Home CompaniesAstraZeneca ENHERTU® Approved in the U.S. as the First HER2 Directed Therapy for Patients with HER2 Low Metastatic Breast Cancer

ENHERTU® Approved in the U.S. as the First HER2 Directed Therapy for Patients with HER2 Low Metastatic Breast Cancer

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Synopsis:

  • Based on DESTINY-Breast04 results which showed Daiichi Sankyo and AstraZeneca’s ENHERTU reduced risk of disease progression or death by 50% and increased overall survival by more than six months versus chemotherapy
  • The drug ENHERTU® (fam-trastuzumab deruxtecan-nxki), manufactured by Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE/STO/Nasdaq: AZN), has been given approval in the United States for the treatment of adult patients with metastatic or unresectable HER2 low (IHC 1+ or IHC 2+/ISH-) breast cancer who have previously received chemotherapy

ENHERTU is a specifically engineered HER2 directed antibody drug conjugate (ADC) being jointly developed and commercialized by Daiichi Sankyo and AstraZeneca.

The approval was granted under the FDA’s Real-Time Oncology Review (RTOR) program following the recent Priority Review and Breakthrough Therapy Designation of ENHERTU in the U.S. in this setting. The expanded approval for ENHERTU in the U.S. enables its use across a wide spectrum of HER2 expression, including patients with HER2 low disease.

About ENHERTU

  • API -fam-trastuzumab deruxtecan-nxki
  • Description -ENHERTU is a HER2-directed antibody and topoisomerase inhibitorconjugate indicated for the treatment of: • adult patients with unresectable or metastatic HER2-positive breast. cancer who have received two or more prior anti-HER2-based. regimens in the metastatic setting.
  • Class –Antineoplastics; Camptothecins; Drug conjugates; Immunoconjugates; Monoclonal antibodies
  • Mechanism of Action –DNA topoisomerase I inhibitors
  • Orphan Drug Status –Yes – Gastric cancer
  • New Molecular Entity –Yes
  • Indication – Breast cancer; Gastric cancer

About the ENHERTU Clinical Development Program

A comprehensive global development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, also are underway.

Regulatory applications for ENHERTU in breast, gastric and non-small cell lung cancers are currently under review in several countries based on the DESTINY-Breast01, DESTINY-Breast03, DESTINY-Breast04, DESTINY-Gastric01, DESTINY-Gastric02 and DESTINY-Lung01 trials, respectively.

Important Safety Information

Indications

ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

  • Unresectable or metastatic HER2-positive breast cancer who have received a prior anti-HER2-based regimen either:
    • In the metastatic setting, or
    • In the neoadjuvant or adjuvant setting and have developed disease recurrence during or within six months of completing therapy
  • Unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy
  • Locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based regimen
Enhertu mechanism of action

Enhertu mechanism of action

In the trial, ENHERTU demonstrated a 49% reduction in the risk of disease progression or death versus physician’s choice of chemotherapy in patients with HER2 low metastatic breast cancer with hormone receptor (HR) positive disease (hazard ratio [HR] = 0.51; 95% confidence interval [CI]: 0.40-0.64; p<0.0001). A median progression-free survival (PFS) of 10.1 months (95% CI: 9.5-11.5) was seen in patients treated with ENHERTU compared to 5.4 months (95% CI: 4.4-7.1) with chemotherapy, as assessed by blinded independent central review (BICR). Results also showed a 36% reduction in the risk of death with ENHERTU compared to chemotherapy in patients with HR positive disease (HR=0.64; 95% CI: 0.48-0.86; p=0.0028) with a median overall survival (OS) of 23.9 months with ENHERTU (95% CI: 20.8-24.8) versus 17.5 months with chemotherapy (95% CI: 15.2-22.4).

In the overall trial population of patients with HER2 low metastatic breast cancer with HR positive or HR negative disease and across levels of HER2 expression (both IHC 1+ and IHC 2+/ISH-) a similar 50% reduction in the risk of disease progression or death was observed between ENHERTU and chemotherapy (HR=0.50; 95% CI: 0.40-0.63; p<0.0001), with a median PFS of 9.9 months (95% CI: 9.0-11.3) for ENHERTU versus 5.1 months (95% CI: 4.2-6.8) in those treated with chemotherapy, as assessed by BICR. A median OS of 23.4 months (95% CI: 20.0-24.8) was seen in patients treated with ENHERTU versus 16.8 months (95% CI: 14.5-20.0) in those treated with chemotherapy (HR=0.64; 95% CI: 0.49-0.84; p=0.001).

