Enhertu achieved a tumour response rate of 45.3% in patients with HER2-positive metastatic colorectal cancer in Phase II DESTINY-CRC01 trial

Results from the Phase II DESTINY-CRC01 trial of AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo)’s Enhertu (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.

Colorectal cancer is the third most common cancer and second most common cause of cancer death globally.¹ There are currently no medicines approved to specifically treat HER2-positive colorectal cancer, which affects approximately 2-5% of patients with colorectal cancer.²

The primary endpoint of confirmed objective response rate (ORR), assessed by independent central review, showed 45.3% of patients with HER2-positive (defined as IHC3+ or IHC2+/ISH+) advanced colorectal cancer treated with Enhertu monotherapy (6.4mg/kg) achieved a tumour response. A disease control rate (DCR) of 83.0% was observed with a median progression-free survival (PFS) of 6.9 months. Median duration of response (DoR) and overall survival (OS) had not yet been reached at the time of data cut-off.

Salvatore Siena, MD, Professor of Medical Oncology, Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, and Niguarda Cancer Center, Milan, Italy and principal investigator of the DESTINY-CRC01 trial, said: “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 advanced disease setting. The results from DESTINY-CRC01 in patients with HER2-positive advanced colorectal cancer are striking and warrant further research, especially considering many of these patients have had numerous prior therapies.”

José Baselga, Executive Vice President, Oncology R&D, said: “These clinically meaningful and durable responses in patients with advanced HER2-positive colorectal cancer support our belief that HER2 is an important treatment target in this disease. Enhertu has now demonstrated impressive clinical activity in four different cancer settings, reinforcing the potential of this remarkable medicine to transform patient outcomes across a range of HER2-targetable tumours.”

Antoine Yver, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo, said: “Metastatic colorectal cancer has a devastating prognosis and there have been limited treatment advances following progression on 1st-line treatment and there are no therapies approved that specifically target HER2. 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 Enhertu to address this unmet medical need.”

Summary of results

CI, confidence interval; CR, complete response; PR, partial response; SD, stable disease; NE, not estimable

i. Enhertu 6.4 mg/kg.

ii. Primary cohort included patients with HER2-positive disease (defined as IHC3+ or IHC2+/ISH+).

iii. As assessed by independent central review.

iv. ORR is (CR + PR).

v. DCR is (CR + PR + SD).

Two exploratory cohorts enrolled patients with tumours with lower levels of HER2 expression (IHC2+/ISH- and IHC1+, respectively). There were no responses seen in these exploratory cohorts.

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

The overall safety and tolerability profile of Enhertu in DESTINY-CRC01 was consistent with that seen in previously reported Enhertu trials. The most common Grade 3 or higher treatment-emergent adverse events were decreased neutrophil count (25.6%) and anaemia (14.1%). There were five cases (6.4%) of interstitial lung disease (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.

Results from DESTINY-CRC01 were presented during the 2020 American Society of Clinical Oncology ASCO20 Virtual Scientific Program on 29 to 31 May 2020.

Colorectal cancer

Colorectal cancer is the third most common cancer and second most common cause of cancer death globally.¹

Approximately 25% of patients have metastatic disease at diagnosis, meaning the disease has spread to distant organs, and about 50% of patients with colorectal cancer will eventually develop metastases.³ Overexpression and amplification of HER2, a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including breast, gastric, lung and colorectal cancers, occurs in approximately 2-5% of all patients with colorectal cancer^.2,4 Research indicates that HER2 amplification may be associated with resistance to anti-epidermal growth factor receptor (EGFR)-targeted therapy and shorter survival.^4,5

DESTINY-CRC01

DESTINY-CRC01 is a global, Phase II, open-label, multi-centre trial testing the safety and efficacy of Enhertu 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 disease (defined as IHC3+ or IHC2+/ISH+). The primary endpoint of the trial is confirmed ORR by independent central review in the primary cohort. ORR, or tumour response rate, represents the percentage of patients whose disease decreased and/or disappears. Secondary endpoints include DCR, DoR, PFS and OS. Two additional exploratory cohorts enrolled patients whose tumours had lower levels of HER2 expression [HER2 IHC2+/ISH- (n=7) and HER2 IHC1+ (n=18), respectively].⁶

Enhertu

Enhertu (trastuzumab deruxtecan, fam-trastuzumab deruxtecan-nxki in the US) 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.

Enhertu (5.4mg/kg) is approved in the US and Japan 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 based on the DESTINY-Breast01 trial.

Enhertu clinical development

A comprehensive development programme is underway globally with six registrational trials evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-targetable cancers including breast, gastric and lung cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

In May 2020, Enhertu received Breakthrough Therapy Designation (BTD) from the US FDA for the treatment of patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more prior regimens including trastuzumab and Orphan Drug Designation for patients with gastric cancer, including gastroesophageal junction cancer. In March 2018, Enhertu received a SAKIGAKE designation for potential use in the same HER2-positive gastric cancer patient population and a supplemental New Drug Application was recently submitted to the Japan Ministry of Health, Labour and Welfare.

In May 2020, Enhertu also received a BTD for the treatment of patients with metastatic non-small cell lung cancer whose tumours have a HER2 mutation and with disease progression on or after platinum-based therapy.

Collaboration between AstraZeneca and Daiichi Sankyo

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

AstraZeneca in oncology

AstraZeneca has a deep-rooted heritage in oncology and offers a quickly growing portfolio of new medicines that has the potential to transform patients’ lives and the Company’s future. With six new medicines launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, the Company is committed to advance oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to AstraZeneca’s main capabilities, the Company is actively pursuing innovative partnerships and investment that accelerate the delivery of our strategy, as illustrated by the investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and ADCs – and by championing the development of personalised combinations, AstraZeneca has the vision to redefine cancer treatment and, one day, eliminate cancer as a cause of death.

AstraZeneca

AstraZeneca (LSE/STO/NYSE: AZN) 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 & Immunology. Based in Cambridge, UK, AstraZeneca operates in over 100 countries and its innovative medicines are used by millions of patients worldwide. Please visit astrazeneca.com and follow the Company on Twitter @AstraZeneca.

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References

1. World Health Organisation. Cancer. The Problem. Available at https://www.who.int/news-room/fact-sheets/detail/cancer.
2. Siena S, et al. Targeting the human epidermal growth factor receptor 2 (HER2) oncogene in colorectal cancer. Ann Oncol. 2018 May; 29(5): 1108–1119.
3. Van Cutsem E, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25(suppl 3): iii1-9.
4. Iqbal N. Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications. Mol Biol Int. 2014; 2014:852748. doi:10.1155/2014/852748.4.
5. Takegawa, et al. HER2 as an Emerging Oncotarget for Colorectal Cancer Treatment After Failure of Anti-Epidermal Growth Factor Receptor Therapy. Clin Colorectal Cancer. 2017;16(4):247-51.
6. Clinicaltrials.gov. NCT03384940. Available at: https://www.clinicaltrials.gov/ct2/show/NCT03384940