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Latest Research and Development of ADCs for HER2 Cancer Therapy

One of the limitation of traditional chemotherapy in the treatment of cancer is dose-limiting toxicity caused by the exposure of non-tumor cells to cytotoxic agents.

Molecular targeted drugs, including specific kinase inhibitors and antibodies may help overcome this limitation. Antibody–drug conjugate or ADC offer a rational strategy for improving efficacy and reducing systemic adverse events.[1]

Antibody-drug Conjugates deliver potent cytotoxic agents directly to tumor cells and drastically improving the therapeutic index of chemotherapeutic agents.

The clinical failure of early ADCs in the 1980s and ’90s have led to improvements in ADC technology, and resulted in the approval of four novel Antibody-drug Conjugates.  While these novel agents are successful in treating patients, further advances in ADC technology are required to streamline their clinical efficacy and reduce toxicity.

[fam-] Trastuzumab deruxtecan (DS-8201a),  a next-generation ADC being developed by Daiichi Sankyo, is expected to satisfies requirements based on currently available evidence.

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. This investigational agent targets and delivers chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.[2]

DS-8201a has several innovative features: a highly potent novel payload with a high drug-to-antibody ratio (DAR), good homogeneity, a tumor-selective cleavable linker, stable linker-payload in circulation, and a short systemic half-life cytotoxic agent in vivo.

In addition, the released cytotoxic payload could exert a bystander effect.

With respect to its preclinical profiles, the investigational agent may provide a valuable therapy with a great potential against HER2-expressing cancers in clinical settings. In a phase I trial, DS-8201a has shown acceptable safety profiles with potential therapeutic efficacy, with the wide therapeutic index.

In a new review article, published in J-STAGE | Chemical and Pharmaceutical Bulletin, Takashi Nakada, Kiyoshi Sugihara, Takahiro Jikoh, Yuki Abe, Toshinori Agatsuma discuss the latest research and development of ADCs.

Reference
[1] Nakada T, Sugihara K, Takahiro Jikoh T, Yuki Abe, Agatsuma T. The Latest Research and Development into the Antibody–Drug Conjugate, [fam-] Trastuzumab Deruxtecan (DS-8201a), for HER2 Cancer Therapy. J-STAGE | Chemical and Pharmaceutical Bulletin | Volume 67 (2019) 3 [Article]
[2] Hofland P. Encouraging Preliminary Results in Treatment of Colorectal Cancer with Trastuzumab Deruxtecan. ADC Review | J. Antibody-drug Conjugates. October 21, 2018 [Article]


Last Editorial Review: March 6, 2019

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Updated Analysis from Ongoing Phase I Trial of DS-8201 Confirms Significant Benefit for HER2+ Breast Cancer Patients Pretreated with Ado-trastuzumab Emtansine

About one in five breast cancers overexpress HER2, a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells, which is associated with aggressive disease.[1]

To be considered HER2-positive, tumor cancer cells are usually tested by one of two methods: immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). [1] IHC test results are reported as: 0, IHC1+, IHC2+ or IHC3+. [1] A finding of IHC3+ is considered HER2-positive.[1] A finding of IHC2+ is borderline and typically is confirmed by a positive FISH test.[1]

Unmet Medical Need
In the treatment of cancer, several unmet medical needs remain today in HER2-expressing metastatic breast cancer (also called stage IV or advanced breast cancer).

Metastatic breast cancer is breast cancer that has spread beyond the breast to other organs in the body, including  bones, lungs, liver or brain.  In many cases, these tumors advance to the point where no currently approved HER2-targeting treatment continues to control the disease, and there is no current standard of care for HER2-positive tumors after treatment with trastuzumab, pertuzumab and ado-trastuzumab emtansine (T-DM1). [2] Additionally, there are no anti-HER2 therapies indicated for HER2 low-expressing tumors (IHC2+/FISH- or IHC1+).


