ENHERTU® (Trastuzumab Deruxtecan) Achieved a Tumour Response Rate of 45.3% (95% CI, 70.2%-91.9%) in Patients with HER2 Positive Metastatic Colorectal Cancer in Phase 2 DESTINY-CRC01 Trial1

Trastuzumab deruxtecan is presently licensed in the US for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2 based regimens in the metastatic setting. It is also currently approved in Japan for the treatment of patients with HER2 positive unresectable or recurrent breast cancer after prior chemotherapy. It is presently not licensed in other geographic areas. 

Tokyo, Basking Ridge, NJ and Munich - (01 June, 2020) – Results from the phase 2 DESTINY-CRC01 trial of Daiichi Sankyo Company, Limited (hereafter, Daiichi Sankyo) and AstraZeneca’s trastuzumab deruxtecan demonstrated clinically meaningful activity in patients with HER2 positive unresectable and/or metastatic colorectal cancer who received at least two prior lines of standard treatment. These results were presented at the 2020 American Society of Clinical Oncology Virtual Scientific Programme (#ASCO20).  

Colorectal cancer is the third most common cancer and second most common cause of cancer death worldwide.2  There is currently no medicine approved to specifically treat HER2 positive colorectal cancer, which affects approximately two to five percent of patients with colorectal cancer.3 

The primary endpoint of confirmed objective response rate (ORR), also called a tumour response rate, which was assessed by independent central review, showed 45.3% (n=24) of patients with trastuzumab deruxtecan monotherapy (6.4 mg/kg) in patients with HER2 positive advanced colorectal cancer (defined as IHC 3+ or IHC 2+/ISH+) achieved a tumour response (95% CI, 31.6%-59.6%). A disease control rate (DCR) of 83.0% (95% CI, 70.2%-91.9%) was observed with a median progression-free survival (PFS) of 6.9 months. Median duration of response (DoR) and overall survival (OS) have not yet been reached at the time of data cut-off.  

“Understanding new ways we can treat patients with colorectal cancer, such as targeting HER2, is critical as patients have few remaining treatment options once progression occurs in the advance disease setting,” said Salvatore Siena, MD, Professor of Medical Oncology, Department of Oncology and Haemato-Oncology, Università degli Studi di Milano, Milan, Italy and principal investigator of the DESTINY-CRC01 trial. “The results from DESTINY-CRC01 in patients with HER2 positive advanced disease are striking and warrant further research especially considering many of these patients have had numerous prior therapies.”  

Pre-specified exploratory analysis evaluated ORR in subgroups including patients previously treated with a prior anti-HER2 regimen (n=16). In these patients an ORR of 43.8% (95% CI, 19.8-70.1) was seen.  

Patients were treated with a median of four prior lines of therapy (range, 2-11) with all patients having received prior chemotherapy treatment with irinotecan and oxaliplatin. The median treatment duration was 4.8 months (range, 1-11). As of data cut-off on August 9, 2019, 38.5% (30 out of 78) of patients remained on treatment across all cohorts. 

The overall safety and tolerability profile of trastuzumab deruxtecan in DESTINY-CRC01 was consistent with that seen in previously reported trastuzumab deruxtecan trials. The most common grade 3 or higher treatmentemergent adverse events were decreased neutrophil count (25.6%) and anaemia (14.1%). There were five cases (6.4%) of ILD and pneumonitis determined by an independent adjudication committee. Two were grade 2 and one was grade 3. Two deaths (grade 5) were determined to be due to ILD. 

“Metastatic colorectal cancer has a devastating prognosis and there have been limited treatment advances following progression on first-line treatment and there are no therapies approved that specifically target HER2,” said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo. “We are encouraged by the tumour response rates seen in patients with previously treated advanced colorectal cancer and we will continue to explore the potential of trastuzumab deruxtecan to address this unmet medical need.”  

“These clinically meaningful and durable responses in patients with advanced HER2 positive colorectal cancer support our belief that HER2 is an important target in this disease,” said José Baselga, MD, PhD, Executive Vice President, Oncology R&D, AstraZeneca. “Trastuzumab Deruxtecan has demonstrated strong clinical activity in this cancer setting.” 

Summary of Results 

Efficacy Measure  Total Evaluable in primary cohort (n=53)i,ii  Confirmed ORR (%) (95% CI)iv,v 45.3% (31.6 - 59.6) ORR (previously HER2 treated) (n=16) (%)  43.8% (19.8 -70.1) CR (%) 1.9% PR (%) 43.4% SD (%) 37.7% DCR (%) (95% CI)iii 83.0% (70.2 - 91.9) Median DoR (months) (95% CI) Not reached (4.2 months – NE) Median PFS (months) (95% CI) 6.9 months (4.1 months - NE) Median OS (months) (95% CI) Not reached (0.74 months – NE) CI, confidence interval; CR, complete response; PR, partial response; SD, stable disease; NE, not estimable i trastuzumab deruxtecan 6.4 mg/kg  ii Primary cohort included patients with HER2-positive disease (defined as IHC3+ or IHC2+/ISH+). iii DCR is (CR+PR+SD) iv As assessed by independent central review. v ORR is (CR + PR) 

Two exploratory cohorts enrolled patients with tumours with lower levels of HER2 expression (HER2 IHC 2+/ISH- and HER2 IHC 1+, respectively). There were no confirmed responses seen in these two exploratory cohorts. 

