ENHERTU Granted Priority Review by FDA for HER2-Positive Metastatic Gastric or GEJ Adenocarcinoma

Compiled by Keke

On October 28, AstraZeneca and Daiichi Sankyo announced that the U.S. FDA has accepted the supplemental Biologics License Application (sBLA) for ENHERTU® (fam-trastuzumab deruxtecan-nxki) for the treatment of HER2-positive metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, granting it Priority Review designation. The Prescription Drug User Fee Act (PDUFA) target date for this application is set for the first quarter of 2021. This marks another step forward for AstraZeneca and Daiichi Sankyo toward securing a new potential blockbuster drug.

It is understood that the recommended first-line treatment for HER2-positive advanced or metastatic gastric cancer is chemotherapy combined with trastuzumab (an anti-HER2 agent). Studies have shown that combination chemotherapy can improve patient survival rates. For first-line treatment of metastatic gastric cancer, anti-HER2 therapy may be used initially; however, there are currently no other approved HER2-targeted therapies available for treatment after disease progression.

It is reported that this sBLA is based on the positive results from the Phase 2 clinical trial DESTINY-Gastric01. This was an open-label, multicenter, randomized controlled trial that compared the safety and efficacy of ENHERTU versus investigator’s choice of chemotherapy in 188 patients from Japan and South Korea with HER2-positive (defined as IHC 3+ or IHC 2+/ISH+) advanced gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma. The enrolled patients had experienced disease progression during or after treatment with two or more prior regimens, including fluoropyrimidine, platinum-based chemotherapy, and trastuzumab. In the study, patients were randomized in a 2:1 ratio to receive either ENHERTU at 6.4 mg/kg or chemotherapy (paclitaxel or irinotecan monotherapy) once every three weeks.

The primary endpoint of the trial was the objective response rate (ORR) in patients, as assessed by independent central review. Additionally, a key secondary endpoint was overall survival (OS). If the primary endpoint demonstrated statistical significance, stratified assessment would be conducted in the pre-specified interim analysis. Other efficacy endpoints included progression-free survival, duration of response, disease control rate, and confirmation of ORR through follow-up scan assessments in confirmed responders at least four weeks after the initial independent review. The trial demonstrated that, compared with chemotherapy (monotherapy with paclitaxel or irinotecan), treatment with ENHERTU resulted in statistically significant and clinically meaningful improvements in both ORR and OS. The ORR was 51% in the ENHERTU group versus 14% in the control group. Furthermore, OS was longer with ENHERTU, with a median of 12.5 months compared to 8.4 months in the control group, thereby meeting the primary endpoint and one of the key secondary endpoints.

Furthermore, in DESTINY-Gastric01, the safety and tolerability profile of ENHERTU was consistent with that observed in the gastric cancer cohort of the Phase 1 clinical trial and in previously published trials involving other tumor types. The most common Grade 3 or higher adverse reactions associated with treatment were decreased neutrophil count, anemia, decreased white blood cell count, and decreased appetite. As determined by an independent review committee, 12 out of 125 patients (9.6%) treated with ENHERTU were confirmed to have treatment-related interstitial lung disease (ILD) or pneumonitis; most cases were Grade 1 or 2, and there were no Grade 5 events (ILD-related deaths).

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate, belonging to the class of antibody-drug conjugates (ADCs). ADCs can target tumors by delivering cytotoxic chemotherapy (“payload”) to cancer cells via a conjugate linked to a specific monoclonal antibody. ENHERTU is designed with a HER2 monoclonal antibody connected to a topoisomerase I inhibitor payload through a tetrapeptide linker. Developed jointly by AstraZeneca and Daiichi Sankyo, this drug (5.4 mg/kg) has been approved in the United States and Japan for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more anti-HER2-based regimens in the metastatic setting.

Just five months prior to receiving Priority Review designation, ENHERTU was granted Breakthrough Therapy designation by the U.S. FDA for the treatment of patients with unresectable or metastatic HER2-positive gastric adenocarcinoma or gastroesophageal junction (GEJ) adenocarcinoma who had previously received two or more prior regimens, including trastuzumab. Additionally, the drug received FDA Orphan Drug designation for the treatment of gastric cancer (including GEJ adenocarcinoma). AstraZeneca invested nearly $7 billion in its partner for the development of this drug, including an upfront payment of $1.35 billion, and the Priority Review significantly accelerated the previously expected approval timeline.

Clearly, ENHERTU has now outpaced its competitor, Roche’s Kadcyla, which failed in a Phase 2/3 trial five years ago as a second-line treatment for patients with the same indication. This setback ultimately led to slower sales growth, with the drug’s peak sales declining from an estimated over $2 billion to approximately $1 billion. In contrast, analysts predict that ENHERTU’s peak sales are likely to exceed $2 billion, while Daiichi Sankyo had previously projected figures as high as $4.5 billion. As AstraZeneca strengthens its oncology portfolio through products such as Imfinzi and Tagrisso, CEO Pascal Soriot is poised to add another blockbuster drug to the company’s lineup during his tenure.

Reference Source:

1.ENHERTU (fam-trastuzumab deruxtecan-nxki) Granted Priority Review in the US For the Treatment of HER2-positive Metastatic Gastric Cancer

2.Enhertu picks up another win for AstraZeneca and Daiichi Sankyo, joining the priority review lane for gastric cancer

Original Title:AstraZeneca/Daiichi Sankyo’s ENHERTU Receives Priority Review in the US for the Treatment of HER2-Positive Metastatic Gastric Cancer