In an interview with PharmaShots, Ken Keller, President and Chief Executive Officer at Daiichi Sankyo and Global Head of the Daiichi Sankyo Oncology Business shared his views on the NICE CDF recommendation for Enhertu in unresectable or metastatic HER2 positive breast cancer and the company's growth and pipeline.

Shots:

• The recommendation from NICE is based on the P-II DESTINY-Breast01 trial of trastuzumab deruxtecan (5.4 mg/kg) in 184 patients with HER2+ metastatic breast cancer who had received two or more prior anti-HER2-based therapies.
• The study demonstrated an ORR of 61.4%, including a 6.5% CRR and a 54.9% PRR. After a median follow-up of 20.5mos., the mDoR was 20.8mos.
• NICE has recommended trastuzumab deruxtecan for use on the CDF meaning that eligible women with metastatic breast cancer in England can access these treatments imminently in advance of a decision from NICE on routine funding through the NHS.

Tuba: Q1. For our readers, are you able to describe what metastatic breast cancer is, it's symptoms, risk factors, diagnosis, treatment options etc.?

Ken: Despite decades of innovation and recent medical developments, breast cancer remains the most common cancer and one of the leading causes of cancer-related deaths in women worldwide. Globally, more than two million cases of breast cancer are diagnosed each year, resulting in nearly 685,000 deaths.[i],[ii] 

Most patients with breast cancer are diagnosed in the early stages when their cancer is localized in the breast (stage 1). However, some patients will eventually develop metastatic disease (stage 4), which is when cancer has spread to distant parts of the body.[iii],[iv]

Most breast cancer deaths are due to complications from metastatic disease, with only around 26-28% of patients surviving beyond five years.6,[v],[vi] For patients diagnosed with metastatic disease at first diagnosis, survival is much lower with only 6% of patients surviving beyond five years.3

Breast cancer is currently classified into three main subtypes, which guide prognosis and treatment decisions. One of the main subtypes is human epidermal growth factor receptor 2 (HER2) positive, which means that there are high levels of HER2 present on the surface of tumor cells or a high number of copies of the HER2 gene.8,[vii] HER2 positive disease accounts for approximately one in five breast cancers (15-20%).[viii],[ix]

Patients with HER2 positive disease are eligible for HER2 directed therapies.5  However,despite recent improvements and approvals of new medicines, metastatic breast cancer remains incurable and additional treatment strategies are needed.[x],[xi] One of the biggest challenges for patients with HER2 positive metastatic disease has been identifying a treatment that produces a durable response in later line settings.[xii]

There has been no clear standard of care for patients with metastatic HER2 positive disease following progression on second-line treatment.16 Patients in the previously treated setting (third- or later-line) generally have a median progression-free survival (PFS) of between 3.3-9.6 months.[xiii],[xiv],[xv]

Tuba: Can you share the clinical data that supports the NICE recommendation for ENHERTU?

Ken: The recommendation from NICE is based on the results of the single arm, global, multicenter, open label, phase 2 DESTINY-Breast01 trial of trastuzumab deruxtecan (5.4 mg/kg) in 184 patients with HER2 positive metastatic breast cancer who had received two or more prior anti-HER2-based therapies.

Results from the data cut-off in June 2020 demonstrated a confirmed objective response rate (ORR) of 61.4% (95% CI: 54.0-68.5), including a 6.5% complete response rate and a 54.9% partial response rate. After a median follow-up of 20.5 months, the median duration of response (DoR) was 20.8 months (95% CI: 15.0-NR). Trastuzumab deruxtecan showed a generally tolerable safety profile with 34 (18.5%) treatment discontinuations due to treatment-emergent adverse events.

For further information about trastuzumab deruxtecan, such as the licensed indication and safety profile, please refer to the summary of product characteristics

Tuba: What does the availability of ENHERTU via the CDF mean for women with metastatic breast cancer in England?

Ken: The Cancer Drugs Fund (CDF) is a source of funding for cancer drugs in England. It provides access to promising new treatments, via managed access arrangements, while further evidence is collected to address clinical uncertainty, giving patients access to these treatments much earlier than before.

As such, NICE has recommended trastuzumab deruxtecan for use on the CDF meaning that eligible women with metastatic breast cancer in England can access these treatments imminently in advance of a decision from NICE on routine funding through the NHS.

Tuba: When can we expect ENHERTU to be available in the UK completely and what are your plans for other EU countries?

