AstraZeneca announces two Lancet Oncology publications of Phase I dose-expansion results of trastuzumab deruxtecan in HER2-positive metastatic breast and gastric cancer

20.7 months median duration of response in HER2-positive metastatic
breast cancer patients previously treated with trastuzumab emtansine

7.0 months median duration of response in HER2-positive metastatic
gastric cancer patients previously treated with trastuzumab

29 April 2019

AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo) today announced the publication of two manuscripts in The Lancet Oncology reporting long-term Phase I safety and preliminary efficacy results of trastuzumab deruxtecan (DS-8201). The HER2-targeting antibody drug conjugate (ADC) and potential new medicine was evaluated in heavily-pretreated patients with HER2-positive metastatic breast cancer (MBC) and gastric cancer.

HER2-positive breast cancer results

The first manuscript reports results for 115 patients who received at least one dose of trastuzumab deruxtecan of which 111 were evaluable for confirmed response. These patients with HER2-positive MBC previously treated with trastuzumab emtansine received trastuzumab deruxtecan at a recommended expansion dose of 5.4 or 6.4 mg/kg in the dose escalation or dose expansion parts of the Phase I trial. Patients enrolled in this part of the trial had a median of seven prior lines of treatment, including trastuzumab and trastuzumab emtansine, and in 86% of cases, pertuzumab.

A confirmed objective response rate (ORR) of 59.5% (95% CI: 49.7, 68.7) and a disease control rate (DCR) of 93.7% (95% CI: 87.4, 97.4) were observed with trastuzumab deruxtecan. Median duration of response (DoR) was 20.7 months (0.0 to 21.8), median progression-free survival (PFS) was 22.1 months (0.8 to 27.9), and median overall survival (OS) has not yet been reached in the trial. 55 (48%) patients remain on treatment with trastuzumab deruxtecan, as of data cut-off on 10 August 2018.

Kenji Tamura, MD, PhD, Department of Breast and Medical Oncology National Cancer Center Hospital, Tokyo, Japan, and lead author on the manuscript, said: “For patients with HER2-positive metastatic breast cancer that progresses after trastuzumab, pertuzumab, and trastuzumab emtansine, optimal treatment is not clearly defined and choices may be limited. These results demonstrate preliminary clinically-meaningful response rates with an impressive duration of response, supporting further development and suggesting a potential role for trastuzumab deruxtecan as a HER2-targeted therapy option in this setting.”

Safety results for 115 patients with HER2-positive MBC, who received at least one dose of trastuzumab deruxtecan 5.4 or 6.4 mg/kg in part one or part two of the trial also were reported. The most common adverse events (AEs) (≥30%, any grade) included nausea, decreased appetite, vomiting, alopecia, fatigue, anaemia, diarrhoea, and constipation. 50% of patients experienced an AE grade ≥3, and 19% percent had a serious AE, including two previously-reported cases of grade 5 treatment-related pneumonitis. Any reported cases of interstitial lung disease (ILD)/pneumonitis in the trastuzumab deruxtecan clinical development programme are evaluated by an independent adjudication committee, and a formal monitoring and management program is in place with ongoing analyses to help optimally characterise the risk. A presentation of ILD risk characterisation at the San Antonio Breast Cancer Symposium in December 2018 in patients with MBC treated at the recommended dose of 5.4 mg/kg showed an overall incidence of 5.6%, with the majority of cases being grades 1 and 2, and 1.1% grade 3 and above, including one (1) case of grade 5.¹

Summary of results

^{i The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at 5.4 mg/kg or 6.4 mg/kg and for whom both baseline andd post-treatment activity data were available.}

^{ii There were 111 patients who had two or more post baseline scans, had progressive disease, or discontinued treatment for any reason before second postbaseline scan and were considered evaluable for confirmed response.}

^{iii Objective response was calculated as the proportion of patients showing complete response or partial response for a minimum of 5 weeks from the first dosing date.}

^{iv Disease control was calculated as the proportion of patients demonstrating complete response, partial response, or stable disease for a minimum of 5 weeks from the first dosing date.}

^{v Duration of response was measured from the time at which complete response or partial response criteria are first met until the first date of objectively documented progressive disease.}

^{vi Censored observation.}

HER2-positive gastric cancer results

The second manuscript reports results for 44 patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer previously treated with trastuzumab who received trastuzumab deruxtecan at a recommended expansion dose of 5.4 or 6.4 mg/kg in the dose escalation or dose expansion parts of the trial. These patients had a median of three prior lines of treatment including trastuzumab.

