EMA Validates Type II Variation Application for Trastuzumab Deruxtecan in HER2+ Metastatic Breast Cancer

Gilles Gallant, BPharm, PhD, FOPQ

The European Medicines Agency (EMA) has validated the Type II Variation application for fam-trastuzumab deruxtecan-nxki (Enhertu) as a treatment for adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received 1 or more anti–HER2-based regimens.¹

The application was based on findings from the phase 3 DESTINY-Breast 03 trial (NCT03529110), which showed that the antibody-drug conjugate resulted in a clinically meaningful and statistically significant improvement in progression-free survival (PFS) over standard-of-care trastuzumab emtansine (T-DM1; Kadcyla) in patients with HER2-positive metastatic breast cancer.

Results presented during the 2021 ESMO Congress showed that the median PFS with trastuzumab deruxtecan had not yet been reached (95% CI, 18.5–not estimable [NE]) compared with 6.8 months (95% CI, 5.6-8.2) with T-DM1 (HR, 0.28; 95% CI, 0.22-0.37; P = 7.8 x 10^-22), translating to a 72% reduction in the risk of disease progression or death.² Moreover, the 12-month PFS rate in the 261 patients who received trastuzumab deruxtecan was 75.8% (95% CI, 69.8%-80.7%) vs 34.1% (95% CI, 27.7%-40.5%) in the 263 patients who received T-DM1.

“We are excited to have submitted a second application this year seeking approval for trastuzumab deruxtecan for a potential third indication in Europe,” Gilles Gallant, BPharm, PhD, FOPQ, senior vice president and global head of Oncology Development, Oncology R&D, at Daiichi Sankyo, stated in a press release. “With this specific application, we look forward to working closely with the EMA to support the review of trastuzumab deruxtecan to be used in an earlier setting for patients with HER2-positive metastatic breast cancer.”

A total of 524 patients with HER2-positive metastatic breast cancer who were previously treated with trastuzumab (Herceptin) and a taxane were randomized to receive either trastuzumab deruxtecan at a dose of 5.4 mg/kg every 3 weeks or T-DM1 at a dose of 3.6 mg/kg every 3 weeks. Patients were clinically stable, treated brain metastases were permitted to enroll.

The primary end point of the trial was PFS by blinded independent central review (BICR). An important secondary end point was overall survival (OS). Other secondary end points comprised BICR-assessed objective response rate (ORR), investigator-assessed PFS, and safety.

Participants were stratified by hormone receptor status, previous treatment with pertuzumab (Perjeta), and history of visceral disease. The median follow-up was 16.2 months in the trastuzumab deruxtecan arm and 15.3 months in the T-DM1 arm.

Baseline characteristics were noted to be well balanced between the investigative and control arms; 50.2% vs 51.0%, respectively, had positive hormone receptor status, 23.8% vs 19.8% had brain metastases, and 70.5% vs 70.3% had visceral disease. The median age of participants who received trastuzumab deruxtecan was 54.3 years (range, 27.9-54.2) vs 54.2 years (range, 20.2-83.0) in those who were given T-DM1.

In the investigative and control arms, respectively, 49.8% and 46.8% of patients received only 1 line of prior therapy in the metastatic setting; 21.5% and 24.7% of patients, respectively, received 2 prior therapies. Notably, 8.8% of those in the trastuzumab deruxtecan arm and 6.8% of those in the T-DM1 arm had previously received 5 or more lines of treatment.

Moreover, 62.1% of those in the trastuzumab deruxtecan arm received prior pertuzumab vs 60.1% of those on the T-DM1 arm; 16.1% and 13.7% of patients, respectively, previously received another anti-HER2 TKI.

The data cutoff for the interim PFS analysis was May 21, 2021. On July 30, 2021, the independent drug monitoring committee recommended that the investigators unblind the study.³

Additional findings from the trial showed that the median OS was NE for both treatment arms (HR, 0.56; 95% CI, 0.36-0.86; P = .007172). Moreover, the OS rates at 12 months in the investigative and control arms, respectively, were 94.1% (95% CI, 90.3%-96.4%) and 85.9% (95% CI, 80.9%-89.7%).

The OS data did not cross the prespecified boundary of P < .000265 at the time of the presentation, although it was noted that this might be due to immature follow-up. Relatively few events were reported in the investigative (n = 33) and control (n = 53) arms at the time of the analysis.

Findings from the investigator assessment on PFS showed that the median PFS with trastuzumab deruxtecan was 25.1 months (95% CI, 22.1–NE) vs 7.2 months (95% CI, 6.8-8.3) with T-DM1 (HR, 0.26; 95% CI, 0.20-0.35; P = 6.5 x 10-24). The 12-month PFS rates in the investigative and control arms were 76.3% (95% CI, 70.4%-81.2%) and 34.9% (95% CI, 28.8%-41.2%), respectively.

Among patients with treated and stable brain metastases, the median PFS was noted to be 3 times longer with trastuzumab deruxtecan (n = 62) compared with T-DM1 (n = 52); the median PFS was 15.0 months (95% CI, 12.6-22.2) and 5.7 months (95% CI, 2.9-7.1), respectively (HR, 0.3796; 95% CI, 0.2267-0.6357).

Moreover, trastuzumab deruxtecan elicited a confirmed ORR of 79.7% (95% CI, 74.3%-84.4%) vs 34.2% (95% CI, 28.5%-40.3%) with T-DM1 (P < .0001). Of those who responded to trastuzumab deruxtecan, the complete response (CR) rate was 16.1% and the partial response (PR) rate was 63.6%; these rates were 8.7% and 25.5%, respectively, among those who responded to T-DM1. Stable disease was achieved by 16.9% of those given trastuzumab deruxtecan vs 42.6% of those who received T-DM1. The disease control rates in the investigative and control arms were 96.6% and 76.8%, respectively.

No new safety signals were reported. The most frequent grade 3 or higher treatment-related, treatment-emergent adverse effects experienced with trastuzumab deruxtecan included neutropenia (19.1%), thrombocytopenia (7.0%), leukopenia (6.6%), nausea (6.6%), anemia (5.8%), fatigue (5.1%), vomiting (1.6%), increased alanine aminotransferase (1.6%), decreased appetite (1.2%), increased aspartate aminotransferase (0.8%), diarrhea (0.4%), and alopecia (0.4%).

Additionally, 10.5% of patients who received trastuzumab deruxtecan experienced interstitial lung disease (ILD) or pneumonitis associated with the drug, per independent adjudication committee assessment. However, most of these events (9.7%) were determined to be low grade; 2.7% of patients experienced grade 1 ILD, 7.0% experienced grade 2 ILD, and 0.8% experienced grade 3 ILD. Notably, no grade 4 or 5 ILD or pneumonitis events were reported.

References

1. Trastuzumab deruxtecan Type II Variation application validated by EMA for patients with HER2 positive metastatic breast cancer treated with a prior anti-HER2-based regimen. News release. Daiichi Sankyo Company, Limited; December 28, 2021. Accessed January 3, 2022. https://bit.ly/3Jz6VLA
2. Cortés J, Kim S-B, Chung W-P, et al. LBA1 trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with HER2+ metastatic breast cancer (mBC): results of the randomized phase III DESTINY-Breast03 study. Ann Oncol. 2021;32(suppl 5):S1287-S1288. doi:10.1016/j.annonc.2021.08.2087
3. Enhertu significantly improved progression-free survival in DESTINY-Breast03 head-to-head trial vs. trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer. News release. AstraZeneca and Daiichi Sankyo Company; August 9, 2021. Accessed January 3, 2022. https://bit.ly/3tRh5zG