Ken: Trastuzumab deruxtecan is currently available via the CDF to eligible patients in England and the data collection period is expected to end when sufficient data have been collected to address the committee's uncertainties. Daiichi Sankyo and AstraZeneca are committed to working with regulatory and payer agencies as they review trastuzumab deruxtecan to ensure that there is equitable patient access across the four UK nations. Discussions with Welsh and Northern Irish health authorities are ongoing. Submission for the appraisal of trastuzumab deruxtecan to the Scottish Medicines Consortium is currently in development, with a decision expected later in 2021.

In January 2021, trastuzumab deruxtecan was granted conditional approval in Europe as a monotherapy 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. The approval is for all EU member states plus Norway, Iceland and Liechtenstein. We are in ongoing discussions with regulatory authorities worldwide regarding next steps for the potential use of trastuzumab deruxtecan for patients with HER2 positive breast cancer.  

Tuba: In which other regions are Daiichi Sankyo and AstraZeneca seeking approval of ENHERTU?

Ken: We are working with heath authorities worldwide to expand the countries where trastuzumab deruxtecan is approved and available. In addition to the UK and the EU, trastuzumab deruxtecan (5.4 mg/kg) is approved under accelerated approval in the U.S. and under the conditional early approval system in Japan for the same HER2 positive breast cancer indication based on the results from the DESTINY-Breast01 trial.

Trastuzumab deruxtecan (6.4 mg/kg) is also approved in the U.S. and Japan for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma who have received a prior trastuzumab-based therapy, based on the results from the DESTINY-Gastric01 trial. We are continuing to work with health authorities worldwide to expand access of trastuzumab deruxtecan to more patients with gastric cancer.

Tuba: What are the specifications of ENHERTU MOA, RoA, dosage and cost?

Ken: Trastuzumab deruxtecan is a HER2 directed antibody drug conjugate (ADC). Trastuzumab deruxtecan is comprised of a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a tetrapeptide-based cleavable linker.

Trastuzumab deruxtecan (5.4 mg/kg) is approved in the U.S., under accelerated approval, and Japan, under the conditional early approval system, as a treatment for 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 based on the DESTINY-Breast01 trial. Trastuzumab deruxtecan is also approved in the U.S. and Japan (6.4 mg/kg) for the treatment of patients with HER2 positive unresectable advanced or recurrent gastric cancer that has progressed after a trastuzumab-containing regimen based on the DESTINY-Gastric01 trial.

Tuba: What are the next steps for ENHERTU?

Ken: Daiichi Sankyo and AstraZeneca have a comprehensive global development program for trastuzumab deruxtecan underway evaluating the efficacy and safety of trastuzumab deruxtecan monotherapy across multiple HER2 targetable cancers, including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Tuba: What is the role of ADCs in the management of HER2-positive breast cancer?

Ken: Trastuzumab deruxtecan is a HER2 directed antibody drug conjugate (ADC). ADCs are targeted cancer medicines, combining target specificity and potent anti-tumor activity in a single molecule. They are designed to address the limitations of traditional chemotherapy, which attacks both normal and cancer cells. ADCs aim to enable the targeted delivery of the cancer-killing medicine (payload) specifically to the tumor cells while sparing the healthy cells.[xvi]

Designed using Daiichi Sankyo's proprietary DXd ADC technology, trastuzumab deruxtecan is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZeneca's ADC scientific platform.

Trastuzumab deruxtecan is comprised of a humanized anti-HER2 IgG1 monoclonal antibody with the same amino acid sequence as trastuzumab attached to topoisomerase I inhibitor payload, an exatecan derivative, via a tetrapeptide-based cleavable linker.

This highly targeted approach allows for the efficient delivery of the therapy specifically inside the cancer cells while reducing exposure to healthy tissue.

Tuba: What other programs/developments does Daiichi Sankyo have/working on to increase its global footprint in oncology?

Ken: Daiichi Sankyo's R&D strategy of 3 and Alpha, anchored by our DXd ADC technology, is to harness the power of true innovation to discover and develop innovative first-in-class and best-in-class treatments that transform the standard of care for patients with cancer.

