in a press release. “Trastuzumab is already available for patients with HER2-positive metastatic breast cancer in the United States and Japan, and we are now one step closer to bringing this important new medicine to patients in Europe.”
A total of 184 heavily pretreated patients with HER2-positive breast cancer were enrolled to the open-label, international, multicenter, phase 2 trial. These patients had previously received trastuzumab emtansine (T-DM1; Kadcyla) and other HER2-directed treatments.2 The trial was comprised of 2 parts. In the first portion, investigators evaluated the pharmacokinetics of the agent in 65 patients to identify the recommended phase 2 dose (RP2D; n = 54). In the second portion of the research, the ADC was evaluated at a dose of 5.4 mg/kg in a total of 134 patients.
The primary end point of the trial was ORR per independent central review (ICR), while secondary end points comprised disease control rate, duration of response (DOR), and progression-free survival (PFS).
To be eligible for enrollment, patients had to be at least 18 years of age, have unresectable and/or metastatic breast cancer with HER2 positivity, and have received previous treatment with T-DM1. Although those with a history of significant interstitial lung disease (ILD) were excluded from the trial, patients with stable, treated brain metastases were permitted.
Earlier data from DESTINY-Breast01 presented during the 2019 San Antonio Breast Cancer Symposium(SABCS) showed that the ADC elicited a confirmed objective response rate (ORR) of 60.3% per ICR (95% CI, 52.9-67.4); this comprised a complete response (CR) rate of 4.3% and a partial response (PR) rate of 56%.3 Moreover, 36.4% (n = 67) achieved stable disease with the ADC, while 1.6% (n = 3) experienced disease progression. Two patients were not determined to be evaluable.
Notably, these responses were found to be consistent across the subgroups analyzed in the trial, including those who had previously received pertuzumab (Perjeta; 64%) and those who had at least 3 prior regimens (59%).
At the time of the presentation, 25 patients (13.6%) had experienced an ILD associated with the ADC by an independent adjudication committee. These data led to the December 2019 FDA approval of trastuzumab deruxtecan in adult patients with unresectable or metastatic HER2-positive breast cancer who have received at least 2 prior anti–HER2-based regimens in the metastatic setting.
Updated data from DESTINY-Breast01 presented during the 2020 SABCS showed that the ADC continued to have impressive signals of efficacy, including prolonged, durable responses and overall survival (OS) rates, with an acceptable safety profile in this patient population.4
At an additional 9.4 months of follow-up, the median DOR with trastuzumab deruxtecan was 20.8 months; the estimated 12-month OS rate was 85% (95%, CI-79%-90%), while the estimated OS rate at 18 months was 74% (95% CI, 67%-80%). The median PFS was 19.4 months, while the preliminary median OS was 24.6 months, although the data are still immature.
Moreover, the confirmed ORR with the ADC was 61.4% (95% CI, 54.0%-68.5%), while the CR rate was 6.5% and the PR rate was 54.9%; 35.9% of patients achieved stable disease, while 1.6% of patients experienced disease progression.
The median OS was estimated at 35% maturity, with 119 patients censored and only 17 patients at risk at 2 years. Additional follow-up is required for more mature survival data.
The safety profile of the ADC proved to be consistent with previous reports with the agent. Specifically, 18.5% of patients discontinued treatment because of toxicities, and 17.9% of these toxicities were determined to be associated with trastuzumab deruxtecan. Treatment-emergent toxicities that were at least grade 3 in severity were reported in 61.4% of patients and 52.7% of these effects were associated with study treatment.
Treatment-emergent adverse effects (TEAEs) linked with discontinuations occurred in 17.9% of patients; TEAEs linked with dose reductions and dose interruptions were reported in 21.2% and 32.6%, of patients, respectively. Ten patients (5.4%) experienced TEAEs that led to death and 3 of these were determined to be related to the ADC.
Three additional cases of ILD were reported at the meeting, as determined by an independent adjudication committee. Most first ILD events were experienced during the first year of treatment with the ADC.