While ESMO 2023 is just about to begin, the leading brands in the Pharma industry including Eli Lilly, AstraZeneca, Novartis, Daiichi Sankyo, etc. are all geared up for this conference to present the data readouts and final analysis. Breast Cancer is one of the most malignant forms of cancer affecting a large segment of the population in the US and the major countries in Europe. The key market players are quite enthusiastic about this indication for treatment. The hype for the session is the primary results of ENHERTU from DESTINY-PanTumor01 study and Datopotamab deruxtecan from TROPION-Breast01 trial and final results of SYD985 from TULIP trial.

Breast Cancer Highlights

• Abstract Number – #LBA11

• Abstract Type - Proffered Paper Session
• Indication - HR+/HER2– breast cancer
• Technology - DXd ADC technology

Title: AstraZeneca to present the primary results of Phase III Pivotal trial TROPION-Breast01 of datopotamab deruxtecan in previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer

Executive Summary - The promising initial results from TROPION-Breast01 suggested that datopotamab deruxtecan could potentially become a substantial treatment option for patients with metastatic HR+, HER2-low, or HER2-negative breast cancer.

Main Content - TROPION-Breast01 is the pivotal trial of datopotamab deruxtecan in patients with previously treated inoperable or metastatic hormone receptor (HR)-positive, HER2-low or negative breast cancer. The encouraging primary outcomes of TROPION-Breast01 highlighted the possibility of datopotamab deruxtecan to emerge as a significant therapeutic choice for individuals with hormone receptor (HR)-positive, HER2-low or HER2-negative breast cancer in the later stages of metastasis.

Datopotamab deruxtecan (Dato-DXd) is an investigational TROP2 directed ADC,designed using Daiichi Sankyo’s proprietary DXd ADC technology, datopotamab deruxtecan is one of six ADCs in the oncology pipeline of Daiichi Sankyo, and one of the most advanced programs in AstraZeneca’s ADC scientific platform. Datopotamab deruxtecan is comprised of a humanized anti-TROP2 IgG1 monoclonal antibody, developed in collaboration with Sapporo Medical University, attached to a number of topoisomerase I inhibitor payloads via tetrapeptide-based cleavable linkers.

If approved, Dato-DXd will be in direct competition with Gilead’s TRODELVY, which was the first TROP2-directed ADC approved in 2020 and then expanded to the HR+/HER2–breast cancer in February 2023. Currently, TRODELVY is approved in a third-line setting and it is the first TROP2-directed ADC to demonstrate OS benefit in HR-positive, HER2 metastatic breast cancer patients who had received prior endocrine-based therapy and at least two chemotherapies.

Dato-DXd is targeting inoperable or metastatic HR+/HER2–breast cancer patients who have been treated with one or two prior lines of systemic chemotherapy. With expected launch in 2026, Dato-DXd is expected to generate revenue of around USD 900 million by 2032 in the US in 2L+ setting.

 

• Abstract Number - #386 MO

• Abstract Type - Mini oral session
• Indication - HER2-positive metastatic breast cancer
• Technology - Duocarmazine linker-drug (LD) technology BronZine

Title – Byondis to present final results of the phase III TULIP trial of Trastuzumab duocarmazine versus physician's choice therapy in pre-treated HER2-positive metastatic breast cancer

Executive Summary - Byondis' hopes for FDA approval were dashed with a complete response letter, but the company remains optimistic as the European Medicines Agency validates their Marketing Authorization Application, anticipating a favorable outcome.

Main Content - Trastuzumab duocarmazine (SYD985), a second-generation ADC, is composed of an antibody backbone, linked to the vc-seco-DUBA payload, a potent duocarmacyn analog with a DAR of 2.8:1. Initial comparisons with T-DM1 indicated SYD985's promising efficacy in HER2-positive and HER2 low expression models, leading to Phase I trials exploring its potential in various HER2-expressing histologies. In breast cancer dose-expansion cohorts, 33% of HER2-positive patients achieved partial responses, along with 28% of HER2-low, hormone receptor-positive patients and 40% of HER2-low, hormone receptor-negative patients showing objective partial responses. 

The drug progressed directly into the TULIP trial, a Phase III trial for HER2-positive metastatic patients. The trial compared 2:1 SYD985 with treatment of physician’s choice (TPC), utilizing predefined standard options such as a combination of chemotherapy and trastuzumab or lapatinib. The study included patients with two or more prior lines of treatment in the metastatic setting or prior T-DM1 use, with a median of four prior therapies. The primary endpoint was centrally reviewed median progression-free survival (PFS), which was 7.0 months for the SYD985 group and 4.9 months for the TPC group, showing a statistically significant hazard ratio (HR) of 0.64. However, no significant benefit was observed in terms of overall survival (OS) during the initial analysis.

Based on the TULIP trial data, Byondis submitted the BLA to the FDA, which was accepted by the FDA in July 2022. However, in May 2023, the FDA issued a complete response letter and suspended the decision on the product’s approvability. The FDA requested additional information that will require time and resources, that extend beyond the current evaluation period. The company is hopeful in Europe as the European Medicines Agency (EMA) has validated the Marketing Authorization Application and the company is awaiting the outcome of the review process.