A confirmed ORR of 43.2% (95% CI: 28.3, 59.0) and a DCR of 79.5% (95% CI: 64.7, 90.2) were seen with trastuzumab deruxtecan. The median DoR was 7.0 months (4.4 to 16.6), median PFS was 5.6 months (95% CI: 3.0, 8.3), and median OS was 12.8 months (1.4 to 25.4). Three patients remain on treatment with trastuzumab deruxtecan as of data cut-off on 10 August 2018.

Kohei Shitara, MD, National Cancer Center Hospital East, Chiba, Japan, and lead author on the manuscript, said: “These results are encouraging given the limited options for patients with advanced HER2-positive gastric cancer that progresses after initial treatment regimens including trastuzumab. There are no other anti-HER2 therapies approved for gastric cancer beyond trastuzumab, and these data support further study of trastuzumab deruxtecan in these patients.”

Safety results for the 44 patients with HER2-positive gastric or gastro-oesophageal junction cancer who received at least one dose of trastuzumab deruxtecan 5.4 or 6.4 mg/kg in part one or part two of the trial also were presented. The most common AEs (≥30%, any grade) included nausea, decreased appetite, anaemia, platelet count decrease, white blood cell count decrease, and constipation. 64% of patients experienced an AE grade ≥3, and 25% had a serious AE. There were two deaths due to treatment-emergent AEs, (one due to pneumonia and one due to progression of disease), and neither were considered treatment related.

Summary of results

^{vii The activity evaluable set included all patients who received at least one dose of trastuzumab deruxtecan at 5.4 mg/kg or 6.4 mg/kg and for whom both baseline andd post-treatment activity data were available.}

^{viii Objective response is calculated as the proportion of patients showing complete response or partial response for a minimum of 5 weeks from the first dosing date.}

^{ix Disease control was calculated as the proportion of patients showing complete response, partial response, or stable disease for a minimum of 5 weeks from the first dosing date.}

^{x Duration of response was measured from the time at which complete response or partial response criteria are first met until the first date of objectively documented progressive disease.}

^{xi Censored observation.}

Hesham Abdullah, Vice President, Head of Late-Stage Immuno-Oncology Development, Research and Development, Oncology, said: “These results reinforce our belief that trastuzumab deruxtecan could become a transformative new medicine for the treatment of HER2-positive breast and gastric cancers. The encouraging response rates and quality of the duration of response in this heavily-pretreated and difficult-to-treat setting demonstrate the value this potential new medicine can bring to patients with unmet medical needs.”

Gilles Gallant, BPharm, PhD, FOPQ, Vice President, DS-8201 Global Team Leader, Oncology Research and Development, Daiichi Sankyo, said: “These long-term Phase I results support our ongoing pivotal development programme with trastuzumab deruxtecan in HER2-positive metastatic breast and gastric cancers, where significant unmet treatment needs remain. Our pivotal Phase II DESTINY-Breast01 trial has completed enrolment and our Phase III DESTINY-Breast02 and DESTINY-Breast03 trials are underway to further evaluate trastuzumab deruxtecan in HER2-positive metastatic breast cancer. We also are enrolling patients with advanced HER2-positive gastric cancer previously treated with trastuzumab in the pivotal Phase II DESTINY-Gastric01 trial.”

NOTES TO EDITORS

About HER2

HER2 is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells that is associated with aggressive disease and poorer prognosis.^2,3 To be considered HER2-positive, tumour cancer cells are usually tested by one of two methods: immunohistochemistry (IHC) or fluorescent in situ hybridisation (FISH). IHC test results are reported as: 0, IHC 1+, IHC 2+, or IHC 3+. A finding of IHC 3+ is considered HER2-positive, and a finding of IHC 2+ is borderline and typically is confirmed by a positive FISH test.^4,5

Unmet need in HER2-positive breast and gastric cancer 

Approximately one in five breast and gastric cancers are HER2-positive.^4,5 Several unmet treatment needs remain today in HER2-positive MBC. Many HER2-positive breast cancers eventually advance to the point where no currently-approved HER2-targeting medicine continues to control the disease; after treatment with trastuzumab, pertuzumab, and trastuzumab emtansine, optimal treatment is less clearly defined and choices may be limited.^6,7

HER2-expressing gastric cancer also is an area of unmet medical need, where treatment advances have been limited, largely due to the late diagnosis, genetic complexity and heterogeneity of the disease.⁸ Currently, there are no approved HER2-targeting therapies for patients with HER2-positive advanced gastric cancer that progresses after treatment with a trastuzumab-containing regimen.