“Approximately half of all patients with breast cancer have tumors that are HER2 low, which have previously been classified as HER2 negative and have not had effective treatment options with HER2 targeted medicines,” said Shanu Modi, MD, medical oncologist, Memorial Sloan Kettering Cancer Center and principal investigator for the trial. “Based on the promising results of the DESTINY-Breast04 trial, clinicians are starting to differentiate levels of HER2 expression and redefine how metastatic breast cancer is classified with a distinct HER2 low patient population that may be eligible for trastuzumab deruxtecan.”

ENHERTU is approved with Boxed WARNINGS for interstitial lung disease (ILD)/pneumonitis and Embryo-Fetal toxicity. The safety of ENHERTU was evaluated in 371 patients with unresectable or metastatic HER2 low (IHC 1+ or IHC 2+/ISH-) breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in the DESTINY-Breast04 trial. The most common adverse reactions (frequency ≥20%), including laboratory abnormalities, were nausea, decreased white blood cell count, decreased hemoglobin, decreased neutrophil count, decreased lymphocyte count, fatigue, decreased platelet count, alopecia, vomiting, increased aspartate aminotransferase, increased alanine aminotransferase, constipation, increased blood alkaline phosphatase, decreased appetite, musculoskeletal pain, diarrhea and hypokalemia. Overall, 12% of patients had confirmed ILD or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD events were primarily low grade, with five grade 3 (1.3%) and no grade 4 events reported. Fatalities due to adverse reactions occurred in 4% of patients including ILD/pneumonitis (three patients); sepsis (two patients); and ischemic colitis, disseminated intravascular coagulation, dyspnea, febrile neutropenia, general physical health deterioration, pleural effusion and respiratory failure.

“Today’s FDA approval marks a monumental moment in breast cancer treatment as ENHERTU is the first-ever HER2 directed medicine to be approved for the treatment of patients with HER2 low metastatic breast cancer,” said Ken Keller, Global Head of Oncology Business, and President and CEO, Daiichi Sankyo, Inc. “With the groundbreaking survival benefit seen in the DESTINY-Breast04 trial, this milestone confirms the importance of targeting lower levels of HER2 expression in the treatment of metastatic breast cancer and we are thrilled that we can now offer ENHERTU to even more patients.”

“The rapid approval of ENHERTU in HER2 low metastatic breast cancer by the FDA underscores the urgency to bring this transformational medicine to patients as quickly as possible,” said Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca. “Patients with HER2 low tumors, who are identified through existing HER2 testing methods, will now have the opportunity to be treated based upon their HER2 status.”

Financial Considerations

Following approval in the U.S., an amount of $200 million is due from AstraZeneca to Daiichi Sankyo as a milestone payment for an indication for ENHERTU in patients with HER2 low metastatic breast cancer who were previously treated with one or two lines of chemotherapy.

Sales of ENHERTU in the U.S. are recognized by Daiichi Sankyo. For further details on the financial arrangements, please consult the collaboration agreement from March 2019.

About DESTINY-Breast04

DESTINY-Breast04 is a global, randomized, open-label, pivotal phase 3 trial evaluating the efficacy and safety of ENHERTU (5.4 mg/kg) versus physician’s choice of chemotherapy (capecitabine, eribulin, gemcitabine, paclitaxel or nab-paclitaxel) in patients with HR positive or HR negative, HER2 low unresectable and/or metastatic breast cancer previously treated with one or two prior lines of chemotherapy. Patients were randomized 2:1 to receive either ENHERTU or chemotherapy.

The primary endpoint of DESTINY-Breast04 is PFS in patients with HR positive disease based on BICR. Key secondary endpoints include PFS based on BICR in all randomized patients (HR positive and HR negative disease), OS in patients with HR positive disease and OS in all randomized patients (HR positive and HR negative disease). Other secondary endpoints include PFS based on investigator assessment, objective response rate based on BICR and on investigator assessment, duration of response based on BICR and safety. DESTINY-Breast04 enrolled 557 patients at multiple sites in Asia, Europe and North America.

About Breast Cancer and HER2 Expression

Breast cancer is the most common cancer and is one of the leading causes of cancer-related deaths worldwide and in the U.S. More than two million patients with breast cancer were diagnosed in 2020 with nearly 685,000 deaths globally. In the U.S., more than 290,000 patients are expected to be diagnosed in 2022, with more than 43,000 deaths. Approximately one in five patients with breast cancer are considered HER2 positive.

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors including breast, gastric, lung and colorectal cancers, and is one of many biomarkers expressed in breast cancer tumors

About Daiichi Sankyo

Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose “to contribute to the enrichment of quality of life around the world.” In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an “Innovative Global Healthcare Company Contributing to the Sustainable Development of Society.”

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