Trastuzumab Deruxtecan Approved in China for HER2-Low Metastatic Breast Cancer

July 12, 2023

China’s National Medical Products Administration has approved trastuzumab deruxtecan monotherapy in adult patients with unresectable or metastatic HER2-low breast cancer who have previously received a systemic therapy in the metastatic setting or whose disease recurred during or within 6 months of adjuvant chemotherapy.

China’s National Medical Products Administration has approved fam-trastuzumab deruxtecan-nxki (Enhertu) for use as a monotherapy in adult patients with unresectable or metastatic HER2-low breast cancer who have previously received a systemic therapy in the metastatic setting or whose disease recurred during or within 6 months of adjuvant chemotherapy.^1,2

The decision is based on findings from the phase 3 DESTINY-Breast04 trial (NCT03734029), in which treatment with trastuzumab deruxtecan resulted in a 50% reduction in the risk of disease progression or death compared with physician’s choice of chemotherapy in all randomized patients. The median progression-free survival (PFS) was 9.9 months (95% CI, 9.0-11.3) and 5.1 months (95% CI, 4.2-6.8), respectively (HR, 0.50; 95% CI, 0.40-0.63; P < .001).³

Moreover, the median overall survival (OS) with trastuzumab deruxtecan was 23.4 months (95% CI, 20.0-24.8) vs 16.8 months (95% CI, 14.5-20.0) with chemotherapy in all patients; this translated to a 36% reduction in the risk of death with the antibody-drug conjugate (ADC; HR, 0.64; 95% CI, 0.49-0.84; P = .001).

“Historically, breast cancer tumors with low levels of HER2 expression have been classified as HER2 negative and have not been eligible for treatment with HER2-directed therapies,” Binghe Xu, MD, director of the National Clinical Research Center for New Anticancer Drugs and tenured professor and former director of the Department of Medical Oncology at Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, stated in a press release.1 “With this approval in China, based on the results of the DESTINY-Breast04 trial, clinicians will now be able to identify and potentially treat a distinct patient population based on HER2-low status.”

The randomized, open-label, phase 3 trial enrolled patients with HER2-low metastatic breast cancer who previously received 1 or 2 lines of chemotherapy.³ HER2-low expression was defined as having an immunohistochemistry (IHC) score of 1+ or 2+ with negative results on in situ hybridization.

Patients must have received chemotherapy in the metastatic setting or have experienced recurrence during or within 6 months following the completion of adjuvant chemotherapy. Those with hormone receptor–positive disease must have received at least 1 prior line of endocrine treatment. Notably, those with treated brain metastases that were deemed stable were able to participate.

If patients had a history of noninfectious interstitial lung disease (ILD) and received glucocorticoids, they were excluded, as were those who had suspected ILD at the time of screening.

Study participants were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan at 5.4 mg/kg intravenously every 3 weeks (n = 373) or physician’s choice of chemotherapy in the form of capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel (Abraxane; n = 184).

Stratification factors comprised HER2-low status (IHC 1+ vs IHC 3+ and ISH negative), prior lines of chemotherapy in the metastatic setting (1 vs 2), and hormone receptor status (positive with vs without prior CDK4/6 exposure vs negative).

PFS in patients with hormone receptor–positive disease served as the primary end point, and key secondary end points included PFS in all patients and OS in both the hormone receptor–positive group and all patients. Other end points of interest included PFS by investigator assessment, confirmed objective response rate (ORR), duration of response (DOR), and efficacy in those with hormone receptor–negative disease.

Of the total 557 patients who were randomized on the trial, 494 had hormone receptor–positive disease and 63 had –negative disease. Of the 494 patients with hormone receptor–positive disease, 331 received trastuzumab deruxtecan and 163 received chemotherapy. In the chemotherapy arm, 51.1% of patients received eribulin, 20.1% received capecitabine, 10.3% received nab-paclitaxel, 10.3% received gemcitabine, and 8.2% received paclitaxel.

The demographic and clinical characteristics were noted to be comparable in the 2 trial groups.

Additional data showed that at the data cutoff date of January 11, 2022, in the hormone receptor–positive group, the median PFS was 10.1 months (95% CI, 9.5-11.5) in the trastuzumab deruxtecan arm vs 5.4 months (95% CI, 4.4-7.1) in the chemotherapy arm (HR, 0.51; 95% CI, 0.40-0.64; P < .001). The PFS benefit derived with the ADC was consistent across key subgroups.

The median OS in this group of patients assigned to the investigative and control arms was 23.9 months (95% CI, 20.8-24.8) and 17.5 months (95% CI, 15.2-22.4), respectively (HR, 0.64; 95% CI, 0.48-0.86; P = .003).

Moreover, the confirmed ORR in all patients was 52.3% (95% CI, 47.1%-57.4%) with trastuzumab deruxtecan vs 16.3% (95% CI, 11.3%-22.5%) with chemotherapy. In the hormone receptor–positive cohort, these rates were 52.6% (95% CI, 47.0%-58.0%) and 16.3% (95% CI, 11.0%-22.8%), respectively.

The median duration of treatment in the investigative and control arms was 8.2 months (range, 0.2-33.3) and 3.5 months (range, 0.3-17.6), respectively. At least 1 toxicity that emerged or worsened following the start of study treatment through 47 days post the last dose occurred in 99.5% of those who received the ADC and 98.3% of those given chemotherapy.

Serious toxicities were experienced by 27.8% of those given the ADC and 25.0% of those given chemotherapy; these effects were grade 3 or higher for 52.6% and 67.4% of patients, respectively.

The most common grade 3 or higher treatment-related adverse effects (AEs) to occur in at least 20% of patients in the investigative (n = 371) and control (n = 172) arms, respectively, were neutropenia (13.7% vs 40.7%), anemia (8.1% vs 4.7%), thrombocytopenia (5.1% vs 0.6%), leukopenia (6.5% vs 19.2%), nausea (4.6% vs 0%), vomiting (1.3% vs 0%), diarrhea (1.1% vs 1.7%), increased aminotransferase levels (3.2% vs 8.1%), fatigue (7.5% vs 4.7%), and decreased appetite (2.4% vs 1.2%).

AEs led to discontinuation in 16.2% of those in the trastuzumab deruxtecan arm and 8.1% of those in the chemotherapy arm. Moreover, 3.8% and 2.9% of patients, respectively, experienced toxicities that resulted in death. Deaths related to trastuzumab deruxtecan included pneumonitis (n = 2), ischemic colitis (n = 1), disseminated intravascular coagulation (n = 1), dyspnea (n = 1), febrile neutropenia (n = 1), and sepsis (n = 1). No drug-related deaths were reported in the control arm.

References

Enhertu approved in China as the first HER2-directed therapy for patients with HER2-low metastatic breast cancer. News release. AstraZeneca. July 12, 2023. Accessed July 12, 2023. https://www.astrazeneca.com/media-centre/press-releases/2023/enhertu-approved-in-china-as-the-first-her2-directed-therapy-for-patients-with-her2-low-metastatic-breast-cancer.html
Enhertu approved in China as the first HER2 directed therapy for patients with HER2 low metastatic breast cancer. News release. Daiichi Sankyo. July 12 ,2023. Accessed July 12, 2023. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202307/20230712_E.pdf
Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690