About HER2 HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including breast, gastric, lung and colorectal cancers. In some tumours, HER2 overexpression is associated with a specific HER2 gene alteration known as amplification and is often associated with aggressive disease and poorer prognosis.4  

HER2 overexpression and amplification occurs in approximately two to five percent of all patients with colorectal cancer.3 Research indicates that HER2 amplification may be associated with resistance to antiepidermal growth factor receptor (EGFR)-targeted therapy and shorter survival.5,6 

About Colorectal Cancer Colorectal cancer is the second most common cancer in women and the third most common cancer in men worldwide.2 In 2018, more than 1.8 million people worldwide received colorectal cancer diagnoses and approximately 881,000 died from the disease.2  

About DESTINY-CRC01 DESTINY-CRC01 is a global, phase 2, open-label, multicenter, trial evaluating the safety and efficacy of trastuzumab deruxtecan in patients (n=78) with HER2 expressing, unresectable and/or metastatic colorectal cancer. DESTINY-CRC01 excluded patients with a mutation in the RAS or BRAF gene. The primary cohort of the trial enrolled patients (n=53) with HER2 positive (defined as IHC 3+ or IHC2+/ISH+) disease. The primary endpoint of the trial is confirmed ORR, assessed by independent central review, in the primary cohort. ORR, or tumour response rate, represents the percentage of patients whose disease decreased and/or disappeared. Secondary endpoints include DCR, DoR, PFS, and OS. Two additional exploratory cohorts enrolled patients whose tumour had lower levels of HER2 expression (HER2 IHC 2+/ISH-, n=7), and HER2 IHC 1+, n=18, respectively). 

About Trastuzumab Deruxtecan Trastuzumab deruxtecan (fam-trastuzumab deruxtecan-nxki in the U.S. only; trastuzumab deruxtecan outside the U.S.) is a HER2 directed antibody drug conjugate (ADC) and is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC Scientific platform.  

ADCs are targeted cancer medicines 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 DXd ADC technology, trastuzumab deruxtecan is comprised of a HER2 monoclonal antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. 

Trastuzumab deruxtecan has not been approved in the UK, the EU, or countries outside of Japan and the United States, for any indication. It is an investigational agent globally for various indications. Safety and effectiveness have not been established for the subject proposed use. 

Trastuzumab deruxtecan is approved in the U.S. for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who received two or more prior anti-HER2 based regimens based on the DESTINY-Breast01 trial. It is also currently approved in Japan for the treatment of patients with HER2 positive unresectable or recurrent breast cancer after prior chemotherapy. 

About the Trastuzumab Deruxtecan Clinical Development Programme 

A comprehensive development programme for trastuzumab deruxtecan is underway globally with six pivotal trials evaluating the efficacy and safety of trastuzumab deruxtecan monotherapy across multiple HER2 targetable cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway. 

 About the Collaboration between Daiichi Sankyo and AstraZeneca In March 2019, Daiichi Sankyo and AstraZeneca entered into a global collaboration to jointly develop and commercialise trastuzumab deruxtecan worldwide, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is solely responsible for the manufacturing and supply. 

About Daiichi Sankyo UK Daiichi Sankyo UK Ltd is a UK affiliate company with corporate origins in Japan. We create and supply innovative products to help the NHS to deliver better patient care in the fields of cardiovascular disease and oncology.   

Our company was founded in 2006 through the merger of Japanese companies Daiichi and Sankyo in Europe. With a rich legacy of scientific expertise dating back more than 100 years, we are the pioneer behind leading pharmaceuticals that have contributed to the improvement of countless lives across the world.  

Our mission is to contribute to the enrichment of quality of life through the discovery and delivery of innovative medicines that address diverse and unmet medical needs.  

We are committed to providing innovation that demonstrates value and supports the NHS in its delivery of sustainable high-quality care, enabling efforts to reduce health inequalities and unwarranted variations and which puts the patient at the heart of the service. 

About AstraZeneca  AstraZeneca is a global, science-led biopharmaceutical company that focuses on the discovery, development and commercialisation of prescription medicines, primarily for the treatment of diseases in three therapy areas - Oncology, Cardiovascular, Renal & Metabolism and Respiratory. AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. 

AstraZeneca operates in five different locations in the UK, where around 8,300 employees work in research and development, manufacturing, supply, sales and marketing. We supply 40 different medicines to the NHS. The UK is also an important location for AstraZeneca’s clinical trials; in 2018, we undertook 201 trials in the UK, involving 376 centres and over 7,000 patients.