US FDA approves Daiichi Sankyo & AstraZeneca’s Enhertu to treat locally advanced /metastatic HER2 positive gastric or gastroesophageal junction

Daiichi Sankyo Company, Limited and AstraZeneca’s Enhertu (fam-trastuzumab deruxtecan-nxki) has been approved in the US for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen.In the US, gastric cancer is more frequently diagnosed in the advanced stage, with only approximately 5% of patients surviving five years. Approximately one in five gastric cancers is HER2 positive.

“Patients with metastatic HER2 positive gastric cancer with progression following first-line treatment have historically faced poor outcomes, including low response to treatment and rapid disease progression,” said Ronan Kelly, MD, MBA, director of the Charles A. Sammons Cancer Center and the W.W. Caruth, Jr. Chair of Immunology at Baylor University Medical Center, Dallas, Texas. “This approval represents the first time a HER2 directed medicine has demonstrated a significant improvement in survival compared to chemotherapy for patients following initial treatment in the metastatic setting and it has the potential to become the new standard of care for this patient population.”

Regular approval by the US Food and Drug Administration (FDA) was based on the positive results from the randomized pivotal DESTINY-Gastric01 phase 2 trial, in which Enhertu demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) and objective response rate (ORR) versus chemotherapy (irinotecan or paclitaxel) in patients with advanced gastric or GEJ adenocarcinoma who had progressed on at least two prior regimens including trastuzumab, a fluoropyrimidine and a platinum-containing chemotherapy. ENHERTU is approved with Boxed WARNINGS for interstitial lung disease (ILD)/pneumonitis and embryo-fetal toxicity.

In the DESTINY-Gastric01 trial, patients (n=126) in the ENHERTU treatment arm had a 41% reduction in the risk of death versus patients (n=62) treated with chemotherapy (based on a hazard ratio [HR] of 0.59; 95% confidence interval [CI] 0.39-0.88; p=0.0097) at a pre-specified interim analysis with a median OS of 12.5 months [95% CI 9.6-14.3] versus 8.4 months [95% CI 6.9-10.7] with chemotherapy.

Confirmed ORR, assessed by independent central review, was a major efficacy outcome. Results showed a confirmed ORR of 40.5% [95% CI 31.8-49.6] with Enhertu compared to 11.3% [95% CI 4.7-21.9] with chemotherapy. Patients treated with Enhertu had a 7.9% complete response rate (n=10) and a 32.5% partial response rate (n=41) compared to a complete response rate of 0% (n=0) and a partial response rate of 11.3% (n=7) for patients treated with chemotherapy. Additionally, Enhertu showed a median duration of response (DoR) of 11.3 months [95% CI 5.6-NR] versus 3.9 months [95% CI 3.0-4.9] with chemotherapy.

Enhertu also demonstrated a median progression-free survival (PFS) of 5.6 months [95% CI 4.3-6.9] compared to 3.5 months [95% CI 2.0-4.3] (HR=0.47; 95% CI 0.31-0.71) with chemotherapy.

Enhertu is approved with Boxed WARNINGS for interstitial lung disease (ILD)/pneumonitis and embryo-fetal toxicity. The safety of Enhertu was evaluated in 187 patients with locally advanced or metastatic HER2 positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. The most common adverse reactions (=20%), including laboratory abnormalities, were hemoglobin decreased, white blood cell count decreased, neutrophil count decreased, lymphocyte count decreased, platelet count decreased, nausea, decreased appetite, anemia, aspartate aminotransferase increased, fatigue, blood alkaline phosphatase increased, alanine aminotransferase increased, diarrhea, hypokalemia, vomiting, constipation, blood bilirubin increased, pyrexia, and alopecia. In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2 positive gastric or GEJ adenocarcinoma treated with Enhertu 6.4 mg/kg, interstitial lung disease occurred in 10% of patients. Median time to first onset of ILD was 2.8 months (range: 1.2 to 21.0).
“Enhertu is the first antibody drug conjugate to receive approval in the US for the treatment of patients with metastatic gastric cancer, and represents a major advance in managing this difficult-to-treat disease,” said Antoine Yver, MD, MSc, executive vice president and global head, oncology research and development, Daiichi Sankyo. “This second indication in the US represents an important step forward in our ambitious plan to accelerate the development of Enhertu across a broad range of HER2 targetable cancers.”

“Today’s approval of Enhertu represents the first HER2 directed medicine approved in a decade for patients with HER2 positive metastatic gastric cancer,” said Dave Fredrickson, executive vice president, oncology business unit, AstraZeneca. “The results from the DESTINY-Gastric01 trial highlight the potential to change clinical practice, showing a forty-one percent improvement in survival and a response rate more than three times higher with Enhertu compared to chemotherapy. We are thrilled to bring this important medicine to more patients and physicians in the US.”

This is the second regulatory approval for Enhertu in the US. Enhertu is also approved in the US under accelerated approval, and in Japan, under the conditional early approval system, for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who has received two or more prior anti-HER2-based regimens in the metastatic setting based on the DESTINY-Breast01 trial. Enhertu is also approved in Japan for HER2 positive unresectable advanced or recurrent gastric cancer that has progressed after chemotherapy based on the DESTINY-Gastric01 trial.

Gastric (stomach) cancer is the fifth most common cancer worldwide and the third leading cause of cancer mortality with a five-year survival rate of 5% for metastatic disease; there were approximately one million new cases reported in 2020 and more than 768,000 deaths. In the US, it is estimated that 27,600 new cases of gastric cancer were diagnosed in 2020 and more than 11,000 people died from the disease.

DESTINY-Gastric01 is an open-label, multi-center, randomized, pivotal phase 2 trial evaluating the safety and efficacy of Enhertu (6.4 mg/kg) versus investigator’s choice of chemotherapy in a primary cohort of 188 patients from Japan and South Korea with HER2 positive (defined as IHC3+ or IHC2+/ISH+), advanced gastric or GEJ adenocarcinoma who had progressed on two or more prior treatment regimens including trastuzumab, a fluoropyrimidine and platinum-containing chemotherapy. Patients were randomized 2:1 to receive Enhertu or investigator’s choice of chemotherapy (paclitaxel or irinotecan monotherapy). Patients were treated with Enhertu 6.4mg/kg once every three weeks or chemotherapy.

The main efficacy outcome measures were ORR assessed by independent central review according to RECIST v1.1 and OS in the intent-to-treat population. Additional efficacy outcome measures were PFS and DoR.

Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the US) is a HER2 directed antibody drug conjugate (ADC). Designed using Daiichi Sankyo’s proprietary DXd ADC technology, Enhertu is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca’s ADC scientific platform.



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