The results seen in patients with HER2 low-expressing breast cancer are compelling and could challenge how we define HER2-positive breast cancer with regards to ADC therapy. Clearly, further study of DS-8201 is warranted in both these types of HER2-expressing breast cancer


Updated study results
Updated safety and efficacy data from two subgroups of evaluable patients with metastatic breast cancer from an ongoing Phase I study of DS-8201, an investigational HER2-targeting antibody-drug conjugate (ADC) being developed by Daiichi Sankyo, presented during a Spotlight Poster Discussion session at the San Antonio Breast Cancer Symposium (SABCS) held December 5 – 9, 2017 in San Antonio, Texas (USA), shows significant benefit in patients with advanced HER2-positive breast cancer.

DS-8201 is the lead product in the ADC Franchise of the Daiichi Sankyo Cancer Enterprise.  Antibody-drug Conjugates or 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 ADC technology, DS-8201 is a smart chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor payload by a tetrapeptide-based linker. It is designed to target and deliver chemotherapy inside cancer cells and reduce systemic exposure to the cytotoxic payload compared to the way chemotherapy is commonly delivered.

Trial results
Among 57 evaluable patients the data showed an overall response rate of 61.4% (35 of 57 patients) and disease control rate of 94.7% (54 of 57 patients) in patients with HER2-positive metastatic breast cancer pretreated with ado-trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche).

In addition, among 50 of these patients who were also pretreated with pertuzumab (Perjeta®; Genentech/Roche), DS-8201 demonstrated a confirmed overall response rate of 62% (31 of 50 patients) and a disease control rate of 94% (47 of 50 patients). In 39 efficacy evaluable HER2-positive patients with hormone-receptor positive disease, DS-8201 demonstrated an overall response rate of 56.4% (22 of 39 patients) and disease control rate of 92.3% (36 of 39 patients).

The majority of patients with HER2-positive metastatic breast cancer were continuing to receive treatment at the time of data cut-off. Preliminary estimates of median progression free survival have reached 10.4 months.

Additionally, preliminary results in another subgroup showed that DS-8201 demonstrated a confirmed overall response rate of 31.6% (6 of 19 patients) and a disease control rate of 84.2% (16 of 19 patients) in 19 efficacy evaluable patients with heavily pretreated HER2 low-expressing breast cancer (defined as IHC2+/ISH- or IHC 1+). In 16 of these patients also classified with hormone-receptor positive disease, DS-8201 demonstrated an overall response rate of 31.3% (5 of 16 patients) and a disease control rate of 87.5% (14 of 16 patients).

Most patients with HER2 low-expressing breast cancer were continuing to receive treatment at the time of data cut-off.

Median progression free survival has not yet been reached.

Compelling data
“These updated data in HER2-positive metastatic breast cancer are exciting in that DS-8201 is showing potential in treating patients who have progressed on several other HER2-targeting agents,” noted Shanu Modi, MD, Breast Medical Oncologist, Memorial Sloan Kettering Cancer Center and study investigator.

“The results seen in patients with HER2 low-expressing breast cancer are compelling and could challenge how we define HER2-positive breast cancer with regards to ADC therapy. Clearly, further study of DS-8201 is warranted in both these types of HER2-expressing breast cancer,” Modi added.

“These data add to the growing evidence that underscore the potential of our smart chemotherapy DS-8201 to treat HER2-expressing breast cancer,” said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.

“While we already have advanced DS-8201 into a pivotal Phase II trial for HER2-positive metastatic breast cancer, we are exploring next steps for the development of DS-8201 in HER2 low-expressing breast cancer.”

NCT02564900
Image 1.0: Study of DS-8201a in subjects with advanced solid malignant tumors (NCT02564900). This is an open-label, two-part, multiple study to evaluate the safety and tolerability of DS-8201a in patients with advanced solid malignant tumors. This trial is sponsored by Daiichi Sankyo Co., Ltd.

