FDA Approves Fam-Trastuzumab Deruxtecan-Nxki for Unresectable HER2+ mBC

Fam-trastuzumab deruxtecan-nxki has been approved by the FDA for the treatment of adult patients with unresectable or HER2-positive metastatic breast cancer who have received a prior anti-HER2- based regimen.

The FDA has granted approval to fam-trastuzumab deruxtecan-nxki for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either in the metastatic setting, or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy, according to an announcement by the FDA.1

The announcement follows a review of results from the phase 3 DESTINY-Breast03 clinical trial as part of the FDA’s Real-Time Oncology Review and Project Orbis programs. In the study, T-DXd showed a statistically significant and clinically meaningful improvement inf progression-free survival (PFS) compared with ado-trastuzumab emtansine (T-DM1;Kadcyla). The treatment was also found to be tolerable in this patient population.

“The impact is that we see a very good response rate, we see the duration of response really being quite long, meaning that people that get benefit, get benefit for quite some time. And that's important for patients as well as for us,” Erika Hamilton, Tennessee Oncology told Targeted OncologyTM, in an interview. “I also anticipate this isn't the last shift we see with trastuzumab deruxtecan, and we're going to continue to refine what order we give these agents in.”

DESTINY-Breast03 is a phase 3, multicenter, randomized, open-label, active-controlled study (NCT03529110). The study included 524 patients who were 1:1 to receive either T-DXd or T-DM1. The primary end point of the study was PFS by blinded independent central review (BICR), and secondary end points included overall survival (OS), objective response rate (ORR), duration of response (DOR), PFS by investigator assessment, and safety.2

According to baseline demographics, subjects in the study had a median age of 54.3 years (range, 27.9-83.1) in the experimental arm compared with 54.2 years (range, 20.2-83.0) in the control arm. Most of the patients were from Asian countries including 57.1% of the T-DXd arm versus 60.8% of the T-DM1 arm. In terms of baseline disease characteristics, most patients in the T-DXd arm versus the T-DM1 arm also had an ECOG performance status of 0 (59.0% vs 66.5%), hormone-receptor-positive disease (50.2% vs 51.0%), no presence of brain metastases (76.2% vs 80.2%), and most had visceral disease (70.5% vs 70.3%), respectively.

History of treatment was also shown in the baseline demographics. The majority of patients, including 92.0% of the T-DXd arm compared with 89.0% of the T-DM1 arm, were previously treated. Most patients in the study had 1 prior line of therapy including 49.8% of the experimental arm versus 46.8% of the control arm. Over 21% of the experimental arm versus 24.7% of the control arm had received 2 prior lines of therapy, however. There were some study subjects also received 5 or more prior lines of therapy. Prior therapy for cancer was predominantly trastuzumab, but 62.1% of the T-DXd arm versus 60.1% of the T-DM1 arm received prior pertuzumab (Perjeta). Among the remaining patients, anti-HER2 therapies were received as prior therapy.

The median follow-up for patients with HER2-positive mBC was 15.5 months (range, 15.1-16.6) in the experimental arm and 13.9 months (range, 11.8-15.1) in the control arms. The median PFS by BICR was not reached (95% CI, 18.5 to not evaluable [NE]) versus 6.8 months (95% CI, 5.6-8.2), respectively (HR, 0.28; 95% CI, 0.22-0.37; P = .0001). The 12-month PFS rate by BICR was 75.8% (95% CI, 69.8%-80.7%) in the T-DXd arm compared with 34.1% (95% CI, 27.7%-40.5%) in the T-DM1 arm.

The median PFS pr investigator assessment was 25.1 months (95% CI, 22.1-NE) with the experimental therapy compared with 7.2 months (95% CI, 6.8-8.3) in the T-DM1 arm (HR, 0.21; 95% CI, 0.20-0.35; P = 6.5 x 10-24. At 12 months, the PFS rate in the T-DXd group was 76.3% (95% CI, 70.4%-81.2%) compared with 34.9% (95% CI, 28.8%-41.2%) in the control arm. PFS was favorable for the experimental arm across all assessed subgroups.

Median OS was not evaluable at the time of the first analysis. The 12-month PFS rate with T-DXd was 94.1% (95% CI, 90.3%-96.4%) versus 85.9% (95% CI, 80.9%-89.7%) in the T-DM1 arm (HR, 0.56; 95% CI, 0.36-0.86); =.007172).

The confirmed ORR in the population treated with T-DXd was 79.7% (95% C 74.3%-84.4%) versus only 34.2% (95% CI, 28.5%-40.3%) in the T-DM1 arm (P <.0001). Complete responses were observed in 16.1% of the T-DXd arm compared with 8.7% of the control arm, and partial responses and stable disease 63.6% and 16.9% versus 25.5% and 42.6%, respectively. Progressive disease was seen in 1.1% of patients in the T-DXd arm versus 17.5% of the control arm. Of those enrolled, 21 patients in the study were not evaluable for response. The disease control rates were 96.6% in the T-DXd versus 76.8% in the T-DM1 arm.

Safety data showed that patients were treated in the study for a median duration of 14.3 months (range, 0.7-29.8) with T-DXd and 6.9 months (range, 0.7-25.1) with T-DM1. Treatment-emergent adverse events (TEAEs) were observed in 98.1% of the T-DXd arm compared with 86.6% of the T-DM1 arm. Events were grade 3 or higher for 45.1% of the experimental arm compared with 39.8% of the control arm. Treatment discontinuation related to a study drug occurred in 12.8% of the T-DXd arm versus 5.0% of the T-DM1 arm, and dose reductions occurred in 21.4% versus 12.6%, respectively. No deaths in the study were seen in either treatment arm.

“I think we're going to see trastuzumab deruxtecan kind of settle in as the preferred second-line agent, maybe except for patients that have active brain metastases where we know tucatinib has an overall survival benefit for those patients,” said Hamilton.

FDA grants regular approval to fam-trastuzumab deruxtecan-nxki for breast cancer. News Release. FDA. May 4, 2022. Accessed May 4, 2022. https://bit.ly/3scmcLm
Cortes J, Kim SB, Chung WP, et al. Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients with her2+ metastatic breast cancer: results of the randomized, phase 3 study DESTINY-Breast03. Presented at: 2021 ESMO Congress; September 16-21, 2021; Virtual. Abstract LBA1.

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