The DXd ADC portfolio of Daiichi Sankyo currently consists of seven ADCs with six in clinical development across multiple types of cancer. The company's three lead ADCs include trastuzumab deruxtecan, a HER2 directed ADC, and datopotamab deruxtecan (Dato-DXd), a TROP2 directed ADC, which are being jointly developed and commercialized globally with AstraZeneca; and patritumab deruxtecan (HER3-DXd), a HER3 directed ADC. Three additional ADCs including DS-7300 (B7-H3), DS-6157 (GPR20) and DS-6000 (CDH6) are being developed through a strategic research collaboration with Sarah Cannon Research Institute.

Each ADC is designed using Daiichi Sankyo's proprietary DXd ADC technology to target and deliver chemotherapy inside cancer cells that express a specific cell surface antigen. Each ADC consists of a monoclonal antibody attached to topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

Tuba: What are the wider company goals for the next 12 months?

Ken: We are dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose to contribute to the enrichment of the quality of life around the world. In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an Innovative Global Healthcare Company Contributing to the Sustainable Development of Society.

In April 2021, we launched our new Oncology Business Unit, aligning U.S. and European oncology businesses, global oncology functions of marketing, market access and pricing, and medical affairs as well as alliance management under one team singularly devoted to people with cancer. The Oncology Business Unit will allow us to bring an unprecedented focus to respond to the rapid changes we see in standards of care, treatment and diagnosis patterns and payer dynamics from both perspectives of business and science.  

Reference:

[i] Sung. H et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal For Clinicians. doi: 10.3322/caac.21660

[ii] WHO. International Agency of Cancer Research. Cancer Today. 2020. Available at: https://gco.iarc.fr/today/home Accessed: May 2021.

[iii] Riggio A et al. The lingering mysteries of metastatic recurrence in breast cancer. BJC. 2021;124:13-26.

[iv] ACS. Survival Rates for Breast Cancer. 2020. Available at: https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-survival-rates.html Accessed: May 2021.

[v] Breast Cancer Survival Statistics. Cancer Research UK. Available from: https://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/breast-cancer/survival. Accessed: May 2021.

[vi] Breast Cancer Facts & Figures | American Cancer Society. Available at: https://www.cancer.org/research/cancer-facts-statistics/breast-cancer-facts-figures.html. Accessed: May 2021.

[vii] Understanding a Breast Cancer Diagnosis. Available at:  https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis.html. Accessed: April 2021.

[viii] Pillai R, et al. HER2 mutations in lung adenocarcinomas: A report from the Lung Cancer Mutation Consortium. Cancer. 2017:123(21):40999-4105. doi: 10.1002/cncr.30869. Epub 2017 Jul 25.

[ix] Ahn S, et al. HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation. J Pathol Transl Med. 2020 Jan; 54(1): 34'44. doi: 10.4132/jptm.2019.11.03

[x] de Melo Gagliato D, Leonardo Fontes Jardim D, Marchesi M, S, P, et al. Mechanisms of resistance and sensitivity to anti-HER2 therapies in HER2+ breast cancer. Oncotarget. 2016;7(39):64431-64446.

[xi] National Comprehensive Cancer Network (NCCN). NCCN Guidelines Version 6.2020. Breast Cancer.

[xii] Taratino P. et al. Third-line treatment of HER2-positive advanced breast cancer: From no standard to a Pandora's box.  Biochim Biophys Acta Rev Cancer. 2021 Jan;1875(1):188487. doi: 10.1016/j.bbcan.2020.188487.

[xiii] Verma S, Miles D, Gianni L, et al. Trastuzumab Emtansine for HER2-Positive Advanced Breast Cancer. New England Journal of Medicine. 2012;367(19):1783-1791.

[xiv] Krop I, E, Kim S,-B, González-Martín A, et al. Trastuzumab emtansine versus treatment of physician’s choice for pretreated HER2-positive advanced breast cancer (TH3RESA): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014;15(7):689-699.

[xv] Saura C, Oliveira M, Feng Y,-H, et al. Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in HER2-Positive Metastatic Breast Cancer Previously Treated With = 2 HER2-Directed Regimens: Phase III NALA Trial. J Clin Oncol. 2020;38(27):3138-3149.

[xvi] Peters and Brown. Antibody drug conjugates as novel anti-cancer chemotherapeutics. Biosci Rep. 2015 Aug; 35(4): e00225. doi: 10.1042/BSR20150089

About Ken Keller:

Ken Keller is the President and Chief Executive Officer at Daiichi Sankyo and the Global Head of the Daiichi Sankyo Oncology Business.

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