FDA Approves Trastuzumab Deruxtecan in HER2-Low Metastatic Breast Cancer


The FDA has approved fam-trastuzumab deruxtecan-nxki for the treatment of patients with unresectable or metastatic HER2-low breast cancer.

The FDA has approved fam-trastuzumab deruxtecan-nxki (Enhertu) for the treatment of adult patients with unresectable or metastatic HER2-low breast cancer.1

The approval was based on data from the phase 3 DESTINY-Breast04 study (NCT03734029), in which trastuzumab deruxtecan doubled progression-free survival (PFS) for patients with HER2-low, hormone receptor–positive metastatic breast cancer (MBC) treated with the antibody-drug conjugate (ADC) and it also reduced the risk of death by 36% compared to physician's choice of chemotherapy.2,3 These data were presented at the 2022 ASCO Annual Meetingand simultaneously published in the New England Journal of Medicine.

Previously, the HER-2 directed ADC was granted breakthrough therapy designation in April 2022 for patients with metastatic HER2-low breast cancer and the FDA accepted an application for the approval of fam-trastuzumab deruxtecan-nxki in this patient population in July, 2022. The FDA also granted accelerated approval for adult patients with unresectable or metastatic HER2-positive breast cancer who have received 2 or more prior anti–HER2-based regimens in the metastatic setting in 2019, and this accelerated approval was transitioned to a full regulatory approval on May 4, 2022.

“Today’s approval highlights the FDA’s commitment to be at the forefront of scientific advances, making targeted cancer treatment options available for more patients,” said Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, in a press release. “Having therapies that are specially tailored to each patient’s cancer subtype is a priority to ensure access to safe and innovative treatments.”

“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.”

Within the DESTINY-Breast04 study, 557 patients were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan at 5.4 mg/kg every 3 weeks (n = 373) or physician’s choice of chemotherapy at locally approved dosing (n = 184). Patients administered chemotherapy received capecitabine (Xeloda; 20.1%), eribulin (Halaven; 51.1%), gemcitabine (10.3%), paclitaxel (8.2%), or nab-paclitaxel (Abraxane; 10.3%).

Of those enrolled in the trial, patient characteristics were balanced between each arm and representative of the overall population of patients with HER2-negative breast cancer. The median age of patients in the trastuzumab deruxtecan arm was 57.5 years (range, 31.5-80.2) with 99.5% being female.

According to investigators, low expression of HER2 was defined as an IHC score of 1+ or 2+ with a negative in situ hybridization (ISH) test, and this represented approximately 65% of breast cancer diagnoses. In the study, 88.7% of patients were hormone receptor–positive while 11.3% were negative. HER2-low was IHC 1+ for 57.6% of patients and IHC 2+ and ISH-negative for 42.4%.

Further, ECOG performance status was split between 0 (53.6%) and 1 (46.4%), and the primary locations of metastases were the brain (6.4%), liver (71.3%), and lung (32.2%). Patients had received a median of 3 (range, 1-9) prior lines of therapy, consisting of targeted or immunotherapy (74.8%), endocrine therapy (93.0%), and chemotherapy (100%).

Among those enrolled in the study, the median PFS was 9.9 months (95% CI, 9.0-11.3) with trastuzumab deruxtecan vs 5.1 months (95% CI, 4.2-6.8) with chemotherapy (HR, 0.50; 95% CI, 0.40-0.63). In this group, the median OS was 23.4 months (95% CI, 20.0-24.8) with trastuzumab deruxtecan and 16.8 months (95% CI, 14.5-20.0) for chemotherapy. These data showed a 6.6-month improvement in survival with the agent (HR, 0.64; 95% CI, 0.49-0.84; P = .001).

Patients with hormone receptor–negative disease had a median PFS was 8.5 months (95% CI, 4.3-11.7) with trastuzumab deruxtecan vs 2.9 months (95% CI, 1.4-5.1) for chemotherapy (HR, 0.46; 95% CI, 0.24-0.89). In the hormone receptor–negative cohort, the median OS was 18.2 months (95% CI, 13.6-not estimable) with trastuzumab deruxtecan compared with 8.3 months (95% CI, 5.6-20.6) with chemotherapy (HR, 0.48; 95% CI, 0.24-0.95).