Adverse events
During this year’s SABCS combined preliminary safety data for both HER2 low-expressing and HER2-positive breast cancer subgroups were reported. The most common adverse events (>30% any grade) included nausea (73.0%), decreased appetite (55.7%), alopecia (40.0%), vomiting (39.1%), anemia (34.8%), diarrhea (33.9%) and constipation (30.4%).

Grade 3 adverse events occurring in >10% of patients included decreased neutrophil count (10.4%) and decreased white blood cell count (10.4%).

Grade 4 adverse events included decreased neutrophil count (4.3%, decreased platelet count (2.6%) and anemia (0.9%). Two cases of potential Grade 5 pneumonitis have been reported and will be assessed by an interstitial lung disease (ILD) adjudication committee.

Trial design
The open-label, two-part Phase I study is currently evaluating DS-8201 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.[3]

The primary objective of the dose escalation phase of the study was to assess the safety and tolerability of DS-8201 and determine the maximum tolerated dose.

Image 2.0: DESTINY-Breast01, a Phase II, Multicenter, Open-Label Study of DS-8201a, an Anti-HER2-Antibody Drug Conjugate (ADC) for HER2-Positive, Unresectable and/or Metastatic Breast Cancer Subjects Who Are Resistant or Refractory to ado-trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche) (NCT03248492). This trial is sponsored by Daiichi Sankyo Co., Ltd.

In the dose expansion part of the Phase I study, DS-8201 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.

Patient enrollment in the two breast cancer cohorts and the HER2-expressing solid tumors cohort is ongoing in the U.S. and Japan.

DS-8201 is currently in Phase II clinical development for HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to T-DM1 (DESTINY-Breast01), Phase II development for HER2-positive advanced gastric cancer resistant or refractory to trastuzumab (DESTINY-Gastric01), and Phase I development for other HER2-expressing advanced/unresectable or metastatic solid tumors. [4][5]

The investigational drug has been granted Breakthrough Therapy designation by the U.S. Food and Drug Administration (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 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.


Last Editorial Review: November 7, 2017

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Copyright © 2017 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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2017 San Antonio Breast Cancer Symposium will Highlight Several Antibody-Drug Conjugates and Other Targeted Therapies

This year’s San Antonio Breast Cancer Symposium (SABCS) is taking place on December 5-9th, 2017, and it is expected to bring in a broad international audience of researchers and physicians to discuss the future of breast cancer research and treatment. Many exciting abstracts and posters will be presented and discussed during the conference, many of which are turning their focus toward precision and targeted therapeutics that have changed the way we look at cancer treatment in the past several decades.

Much of today’s cancer research developments are being made in targeted therapy spaces, such as antibody-drug conjugates or ADCs. At SABCS, the exciting presentations and posters dealing with ADCs, and other targeted therapeutics, are expected to provide invaluable information to physicians and researchers that are dealing with hard-to-treat patient populations that need more potent and better tolerable treatment options than what are currently available. A summary of notable presentations and posters dealing with targeted therapeutics at SABCS can be found here.


For an overview of oral and poster presentations about antibody-drug conjugates (ADCs) to be presented during the annual San Antonio Breast Cancer Symposium, December 5-9, 2017, Click here.


Sacituzumab govitecan (IMMU-132)
A general session at San Antonio breast cancer symposium will focus on Sacituzumab govitecan (IMMU-132), a novel ADC that is being investigated in as >3rd line therapy for patients with relapsed/refractory metastatic triple negative breast cancer (mTNBC). The data from this study will be presented and discussed on Wednesday, December 6th, at 11:00am in Hall 3. (Abstract GS1-07)

Previously, Sacituzumab govitecan was granted Breakthrough Designation based on promising data seen in a phase I/II basket trial for patients with multiple, advanced epithelial cancers. Breakthrough therapy designation is granted in order to expedite the development and review of treatments that may demonstrate substantial benefit over the current available treatments, so patients with serious, life-threatening diseases can have access to them treatments as soon as possible.

