AstraZeneca and Daiichi Sankyo Launch Global Phase 2 DESTINY-Lung02 Trial of Enhertu in HER2-Mutated Metastatic Non-Small Cell Lung Cancer

March 29, 2021/BioValleyBIOON/--AstraZeneca(AstraZeneca) and Daiichi Sankyo recently jointly announced the global Phase 2Clinical TrialsDESTINY-Lung02 has administered the first dose to a patient. The trial was conducted in patients with HER2-mutant metastatic non-small cell lung cancer (NSCLC) who experienced disease relapse or progression during or after at least one prior platinum-based regimen, evaluating the efficacy and safety of two different doses (5.4 mg/kg and 6.4 mg/kg) of the targeted antibody-drug conjugate (ADC) Enhertu (trastuzumab deruxtecan).

Lung cancer is the leading cause of cancer-related deaths in both men and women, accounting for approximately one-fifth of all cancer deaths worldwide. Of all lung cancer cases, 80%–85% are classified as non-small cell lung cancer (NSCLC). The prognosis is particularly poor for patients with metastatic disease, as only about 6% survive more than five years after diagnosis.

HER2 is a tyrosine kinase receptor, which is a growth-promoting protein expressed in variousTumorsurface, including lung cancer,Breast Cancer, gastric cancer, and colorectal cancer. HER2 gene alterations (referred to as HER2 mutations) have been identified as a distinct molecular target in NSCLC, particularly adenocarcinoma, and are reported in approximately 2%-4% of NSCLC patients. These HER2 gene mutations have been consistently associated independently with cancer cell growth and poor prognosis.. Currently, no drugs have been specifically approved for the treatment of HER2-mutated NSCLC.

Senior Vice President of Daiichi Sankyo andTumorDr. Gilles Gallant, Head of Development, stated: “The identification of HER2 mutations as a distinct molecular target in NSCLC has opened up a new and exciting area of research. Our preliminary findings on Enhertu from the DESTINY-Lung01 trial demonstrated impressive early results in patients with HER2-mutated metastatic NSCLC. Building on these results, we initiated the DESTINY-Lung02 trial to further evaluate the safety and efficacy of two different doses of Enhertu in treating this specific subtype of NSCLC.”

In late January 2021, Daiichi Sankyo and AstraZeneca at the 21st World Conference on Lung Cancer (WCLC) 2020, hosted online by the International Association for the Study of Lung CancerMeetingpublished the Phase II DESTINY-Lung01Clinical TrialNew Data from the Non-Small Cell Lung Cancer (NSCLC) Cohort. Interim analysis data indicate that Enhertu demonstrates highly promising durable anti-TumorActivity.

In Cohort 1 of the Phase II DESTINY-Lung01 trial, 49 patients with HER2-overexpressing (defined as IHC 3+ or IHC 2+) metastatic non-small cell lung cancer (NSCLC) who had previously received multiple regimens (chemotherapy, molecular targeted therapy, and immunotherapy) were enrolled. The median number of prior treatment regimens was three, with the majority having received platinum-based chemotherapy (91.8%) or immunotherapy (73.5%). In the study, these patients (n=49) received Enhertu (6.4 mg/kg), with a median treatment duration of 18 weeks. As of the data cutoff date of May 30, 2020, 22% of patients were still receiving Enhertu treatment.

Results presented at the conference showed that, based on independent central review and assessment, patients with HER2-overexpressing metastatic non-small cell lung cancer (NSCLC) who had previously received multiple treatment regimens achieved a confirmed overall response rate (ORR) of 24.5%, a disease control rate (DCR) of 69.4%, and a median progression-free survival (PFS) of 5.4 months after treatment with Enhertu (6.4 mg/kg). After a median follow-up of 6.1 months, the estimated median duration of response (DOR) was 6.0 months, and the median overall survival (OS) was 11.3 months.

Interim data from the HER2-mutant (HER2m) metastatic NSCLC cohort (n=42) of the DESTINY-Lung01 study were previously presented at the 2020 American Society of Clinical Oncology (ASCO) Virtual Meeting and subsequently published at the WCLC. The results demonstrated that Enhertu also achieved clinically meaningfulTumorReaction.

In recent years, the introduction of targeted therapies and checkpoint inhibitors has improved treatment outcomes for patients with advanced non-small cell lung cancer (NSCLC). However, new therapeutic approaches are needed for patients who are ineligible for effective treatments or whose disease continues to progress. Currently, no HER2-directed therapies have been approved for the treatment of NSCLC with HER2 genetic abnormalities.

May 2020, United StatesFDAGranted Breakthrough Therapy Designation (BTD) for Enhertu for the treatment of patients whose disease has progressed during or after platinum-based chemotherapy,Tumorpatients with metastatic NSCLC harboring HER2 mutations. If approved, Enhertu has the potential to become the first HER2-directed therapy approved for the treatment of NSCLC.

Enhertu is a next-generation antibody-drug conjugate (ADC) that links trastuzumab, a humanized monoclonal antibody targeting HER2, to a novel topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd) via a tetrapeptide linker. This enables targeted delivery of the cytotoxic agent into cancer cells, thereby reducing systemic exposure to the cytotoxic agent compared with conventional chemotherapy.

In March 2019, AstraZeneca and Daiichi Sankyo reached an agreement worth a total of $6.9 billion for immuneTumorAcademic collaboration to jointly develop Enhertu worldwide for cancer patients with varying levels of HER2 expression or HER2 mutations, including gastric cancer, colorectal cancer, lung cancer, and HER2-low breast cancer. Daiichi Sankyo retains exclusive rights for the Japanese market and will be fully responsible for manufacturing and supply.

To date, Enhertu has been approved for the treatment of two types of cancer: (1) adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received at least two HER2-directed regimens; and (2) patients with HER2-positive unresectable advanced or recurrent gastric cancer.

The industry holds a highly optimistic view of Enhertu’s commercial prospects. Previously, the pharmaceutical market research firm EvaluatePharma predicted that Enhertu’s sales in 2024 would reach $2.5 billion. Other industry analysts have forecast that Enhertu’s annual peak sales will exceed $4 billion. (Bioon.com)

Original Source: DESTINY-Lung02 Phase 2 Trial of ENHERTU® Initiated in Patients with HER2-Mutated Metastatic Non-Small Cell Lung Cancer