NICE Recommends Trastuzumab Deruxtecan for Previously Treated HER2+ Metastatic Breast Cancer

The United Kingdom’s National Institute for Health and Care Excellence (NICE) has endorsed fam-trastuzumab deruxtecan-nxki (Enhertu) for use within the Cancer Drugs Fund (CDF) for adult patients with HER2-positive, unresectable or metastatic breast cancer following at least 1 anti-HER2 treatment.¹

NICE’s recommendation is based on data from an interim analysis of the phase 3 DESTINY-Breast03 trial (NCT03529110) evaluating trastuzumab deruxtecan vs ado-trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive unresectable and/or metastatic breast cancer previously treated with trastuzumab (Herceptin) and a taxane. The 12-month progression-free survival (PFS) rate was 75.28% (95% CI, 69.8%-80.7%) with trastuzumab deruxtecan compared with 34.1% (95% CI, 27.7%-40.5%) with T-DM1, according to blinded independent central review (HR for disease progression or death, 0.28; 95% CI, 0.22-0.37; P < .001).

“HER2-positive disease impacts 1 in 5 [patients] with breast cancer, and previously treated patients typically experience disease progression in less than a year with historical standard-of-care treatment,” Peter Schmid, MD, PhD, professor of cancer medicine and director at Barts Breast Cancer Centre, said in a news release. “The DESTINY-Breast03 trial showed that trastuzumab deruxtecan improved survival compared to trastuzumab emtansine, further highlighting its potential to redefine the treatment of HER2 positive metastatic breast cancer.”

In November 2022, Japan’s Ministry of Health, Labor, and Welfare (MHLW) approved trastuzumab deruxtecan for adults with HER2-positive unresectable or recurrent breast cancer after prior chemotherapy that included trastuzumab (Herceptin) and a taxane based on findings from DESTINY-Breast03.²

In findings presented at the 2022 San Antonio Breast Cancer Symposium (SABCS), the median overall survival (OS) was not reached (NR; 95% CI, 40.5–not evaluable [NE]) in the trastuzumab deruxtecan arm (n = 261) compared with NR (95% CI, 34.0-NE) in the T-DM1 arm (n = 263; HR, 0.64; 95% CI, 0.47-0.87; P = .0037) at a median follow-up of 28.4 months (range, 0.0-46.9). The 1-year and 2-year OS rates in the trastuzumab deruxtecan arm were 94.1% (95% CI, 90.4%-96.4%) and 77.4% (95% CI, 71.7%-82.1%), respectively. Comparatively, in the T-DM1 arm, the 1-year and 2-year OS rates were 86.0% (95% CI, 81.1%-89.8%) and 69.9% (95% CI, 63.7%-75.2%), respectively.³

Data from the phase 3 CLEOPATRA trial (NCT00567190) established trastuzumab (Herceptin) plus taxane with pertuzumab (Perjeta) as the standard of care for HER2-positive metastatic breast cancer in first line. Findings from the phase 3 EMILIA trial (NCT00829166) established T-DM1 as the standard of care following trastuzumab and a taxane for metastatic, HER2-positive breast cancer in the second-line setting and beyond. However, since the DESTINY-Breast03 trial showcased the efficacy of trastuzumab deruxtecan in this setting, this agent is now considered the preferred second-line treatment with T-DM1 as an alternative option.

“Trastuzumab deruxtecan demonstrated a clinically meaningful and statistically significant improvement in OS versus TDM-1 as well as [a] continued PFS benefit,” Sara A. Hurvitz, MD, a medical oncologist at UCLA, said in a presentation of the data at SABCS. “[Trastuzumab deruxtecan] reduced the risk of death by 36%, [the] median PFS was nearly 4 times greater with [trastuzumab deruxtecan] than with T-DM1, and 78.5% of patients experienced a confirmed objective response.”

DESTINY-Breast03 was an open-label, multicenter study that enrolled patients with unresectable or metastatic HER2-positive breast cancer. Patients must have previously undergone treatment with trastuzumab and a taxane in the metastatic or neoadjuvant setting and experienced a recurrence within 6 months of therapy. Eligible patients were stratified based on hormone receptor status, prior treatment with pertuzumab, and history of visceral disease.

Enrolled patients were randomly assigned 1:1 to trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks or T-DM1 at 3.6 mg/kg every 3 weeks. The primary end point was PFS. OS was the key secondary end point, with overall response rate (ORR), duration of response (DOR), and safety representing other secondary end points.

Nearly all patients in both the trastuzumab deruxtecan (99.6%) and T-DM1 arms (95.4%) experienced any grade treatment-emergent adverse effects (TEAEs). Serious TEAEs (25.3% vs 22.2%), TEAEs associated with drug discontinuation (21.4% vs 9.2%), and TEAEs associated with drug interruption (52.9% vs 29.1%) were all present in both arms. Six patients in both arms experienced TEAEs that were associated with death, although none of these were drug related.

Rates of grade 3 or greater TEAEs were similar between the trastuzumab deruxtecan and T-DM1 arms (56.4% vs 51.7%, respectively). Study authors noted that the rates of interstitial lung disease (ILD) and pneumonitis were consistent with other trials assessing trastuzumab deruxtecan in metastatic breast cancer. However, the rate of ILD/pneumonitis had increased from 10.5% to 15.2% since the PFS interim analysis. The rate of grade 3 events stayed consistent (0.8%), and there were no grade 4/5 drug-related ILD/pneumonitis events.

References

1. NICE extends use of Enhertu (trastuzumab deruxtecan) to earlier in the treatment of HER2 positive metastatic breast cancer. News release. Daiichi Sankyo and AstraZeneca. December 20, 2022. Accessed December 20, 2022.
2. Enhertu® approved in Japan for patients with previously treated HER2 positive metastatic breast cancer. News release. Daiichi Sankyo. November 24, 2022. Accessed December 20, 2022. http://bit.ly/3VAtBjW
3. Hurvitz SA, Hegg R, Chung WP, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: Updated survival results of the randomized, phase 3 study DESTINY-Breast03. Presented at: 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX. Abstract GS2-02.