About the trastuzumab deruxtecan Phase I trial

An open-label, two-part Phase I trial is currently evaluating trastuzumab deruxtecan in patients with advanced/unresectable or metastatic solid tumours that are refractory or intolerant to standard treatment, or for whom no standard treatment is available. The primary objectives of the dose escalation part of the trial were to assess the safety, tolerability, and activity of trastuzumab deruxtecan and determine the recommended dose for expansion. These data were published in The Lancet Oncology.⁹

In the dose expansion part of the trial, trastuzumab deruxtecan is being evaluated at two recommended doses (5.4 mg/kg and 6.4 mg/kg) in five patient cohorts, including HER2-positive advanced or MBC and gastric cancer, HER2-low expressing breast cancer, and other HER2-expressing solid tumours. Enrolment for patients with HER2-positive breast cancer and HER2-positive gastric/gastro-oesophageal cancer has completed. Overall, 292 patients have been enrolled into this Phase I trial of trastuzumab deruxtecan.

About trastuzumab deruxtecan

Trastuzumab deruxtecan (DS-8201; [fam-] trastuzumab deruxtecan in US only) is the lead potential new medicine in the ADC franchise of the Daiichi Sankyo Cancer Enterprise and the most advanced programme in AstraZeneca’s ADC scientific platform. ADCs are targeted cancer medicines that deliver cytotoxic agents to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

A broad and comprehensive development programme with trastuzumab deruxtecan is underway in North America, Europe and Asia, including five pivotal trials in HER2-expressing breast and gastric cancers, including in breast cancer patients with HER2-low expression. Trastuzumab deruxtecan is also in Phase II development for HER2-expressing advanced colorectal cancer and metastatic non-squamous HER2-overexpressing or HER2-mutated NSCLC, and Phase I development in combination with nivolumab for HER2-expressing metastatic breast and bladder cancers.

Trastuzumab deruxtecan was granted Breakthrough Therapy Designation in 2017 by the US 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 trastuzumab emtansine. Fast Track Designation was also granted in the US for the treatment of HER2-positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted medicines, including trastuzumab emtansine. Trastuzumab deruxtecan has received SAKIGAKE designation for the treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer by the Japan Ministry of Health, Labour and Welfare.

About the Collaboration between AstraZeneca and Daiichi Sankyo

In March 2019, AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise trastuzumab deruxtecan as a medicine worldwide, except in Japan where Daiichi Sankyo will maintain exclusive rights. Daiichi Sankyo will be solely responsible for manufacturing and supply.

About 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 at least six new medicines to be launched between 2014 and 2020, and a broad pipeline of small molecules and biologics in development, we are committed to advancing Oncology as a key growth driver for AstraZeneca focused on lung, ovarian, breast and blood cancers. In addition to our core capabilities, we actively pursue innovative partnerships and investments that accelerate the delivery of our strategy as illustrated by our investment in Acerta Pharma in haematology.

By harnessing the power of four scientific platforms – Immuno-Oncology, Tumour Drivers and Resistance, DNA Damage Response and Antibody Drug Conjugates – 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.

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. For more information, please visit astrazeneca.com and follow us on Twitter @AstraZeneca.

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References

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2 American Cancer Society. Breast Cancer HER2 Status. Available at https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-her2-status.html. Accessed April 2019.

3 Tandon A, et al. HER-2/neu Oncogene Protein and Prognosis in Breast Cancer. J Clin Oncol. 1989;7(8):1120-8.

4 Sledge G, et al. Past, Present, and Future Challenges in Breast Cancer Treatment. J Clin Oncol. 2014;32(19):1979-1986.

5 American Cancer Society. Tests for Stomach Cancer. Available at https://www.cancer.org/cancer/stomach-cancer/detection-diagnosis-staging/how-diagnosed.html. Accessed April 2019.

6 de Melo Gagliato D, et al. Mechanisms of Resistance and Sensitivity to Anti-HER2 Therapies in HER2+ Breast Cancer. Oncotarget. 2016;7(39):64431-46.

7 National Comprehensive Cancer Network (NCCN). NCCN Guidelines. Breast Cancer. Available at https://nccn.org. Accessed April 2019.

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9 Doi T, et al. Safety, Pharmacokinetics, and Antitumour Activity of Trastuzumab Deruxtecan (DS-8201), a HER2-Targeting Antibody-Drug Conjugate, in Patients with Advanced Breast and Gastric or Gastro-Oesophageal Tumours: a Phase 1 Dose-Escalation Study. Lancet Oncol. 2017;18(11):1512-22.