This week Daiichi Sankyo confirmed a clinical research collaboration with Merck KGaA, Darmstadt, Germany and Pfizer to evaluate [fam-] trastuzumab deruxtecan, an antibody-drug conjugate or ADC also known as DS-8201, in combination with avelumab (Bavencio®; EMD Serono/Pfizer), a human anti-programmed death ligand-1 (PD-L1) antibody, and a novel, investigational DNA damage response (DDR) inhibitor in patients with human epidermal growth factor receptor 2 (HER2-) expressing and mutated solid tumors.
[Fam-] Trastuzumab Deruxtecan, Daiichi Sankyo’s lead product, is designed to deliver a cytotoxic chemotherapeutic payload directly to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.
Using Daiichi Sankyo’s proprietary ADC technology, [fam-] trastuzumab deruxtecan includes a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload which are linked via a tetrapeptide-based linker. The drug is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload compared to the way chemotherapy is commonly delivered.
Daiichi Sankyo has entered also entered into separate a clinical trial collaboration to conduct preclinical studies evaluating [fam-] trastuzumab deruxtecan in combination with avelumab, the DDR inhibitor and other investigational compounds currently included in the Merck KGaA and Pfizer’s pipelines.
“The collaboration is another milestone in our development strategy to maximize the potential of [fam-] trastuzumab deruxtecan for various HER2 expressing and mutated cancers in combination with immunotherapy and other agents with novel mechanisms of action,” said Tom Held, Vice President, Head, antibody-drug conjugate task force, oncology research and development, Daiichi Sankyo.
“We look forward to working with Merck KGaA and Pfizer to determine an appropriate combination strategy to help further improve outcomes for patients. In particular, we are enthusiastic about better understanding the potential of combining [fam-] trastuzumab deruxtecan with DNA damage response agents,” Held added.
In the new trial, [fam-] trastuzumab deruxtecan will be investigated in combination with avelumab, a human anti-programmed death ligand-1 (PD-L1) antibody, which has in preclinical models has shown to engage both the adaptive and innate immune functions.
By blocking the interaction of PD-L1 with PD-1 receptors, avelumab releases the suppression of the T cell-mediated anti-tumor immune response in preclinical models. Avelumab has also been shown to induce NK cell-mediated direct tumor cell lysis via antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro.
The drug is currently being evaluated in the JAVELIN clinical development program, which involves at least 30 clinical programs, including eight Phase III trials, and more than 9,000 patients across more than 15 different tumor types.
In November 2014, Merck KGaA, Darmstadt, Germany and Pfizer announced a strategic alliance to co-develop and co-commercialize avelumab.
Under the terms of the agreement, Daiichi Sankyo will conduct a three-part Phase Ib multicenter, open-label study to determine the safety and efficacy of [fam-] trastuzumab deruxtecan in combination with avelumab and/or a novel DDR inhibitor.
The first part of the study (Part A) will include a dose-escalation and dose-expansion phase to evaluate the maximum tolerated dose, safety and efficacy of [fam-] trastuzumab deruxtecan in combination with avelumab. Patients with HER2 expressing cancer refractory to standard treatment will be enrolled into the dose-escalation phase of Part A of the study. The study design includes four cohorts of patients who will be enrolled into the dose-expansion phase.
The second part of the study (Part B) will include a dose-escalation and dose-expansion phase to evaluate the maximum tolerated dose, safety and efficacy of [fam-] trastuzumab deruxtecan in combination with the DDR inhibitor in patients with HER2 expressing or mutated advanced/metastatic solid tumors.
The third part of the study (Part C) will evaluate the triple combination of [fam-] trastuzumab deruxtecan, avelumab and the novel DDR inhibitor in patients with HER2 expressing cancer once the recommended expansion doses are known from Parts A and B.
The primary endpoints of each part of the study are maximum tolerated dose (MTD), recommended expansion dose (RED) and objective response rate (ORR). Secondary endpoints include duration of response, disease control rate, progression-free survival (PFS), overall survival (OS), time to response (TTR) and key safety endpoints.
The study is expected to enroll approximately 200 patients in the U.S., Europe and Asia.
Comprehensive development program
The trial collaboration is part of a broad and comprehensive development program with [fam-] trastuzumab deruxtecan in North America, Europe and Asia. [Fam-] trastuzumab deruxtecan is currently in phase III development versus ado-trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche) in a trial called DESTINY-Breast03. The drug is also investigated versus investigator’s choice post ado-trastuzumab emtansine (DESTINY-Breast02) for HER2 positive metastatic breast cancer, is studies in a pivotal phase II clinical development for HER2 positive metastatic breast cancer resistant or refractory to ado-trastuzumab emtansine (DESTINY-Breast01).
[fam-] trastuzumab deruxtecan is also investigated in a pivotal phase II development for HER2 positive advanced gastric cancer resistant or refractory to trastuzumab (Herceptin®; Genentech/Roche in DESTINY-Gastric01, a phase II development for HER2 expressing advanced colorectal cancer, a phase II development for metastatic non-squamous HER2 overexpressing or HER2 mutated NSCLC and a phase I development in combination with nivolumab for HER2 expressing metastatic breast and bladder cancer.
[Fam-] trastuzumab deruxtecan has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (FDA) for the treatment of patients with HER2 positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab and pertuzumab and have disease progression after ado-trastuzumab emtansine, and Fast Track designation for the treatment of HER2 positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2 targeted therapies including ado-trastuzumab emtansine by the U.S. Food and Drug Administration (FDA). [Fam-] trastuzumab deruxtecan has received SAKIGAKE Designation for the treatment of HER2 positive advanced gastric or gastroesophageal junction cancer by the Japan Ministry of Health, Labour and Welfare (MHLW).
*DS-8201 is known as [fam-] trastuzumab deruxtecan in United States and known in other parts of the world as trastuzumab deruxtecan, is the lead product in the investigational ADC Franchise of the Daiichi Sankyo.