Enhertu wins Korean approval for HER2-low and HER2-ultra-low metastatic breast cancer

Daiichi Sankyo Korea and AstraZeneca Korea said Monday that the antibody-drug conjugate (ADC) cancer therapy Enhertu (trastuzumab deruxtecan) received approval from the Ministry of Food and Drug Safety (MFDS) for the treatment of HER2-low and HER2-ultra-low metastatic breast cancer.

The newly added approval for Enhertu is for “the treatment of patients with HER2-low expression (IHC 1+ or IHC 2+/ISH-) or HER2-ultra-low expression (IHC 0 with membrane staining) breast cancer who have received one or more prior endocrine therapies in the metastatic setting, as a single agent in unresectable or metastatic disease.”

Antibody-drug conjugate (ADC) cancer therapy Enhertu (Courtesy of Daiichi Sankyo Korea)

Enhertu was initially developed by Daiichi Sankyo and was jointly commercialized with AstraZeneca. In Korea, it is co-developed and co-marketed by Daiichi Sankyo Korea and AstraZeneca Korea, with distribution handled by Daiichi Sankyo Korea.

Endocrine therapy is the first line of treatment for hormone receptor-positive (HR+) metastatic breast cancer. Chemotherapy follows if resistance develops.

Previously, Enhertu was approved for use in HR+ and HER2-low expression (IHC 1+ or IHC 2+/ISH-) patients who had received at least one prior chemotherapy regimen. However, this approval now extends Enhertu treatment to HR+ patients with HER2-low expression as well as those with HER2-ultra-low expression metastatic breast cancer. Furthermore, Enhertu can now be used earlier, without prior chemotherapy, in patients who have received one or more endocrine therapies.

This expanded indication is based on the DESTINY-Breast06 study, a multicenter, randomized, open-label phase 3 trial comparing Enhertu (5.4 mg/kg every three weeks) with chemotherapy (capecitabine, nab-paclitaxel, or paclitaxel).

In this study, HER2 ultra-low expression was defined as faint and incomplete HER2 staining observed in 10 percent or fewer tumor cells (IHC 0, where IHC >0 and <1+ were considered positive in this study).

Results showed that in HR+ and HER2-low metastatic breast cancer patients who had not received prior chemotherapy, the Enhertu group (n=359) demonstrated a statistically significant improvement in median progression-free survival (mPFS), assessed by blinded independent central review (BICR), compared to the chemotherapy group (n=354), reducing the risk of disease progression or death by approximately 38 percent (mPFS 13.2 months vs. 8.1 months; HR: 0.62; 95 percent CI, 0.52-0.75; p<0.001).

“Enhertu showed over a year of progression-free survival in patients previously classified as HR+ and HER2-, who had low or very low HER2 expression,” said Professor Sohn Joo-hyuk of Yonsei Cancer Hospital. “As targeted therapy now outperforms chemotherapy for patients resistant to endocrine therapy, it is important to reassess HR+ patients previously diagnosed as ‘HER2 IHC 0’ to confirm HER2 expression levels.”

In the overall intention-to-treat (ITT) analysis population, including HER2-low and HER2-ultra-low expression patients, the mPFS in the Enhertu group (n=436) was 13.2 months, compared to 8.1 months in the chemotherapy group (n=430), representing a reduction in the risk of disease progression or death by about 36 percent (HR: 0.64; 95 percent CI, 0.54-0.76; p<0.001).

Additionally, the objective response rate was approximately 1.8 times higher (57.3 percent vs. 31.2 percent) and the clinical benefit rate was about 1.5 times higher (76.6 percent vs. 51.9 percent) compared to the chemotherapy group. Complete remission (CR), which did not occur in the chemotherapy group, was observed in about 3 percent of the Enhertu group.

In an exploratory subgroup analysis of patients with ultra-low HER2 expression, Enhertu demonstrated efficacy similar to that observed in the overall population. The safety profile of the Enhertu group was consistent with previous reports, and no new safety signals were observed.

Professor Sohn said, “Using Enhertu earlier in HER2-low patients without prior chemotherapy showed an mPFS of 10.1 months, compared to 3.1 months in DESTINY-Breast04. Starting Enhertu earlier may allow longer-term disease control.”

HR+/HER2- is the most common subtype in breast cancer, accounting for about 70 percent of all breast cancers. Although this subtype is known to have a relatively favorable prognosis compared to other breast cancer subtypes, chemotherapy remains the only treatment option for patients who are unsuitable for or resistant to endocrine therapy. The progression-free survival expected from first-line treatment is only about six months, indicating a high unmet clinical need.