The ADC has received FDA Fast Track designation for the treatment of patients with triple-negative breast cancer, small-cell and non-small-cell lung cancers, and has also been designated an orphan drug for the treatment of patients with small-cell lung or pancreatic cancer in the U.S., and for the treatment of patients with pancreatic cancer in the European Union. [1] Now, Sacituzumab govitecan has been evaluated for use as a single agent for patients with metastatic triple negative breast cancer who have no other treatment options to turn to.

Metastatic triple-negative breast cancer is an aggressive breast cancer type that currently has very limited treatment options.  After the first line therapy, median overall survival for this disease is 6-13 months, and median progression free survival is typically 3-4 months. [2]

Sacituzumab govitecan targets Trop-2, which is expressed in over 90% of triple negative breast cancer, as well as most epithelial cancers, and delivers SN-38, the active metabolite of irinotecan. In the study that will be discussed at SABCS, 110 metastatic triple negative breast cancer patients saw an overall response rate of 34%, a clinical benefit rate of 46% and a progression free survival of 7.6 months. These promising results have led to the ADC’s submission for consideration of accelerated approval.

A randomized global confirmatory phase III trial using Sacituzumab govitecan is currently underway, and the drug is also being evaluated for use in combination with other drugs in triple negative breast cancer and other breast cancer subsets. To learn more about sacituzumab govitecan, and to follow ongoing clinical trials, click here.[3]

DS-8201a
Later in the week at SABCS, researchers at Daiichi Sankyo will take part in a poster discussion session,  where attendees will learn about the latest findings from an ongoing phase I study of DS-8201a, an ADC under investigation in HER2 breast cancers. DS-8201 uses a novel linker to deliver a topoisomerase I inhibitor, and has a high drug to antibody ratio of (8:1).

In pre-clinical studies, DS-8201 has shown efficacy when used in adotrastuzumab emtansine (T-DM1) resistant HER2 breast cancer, as well as breast cancer that is low in HER2 expression. Now, researchers are focused on a current phase I trial in patients with breast cancer, gastric cancer, and other HER2 expressing tumors. The breast cancer patient cohort will be the focus of the poster discussion on Thursday, December 7th, at 7am in the Stars st Night Ballrooom 1 & 2. (Abstract #1094)

DS-8201 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). [4]

In the current trial (NCT02564900), 146 patients are being treated in two phases, a dose escalation part 1, and a dose expansion part 2. Part 2 of this study involved 46 patients with breast cancer that have received an average of five prior regimens in the metastatic setting. Since these patients are in the metastatic stage and significantly pre-treated, targeted therapeutics like DS-8201a become extremely important, as they are left with little to no treatment options.

DS-8201a in Human Epidermal Growth Factor Receptor 2 (HER2)-Positive Breast Cancer (NCT02564900)

The available results have shown that DS-8201a is well-tolerated and has significant activity for patients that were pre-treated with T-DM1/ pertuzumab, as well as in patients with low expressing HER2 breast cancer. For these patients, an overall response rate of 41% was observed. In a cohort of patients had received prior T-DM1, treatment with DS-8201a achieved a higher Overall Response Rate (ORR) of 41% compared to the reported response these patients had to their prior T-DM1 treatment with an ORR of 23%. In the subset of 24 pts from cohort 2a who had received prior treatment with pertuzumab and T-DM1, the confirmed ORR was 44%. [5]

“The initiation of this Phase II study represents an important next step to rapidly advance the development of DS-8201, as we will obtain a better understanding of how the smart delivery of chemotherapy directly to targeted cancer cells may help patients with HER2-expressing metastatic breast cancer,” said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.

Future of Breast Cancer Research 
In addition to the discussions taking place over antibody-drug conjugates at this year’s San Antonio Breast Cancer Symposium, there are numerous posters that cover other targets therapeutics being developed and evaluated. The San Antonio Breast Cancer Symposium is designed to provide state-of-the-art information on the latest therapeutic options and challenges being researched in breast cancer and pre-malignant breast disease, to an international audience of  physicians and researchers.

