Datopotamab Deruxtecan Demonstrates Promising Early Clinical Activity in Advanced Non-Small Cell Lung Cancer

January 30, 2021/Bio ValleyBIOON/--AstraZeneca(AstraZeneca) and Daiichi Sankyo recently at the 21st World Conference on Lung Cancer (WCLC) 2020, hosted online by the International Association for the Study of Lung CancerMeetingNew data from the Phase I TROPION-PanTumor01 trial of the TROP2-targeting antibody-drug conjugate (ADC) datopotamab deruxtecan (Dato-DXd; DS-1062) were presented. The data demonstrated encouraging results and favorable clinical activity in the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC).

TROPION-PanTumor01 is a Phase 1 trial that enrolled patients with advanced or metastatic non-small cell lung cancer (NSCLC) who had previously received multiple lines of therapy (n=159), to evaluate three doses of datopotamab deruxtecan (4 mg/kg, 6 mg/kg, and 8 mg/kg). In all three dose groups, the majority of patients had previously received three or more prior lines of therapy, including platinum-based chemotherapy (94%) or immunotherapy (84%). The median follow-up time was 7.4 months. As of the data cutoff date (September 4, 2020), 39% of patients were still receiving treatment with datopotamab deruxtecan.

The results showed that, as of the data cutoff date of September 4, 2020, independent central review observed an objective response rate (ORR) ranging from 21% to 25% among 159 patients with advanced or metastatic non-small cell lung cancer (NSCLC) receiving different doses. There were 32 confirmed complete or partial responses, and an additional 5 unconfirmed complete or partial responses. Due to immature follow-up across the dose groups, the efficacy data are preliminary; however, these initial efficacy results may support the durability of clinical activity. The disease control rates (DCR) for the three doses of datopotamab deruxtecan ranged from 67% to 80%, with a median progression-free survival (PFS) of 4.3 to 8.2 months.

In this trial, datopotamab deruxtecan demonstrated a manageable safety profile, consistent with previous reports. Overall, the 4 mg/kg and 6 mg/kg doses were better tolerated than the 8 mg/kg dose. The most common grade ≥3 treatment-emergent adverse events (TEAEs) included mucosal inflammation,AnemiaStomatitis and fatigue occurred at higher overall rates in patients treated at the 8 mg/kg dose. Fourteen cases (8%) of interstitial lung disease (ILD) were identified by an independent adjudication committee. The majority of ILD cases (12/14) occurred in the 8 mg/kg cohort, including three fatalities (Grade 5). One case of Grade 3 ILD occurred in the 4 mg/kg dose group, and one case of Grade 2 ILD occurred in the 6 mg/kg dose group.

Lung cancer is the leading cause of cancer-related deaths in both men and women, accounting for approximately one-fifth of global cancer mortality, with 80–85% of cases classified as non-small cell lung cancer (NSCLC). The prognosis is particularly poor for patients with metastatic disease, with only 6–10% surviving more than five years after diagnosis.

TROP2 (trophoblast cell surface antigen 2) is a transmembrane glycoprotein that is overexpressed in many cancers. TROP2 expression is associated with poor overall survival and disease-free survival in various solid tumors. TROP2 expression has been observed in up to 64% of adenocarcinomas and up to 75% of squamous cell carcinomas in non-small cell lung cancer (NSCLC).

In recent years, the introduction of targeted therapies and checkpoint inhibitors has improved treatment outcomes for patients with advanced NSCLC. However, new treatment options are needed for those who are ineligible for effective therapies or whose cancer continues to progress. Currently, no TROP2-directed therapy has been approved for the treatment of NSCLC.

In March 2019, AstraZeneca and Daiichi Sankyo signed an agreement with a total value of up to $6.9 billion for immuno-Tumorcollaborated to jointly develop the HER2-targeted ADC therapy Enhertu (trastuzumab deruxtecan, DS-8201) for the treatment of patients with various cancers exhibiting different levels of HER2 expression or HER2 mutations, including gastric cancer, colorectal cancer, and lung cancer, as well as those with low HER2 expressionBreast Cancer。

In July 2020, the two parties signed another agreement with a total value of up to $6 billion for immunotherapy.Tumoracademic collaboration to jointly develop the TROP2-targeting ADC therapy datopotamab deruxtecan (DS-1062), which is currently in Phase I clinical trials for the treatment of non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC).

In August 2020, the two parties entered into aClinical TrialCollaboration to evaluate patritumab deruxtecan (U3-1402) in combination with Tagrisso (generic name: osimertinib) for the treatment of patients with EGFR-mutated advanced or metastatic non-small cell lung cancer (NSCLC).

Enhertu, datopotamab deruxtecan, and patritumab deruxtecan are all next-generation ADC drugs developed by Daiichi Sankyo using DXd ADC technology, utilizing a tetrapeptide linker to targetTumorHumanized monoclonal antibodies targeting specific cell surface antigens—namely, anti-HER2 monoclonal antibody (trastuzumab), anti-TROP2 monoclonal antibody, and anti-HER3 monoclonal antibody (patritumab)—are conjugated with a novel topoisomerase I inhibitor, an exatecan derivative (DX-8951 derivative, DXd). This conjugation enables targeted delivery of the cytotoxic agent into cancer cells, thereby reducing systemic exposure to the cytotoxic agent compared with conventional chemotherapy.

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 anti-HER2 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. Pharmaceutical market research firm EvaluatePharma previously 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: Datopotamab deruxtecan and Enhertu show promising early clinical activity in patients with advanced non-small cell lung cancer