The overall response rate (ORR) was 52.3% (95% CI, 47.1%-57.4%) for patients treated with trastuzumab deruxtecan compared with 16.3% (95% CI, 11.3%-22.5%) with those given chemotherapy. Then in the hormone receptor–negative arm, the ORRs demonstrated were 50.0% (95% CI, 33.8%-66.2%) for trastuzumab deruxtecan (n = 40) vs 16.7% (95% CI, 3.6%-41.4%) for chemotherapy (n = 18). The ORR for patients with hormone receptor–positive disease was 52.6% (95% CI, 47.0%-58.0%) for trastuzumab deruxtecan (n = 333) vs 16.3% (95% CI, 11.0%-22.8%) for chemotherapy (n = 166). Median duration of response for patients in this group was 10.7 months with trastuzumab deruxtecan vs 6.8 months for physician's choice of chemotherapy.

Additionally, a consistent improvement in PFS across subgroups was demonstrated with trastuzumab deruxtecan as patients with hormone receptor–positive disease with a HER2 IHC score of 1+ had a median PFS of 10.3 months (95% CI, 8.6-12.3) with trastuzumab deruxtecan compared with 5.3 months (95% CI, 4.1-7.8) with chemotherapy (HR, 0.48; 95% CI, 0.35-0.65). For patients with hormone receptor–positive HER2 IHC 2+ and ISH-negative disease, the median PFS was 10.1 months (95% CI, 8.2-12.2) for trastuzumab deruxtecan compared with 5.9 months (95% CI, 4.3-7.9) for chemotherapy (HR, 0.55; 95% CI, 0.38-0.80).

Patients with hormone receptor–positive disease who had received prior treatment with a CDK4/6 inhibitor had a median PFS of 10.0 months (95% CI, 8.3-11.4) with trastuzumab deruxtecan vs 5.4 months (95% CI, 4.0-7.8) for chemotherapy (HR, 0.55; 95% CI, 0.42-0.73). Those with hormone receptor–positive disease who did not receive a CDK4/6 inhibitor demonstrated a median PFS of 11.7 months (95% CI, 9.5-17.7) with trastuzumab deruxtecan and 5.9 months (95% CI, 4.3-8.2) for chemotherapy (HR, 0.42; 95% CI, 0.28-0.64). Further, the median treatment duration was 8.2 months for trastuzumab deruxtecan and 3.5 months for chemotherapy at the time of the data cutoff.

In regard to safety, adverse events (AE) led to 16.2% of patients discontinuing treatment in the trastuzumab deruxtecan arm compared with 8.1% in the chemotherapy arm. Because of AEs found in 22.6% of patients in the trastuzumab deruxtecan group and 38.4% for chemotherapy, dose reductions were required. Treatment-emergent adverse events (TEAE) were also observed in 99.5% of those given trastuzumab deruxtecan vs 98.3% of those treated with physician’s choice of therapy. Exposure adjusted AE rates were 1.30 per patient year for trastuzumab deruxtecan and 2.66 for physician’s choice of chemotherapy. Additionally, serious AEs were reported in 27.8% of patients in the trastuzumab deruxtecan arm and for 25.0% in the physician’s choice arm.

The treatment-related AEs which were most frequently observed in each arm were nausea (73% vs 23.8%), fatigue (47.7% vs 42.4%), skin and subcutaneous tissue disorders, including alopecia (37.7% vs 32.6%), vomiting (34% vs 9.9%), neutropenia (33.2% vs 51.2%), and anemia (33.2% vs 22.7%). A total of 14 drug-related deaths were reported with trastuzumab deruxtecan (3.8%) vs 5 for physician’s choice of therapy (2.9%), and adjudicated interstitial lung disease (ILD)/pneumonitis occurred in 45 patients treated with trastuzumab deruxtecan (12.1%), including 5 patients who had a grade 3 event and 3 who had a grade 5 event.

Overall, the study showed trastuzumab deruxtecan to demonstrate superior and clinically meaningful efficacy in PFS and OS in patients with previously treated patients with HER2-low metastatic breast cancer with hormone receptor-positive or hormone receptor-negative disease vs standard of care physician’s choice of chemotherapy. The safety profile of trastuzumab deruxtecan was also consistent with what has been seen in previous clinical trials and no new safety concerns were identified.

“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.

  1. FDA Approves First Targeted Therapy for HER2-Low Breast Cancer. News release. FDA. August 05, 2022. Accessed August 05, 2022. https://bit.ly/3zW0cbL
  2. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): results of DESTINY-Breast04, a randomized, phase 3 study. J Clin Oncol. 2022;40 (suppl 17):abstr LBA3. doi:10.1200/JCO.2022.40.17_suppl.LBA3
  3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. Published online June 5, 2022. doi:10.1056/NEJMoa2203690
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