Targeted therapeutics are undoubtedly making a strong appearance at this year’s meeting, and are expected to continue to revolutionize the way we treat breast cancer. A complete summary of the other exiting posters in the area of targeted therapeutics can be found here.


Last Editorial Review: November 29, 2017
Last update: November 5, 2017

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Copyright © 2017 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Pivotal Phase II Study of DS-8201 in Patients with HER2-Positive Metastatic Breast Cancer Initiated

Researchers at Daichi Sankyo initiation the DESTINY-Breast01, a pivotal phase II study evaluating the safety and efficacy of DS-8201, an investigational HER2-targeting antibody-drug conjugate or ADC, in patients with HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to ado-trastuzumab emtansine (T-DM1 | Kadcyla®; Genentech/Roche).

About one in five patients with breast cancer overexpress HER2, a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells, which is associated with aggressive disease.[1]

Depending on several factors, including the biomarker classification, breast cancer is typically treated with various combinations of surgery, radiation, chemotherapy, hormone therapy or targeted therapy.

But many HER2-positive tumors progress to the point where no currently approved HER2-targeting treatments can continue to control the disease. Furthermore, there is no HER2-targeting therapies approved for HER2-weak positive tumors after treatment with trastuzumab, pertuzumab and T-DM1. [2]


The Pivotal phase II DESTINY-Breast01 study examines the efficacy and safety of DS-8201 in patients with HER2-positive unresectable and/or metastatic breast cancer who are resistant or refractory to ado-trastuzumab emtansine (T-DM1)


DS-8201 is the lead investigational drug being developed by the ADC Franchise of the Daiichi Sankyo Cancer Enterprise.  ADCs are a type of targeted cancer medicine that deliver cytotoxic chemotherapy or  payload to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

Using Daiichi Sankyo‘s proprietary ADC technology, DS-8201 is a ‘smart’ chemotherapy comprised of a humanized HER2 antibody attached to a novel topoisomerase I inhibitor (DXd) payload by a tetrapeptide linker. The agent is designed to deliver enhanced cell destruction upon release inside the cell and reduce systemic exposure to the cytotoxic payload (or chemotherapy) compared to the way chemotherapy is commonly delivered.

“The initiation of this phase II study represents an important next step to rapidly advance the development of DS-8201, as we will obtain a better understanding of how the smart delivery of chemotherapy directly to targeted cancer cells may help patients with HER2-expressing metastatic breast cancer,” said Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.

“In addition to this pivotal study, we will continue to evaluate DS-8201 in other HER2-expressing cancers as well as in combination with other therapies where science suggests that it may help improve patient outcomes.”

In an interview for The Onco’Zine Brief, a podcast on PRX, Public Radio Exchange, during the 2017 annual meeting of the American Society of Clinical Oncology, or ASCO, which took place June 2nd to 5th in Chicago, Illinois, Yver, explained the progress Daiichi Sankyo has made in the development of DS-8201, and how this investigational drug has demonstrated a favorable safety profile and promising antitumor activity.[3]

Clinical trial
DESTINY-Breast01 is a pivotal phase II, open-label, global, multicenter, two-part study evaluating the safety and efficacy of DS-8201 in patients with HER2-positive unresectable and/or metastatic breast cancer resistant or refractory to T-DM1. The primary endpoint of the study is objective response rate. Secondary objectives include duration of response, disease control rate, clinical benefit rate, progression-free survival and overall survival. The first part of the study will include a pharmacokinetic stage and a dose finding stage to identify the recommended dose of DS-8201 to be evaluated in the second part of the study.

The second part of the study will enroll patients into one of two cohorts: patients resistant or refractory to T-DM1 (part 2a) and patients who discontinued treatment with T-DM1 for reasons other than resistant or refractory disease (part 2b). DESTINY-Breast01 is expected to enroll more than 230 patients at up to 90 sites in North America, Europe, Japan and other countries in Asia.

Other trials
In addition to the DESTINY-Breast01 study, DS-8201 is in phase I development for HER2 low-expressing breast cancer, HER2-positive gastric cancer, and other HER2-expressing solid tumors.

