Updated phase I safety and efficacy data for [fam-] trastuzumab deruxtecan (DS-8201), an investigational HER2 targeting antibody drug conjugate (ADC) being developed by Daiichi Sankyo, shows a confirmed high overall response rate and a disease control rate in patients with heavily pretreated HER2 mutated non-small cell lung cancer (NSCLC).
Trastuzumab deruxtecan is a targeted cancer agent that deliver cytotoxic chemotherapy (“payload”) to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells. Designed using Daiichi Sankyo’s proprietary ADC technology, [fam-] trastuzumab deruxtecan is comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. The investigational agent is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered. The drug is also the lead product in the investigational ADC Franchise of the Daiichi Sankyo Cancer Enterprise.
Unmet medical need
Lung cancer is the most common cancer in the world and the leading cause of cancer deaths.1 There were approximately 1.8 million new cases of lung cancer reported globally and approximately 1.6 million deaths in 2012.  Non-small cell lung cancer (NSCLC) accounts for approximately 80 to 85% of all cases.  The five-year survival rate for metastatic NSCLC is only one percent.
The introduction of targeted therapies and checkpoint inhibitors in recent years has improved the treatment landscape for metastatic NSCLC patients, who previously had limited options beyond systemic chemotherapy. However, for those who are not eligible for available treatments, or whose cancer continues to progress, new approaches are needed to help manage the disease.
HER2 overexpression has been reported in rates ranging from 4 to 35% of NSCLC, depending on the published series and methods, and is associated with poor disease prognosis and shortened overall survival. HER2 mutations have more recently been identified as distinct molecular targets for NSCLC and have been reported in up to 5 percent of NSCLC.7,8 Currently, no therapy is specifically approved for HER2 mutated or HER2 overexpressing non-small cell lung cancer.
Phase I Study
An open-label, two-part phase I study is currently evaluating [fam-] trastuzumab deruxtecan in patients with advanced/unresectable or metastatic solid tumors that are refractory or intolerant to standard treatment, or for whom no standard treatment is available. The primary objective of the dose escalation phase of this study was to assess the safety and tolerability of and determine the maximum tolerated dose. Data from this part of the study were published in the Lancet Oncology. 
In the dose expansion part of the phase 1 study, [fam-] trastuzumab deruxtecan is given in one of two doses (5.4 mg/kg and 6.4 mg/kg) to patients with HER2 positive advanced or metastatic breast cancer and gastric cancer, HER2 low expressing breast cancer and other HER2 expressing solid tumors including NSCLC. Overall, 292 patients have been enrolled into this phase 1 study of [fam-] trastuzumab deruxtecan.
The latest data were presented for a subgroup of patients with heavily pretreated HER2 mutated or HER2 expressing non-small cell lung cancer (NSCLC) during an Oral Session at the 19th World Conference on Lung Cancer hosted by the International Association for the Study of Lung Cancer (IASLC) in Toronto, Canada.
The results where based on an updated subgroup analysis of 11 patients with HER2 mutated NSCLC receiving a recommended expansion dose of 6.4 mg/kg. The data shows that [fam-] trastuzumab deruxtecan has a confirmed overall response rate of 72.7% (8 of 11 patients) and disease control rate of 100% (11 of 11 patients). Preliminary estimate of median duration of response has reached 11.5 months (95% CI: 0.03+, 11.5) and median progression-free survival has reached 14.1 months (95% CI: 4.0+, 14.1) for this subgroup of patients.
“These preliminary results seen with [fam-] trastuzumab deruxtecan are encouraging, particularly given the existing unmet medical need for patients with metastatic NSCLC with HER2 alterations that have progressed on several prior therapies,” said Junji Tsurutani, MD, PhD, Advanced Cancer Translational Research Institute, Showa University, Tokyo, Japan, a study investigator.
“These results also demonstrate that continued evaluation of treatments that target the HER2 receptor is warranted in patients with NSCLC,” Tsurutani added.
In addition, an updated subgroup analysis of 17 patients with heavily pretreated HER2 mutated or HER2 expressing (defined as IHC ≥1+ or amplified) NSCLC showed that [fam-] trastuzumab deruxtecan demonstrated a confirmed overall response rate of 58.8% (10 of 17 patients) and a disease control rate of 88.2% (15 of 17 patients). Preliminary estimate of median duration of response has reached 9.9 months (95% CI: 0.0+, 11.5) and median progression-free survival has reached 14.1 months (95% CI: 0.9, 14.1).
Patient enrollment Phase II study
“Patient enrollment is currently underway into our phase II study of [fam-] trastuzumab deruxtecan in patients with advanced HER2 mutated or HER2 overexpressing NSCLC,” said Gilles Gallant, BPharm, PhD, Vice President, DS-8201 Global Team Leader, Oncology Research and Development, Daiichi Sankyo.
“Since there are no therapies specifically approved to treat patients with HER2 altered NSCLC, continued study of [fam-] trastuzumab deruxtecan is needed to better understand the potential role of a HER2 targeting antibody drug conjugate in treating these patients,” Gilles Gallant further noted.
Updated preliminary safety data for this subgroup of patients with heavily pretreated HER2 mutated or HER2 expressing NSCLC receiving [fam-] trastuzumab deruxtecan were also reported. The most common adverse events (>30%, any grade) included nausea (50.0%), decreased appetite (50.0%), alopecia (50.0%), fatigue (44.4%) and vomiting (38.9%). Grade 3 adverse events occurring in >10 percent of patients included decreased neutrophil count (11.1%). As previously reported, one (1) grade 5 event of pneumonitis was observed in this cohort, which was adjudicated as unrelated to [fam-] trastuzumab deruxtecan by an independent adjudication committee. Any reported cases of interstitial lung disease (ILD)/pneumonitis in the [fam-] trastuzumab deruxtecan clinical development program are evaluated by an independent adjudication committee.
A broad and comprehensive development program with [fam-] trastuzumab deruxtecan is underway in North America, Europe and Asia. [Fam-] trastuzumab deruxtecan is in pivotal phase 2 clinical development for HER2 positive metastatic breast cancer resistant or refractory to ado-trastuzumab emtansine (DESTINY-Breast01); pivotal phase 2 development for HER2 positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01); phase II development for HER2 expressing advanced colorectal cancer; phase 2 development for metastatic non-squamous HER2 overexpressing or HER2 mutated NSCLC; and, phase 1 development in combination with nivolumab for HER2 expressing metastatic breast and bladder cancer.
[Fam-] trastuzumab deruxtecan has been granted Breakthrough Therapy designation 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 (T-DM1), 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 T-DM1 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).