Earlier, the U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy designation to DS-8201 for the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer who have been treated with trastuzumab (Herceptin®; Genentech/Roche) and pertuzumab (Perjeta®; Genentech/Roche) and have disease progression after ado-trastuzumab emtansine, 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.


Last Editorial Review: August 29, 2017

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Copyright © 2017 InPress Media Group. All rights reserved. Republication or redistribution of InPress Media Group content, including by framing or similar means, is expressly prohibited without the prior written consent of InPress Media Group. InPress Media Group shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. ADC Review / Journal of Antibody-drug Conjugates is a registered trademarks and trademarks of InPress Media Group around the world.

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Phase I Study Shows Daichi Sankyo’s Anti-HER2 Antibody-drug Conjugate DS-8201a to be Well-tolerated without Dose-limiting Toxicities

Safety and preliminary efficacy data from a phase I study of DS-8201a (Daiichi Sankyo Company), a novel investigational HER2-targeting antibody drug conjugate or ADC, suggest that the investigational drug candidate is well-tolerated with no dose-limiting toxicities.

These results come from the dose escalation part of a two-part phase I study of DS-8201a presented during a late-breaking poster discussion session during the ESMO 2016 Congress, the annual meeting of the European Society for Medical Oncology, being held October 7 – 11, 2016 in Copenhagen, Denmark.

esmo_2016_logoDS-8201a is an investigational antibody drug conjugate comprised of a humanized anti-HER2 antibody attached by a peptide linker to a novel topoisomerase I inhibitor (DXd) payload, utilizing Daiichi Sankyo’s proprietary payload and linker-payload technology.

Unique Mechanism of Action
Preclinical models have demonstrated that DS-8201a has a unique mechanism of action (MOA) where it selectively binds to the HER2 receptor on a tumor cell surface, triggering an antibody-dependent cell cytotoxic or ADCC response. [1] DS-8201a is then internalized via endocytosis (transportation into cells by an energy-using process) and the intracellular lysosomal enzymes break down the peptide to release the DXd payload, which then inhibits topoisomerase I activity, causing DNA damage and cell death. [1]

The linker-payload combination of DS-8201a allows for a higher drug-to-antibody ratio or DAR of about 8 compared to a DAR of about 3.5 seen with ado-trastuzumab emtansine (T-DM1; Kadcyla®; Genentech/Roche). [1] The higher DAR of DS-8201a may help target low expressing HER2 tumors by supplying more payload per antibody to a tumor. [1]


“…These preliminary results are compelling and warrant further clinical evaluation of DS-8201a in several different patient populations expressing HER2…”


Phase I results
DS-8201a, given as an intravenous infusion every three weeks, is currently being evaluated in an open-label two-part phase I study in patients with advanced/unresectable or metastatic breast cancer, gastric or gastroesophageal junction adenocarcinoma, or other solid tumors that is/are refractory to or intolerable with standard treatment or for which no standard treatment is available.

The primary objective of part I of the study (dose escalation) is to assess the safety and tolerability of DS-8201a and determine the maximum tolerated dose or MTD. Secondary objectives include evaluating the pharmacokinetics, efficacy and human anti-human antibody (HAHA) against DS-8201a.

The second part of the study, the dose expansion, of the ongoing phase I clinical trial is enrolling patients in Japan and the United States into one of four cohorts including patients with HER2+ breast cancer previously treated with ado-trastuzumab emtansine as well as patients with HER2+ gastric or gastroesophageal junction adenocarcinoma previously treated with trastuzumab (Herceptin®; Genentech/Roche), patients with HER2 low expressing breast cancer and patients with other solid cancers that express HER2, also known as human epidermal growth factor receptor 2.

Trial design
The study enrolled 22 patients.  This included 16 (73%) patients with breast cancer, 5 (23%) patients with  gastric cancer, 1 (5%) patient gastroesphageal junction adenocarcinoma.  All patients were treated in the dose escalation part of the study.

The maximum tolerated dose was not reached (0.8-8.0 mg/kg given every three weeks) and there have been no dose-limiting toxicities at pharmacologically-active exposure and a favorable pharmacokinetic profile. Seven grade 3 adverse events were seen in three patients (1 hypokalemia, 1 anemia, 1 neutrophil count decreased, 2 lymphocyte count decrease, 1 ALP increase and 1 cholangitis). Most common adverse events were mild or moderate gastrointestinal and hematological events.

Preliminary overall efficacy results in 20 evaluable patients demonstrated an objective response rate or ORR of 35% (seven partial responses) and disease control rate of 90%, including 12 patients previously treated with ado-trastuzumab emtansine and five patients with HER2 low expression (IHC2+/FISH- or IHC1+).

In 15 patients with HER2+ disease defined as IHC3+ or IHC2+/FISH+, the disease control rate was 100%. At the time of the analysis, 17 patients remained on treatment, and five of the first 10 patients have been under active treatment (0.8 to 6.4 mg/kg) for more than 24 weeks. The median progression-free survival had not been reached.

Among 12 evaluable patients with HER2-positive breast cancer who had prior T-DM1, the ORR was 42% and the disease control rate was 92%.

Large unmet need
HER2 is a tyrosine kinase receptor growth-promoting protein found on the surface of some cancer cells.[2] About one in five breast cancers overexpress the HER2/neu gene, which causes these cancers to grow more aggressively. [2] To be considered HER2+, cancer cells are tested by one of two methods: immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH).2 IHC test results are reported as: 0, IHC1+, IHC2+ or IHC3+. A finding of IHC3+ is considered HER2+.2 A finding of IHC2+ is borderline and typically is confirmed by a positive FISH test.[2]

Several unmet needs remain today in HER2+ metastatic breast cancer. Many tumors advance to the point where no currently approved HER2-targeted treatment continues to control the disease.[3] Additionally, there are no existing options indicated for HER2 low expressing tumors (IHC2+/FISH- or IHC1+) as well as HER2 heterogeneously expressing tumors (tumors with some tumor cells having high HER2 expression and some having low HER2 expression), which generally have poor prognosis. [1][4]

“Despite recent advances in treating HER2+ breast and gastric cancer, there still remains a large unmet need for patients with HER2+ disease whose tumors are no longer controlled by currently approved targeted HER2 treatments or for tumors that express low HER2,” noted Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.

“These preliminary results are compelling and warrant further clinical evaluation of DS-8201a in several different patient populations expressing HER2,” Yver added.

“The components that make up DS-8201a are unique from any other antibody drug conjugate currently in clinical development and may explain the clinical activity observed at such an early phase of development,” said José Baselga, MD, PhD, Physician-in-Chief and Chief Medical Officer at Memorial Sloan Kettering Cancer Center, New York, NY.

“While the results of this study provide important preliminary proof-of-concept for the novel mechanism of action of DS-8201a, additional research will be needed to further confirm these findings,” Baselga said.

HER2+ Breast Cancer Subgroup Analyses
A total of 18 patients enrolled in the study received one or more prior anti-HER2 therapies (18 received trastuzumab, 13 ado-trastuzumab emtansine, 5 pertuzumab, 4 lapatinib). In 12 evaluable HER2+ breast cancer patients previously treated with ado-tratuzumab emtansine, the objective response rate was 42% with a disease control rate of 92%.

“It is impressive that DS-8201a showed activity in these patients since many were heavily pre-treated with more than one HER2-targeting agent including T-DM1, and some with very substantial tumor load or large tumors,” said Kenji Tamura, MD, PhD, Chairman, Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan and lead investigator of the study.

“This finding will be further evaluated in the second part of this study where one cohort will include only advanced breast cancer patients previously treated with T-DM1,” Tamura noted.


Last Editorial Review: October 24, 2016

Featured Image: Front view of the Little Mermaid statue on large boulders in Denmark with harbor under blue sky in the background. Courtesy: © Fotolia. Used with permission.

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