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U.S. Food and Drug Administration Rejects Sacituzumab Govitecan

The U.S. Food and Drug Administration (FDA) has rejected sacituzumab govitecan also known as IMMU-132, a novel, investigational, antibody-drug conjugate or ADC consisting of SN-38, the active metabolite of irinotecan, conjugated to a humanized monoclonal antibody targeting trophoblastic antigen-2 (Trop2), which is expressed in approximately 80% to 90% of breast cancers.

In an edition of The Onco’Zine Brief on PRX (Public Radio Exchange), recorded during the Annual Meeting of the American Society of Clinical Oncology (ASCO), held in Chicago, Illinois, June 1 – 5, 2018, Peter Hofland and Sonia Portillo spoke with Michael Pehl, President and Chief Executive Officer of Immunomedics about advancements in the development of targeted anti-cancer drugs such as antibody-drug conjugates. Developing successful antibody-drug conjugates has remained a challenge for several decades. And to date only 4 different antibody-drug conjugates have been approved for the treatment of various forms of cancer. Hofland and Portillo ask Pehl how antibody-drug conjugate can be used for the treatment of advanced or metastatic triple negative breast cancer, a form of breast cancer that occurs in about 10% – 20% of all cases of breast cancer. Hofland and Portillo also spoke with Pehl about Immunomedics submitted a Biologics License Application (BLA) to the U.S. Food and Drug Administration (FDA) for a new antibody-body drug conjugate for the treatment of patients with advanced or metastatic triple negative breast cancer who previously received at least two prior therapies for metastatic disease [Click here to listen to the program].
Triple-negative breast cancer
The investigational drug is designed for the treatment of patients with triple-negative breast cancer (TNBC) who have failed at least 2 prior therapies for metastatic disease.

About 15% of all diagnosed breast cancers is triple-negative breast cancer and, according to the American Cancer Society, the an annual incidence of the disease in the United States alone is estimated to be about 40,000 patients, with 20,000 diagnosed with metastatic TNBC, in the United States alone.

Triple-negative breast cancer does not express estrogen, progesterone or the HER2 receptor. As a result, the disease is insensitive to most of the available targeted therapies for breast cancer treatment, including HER2-directed therapies like trastuzumab (Herceptin®; Genentech/Roche), and endocrine therapies such as tamoxifen or the aromatase inhibitors.

Viable treatment
“We believe in sacituzumab govitecan’s potential to be a viable treatment option for these patients,” said Michael Pehl, President and Chief Executive Officer of Immunomedics.

This believe was, in part, based on a Breakthrough Therapy Designation the company received in February 2016 and results from various clinical trials investigating the activity of sacituzumab govitecan in patients with advanced cancers. One of the trials, presented at the 2018 annual meeting of the American Society of Clinical Oncology (ASCO), showed that sacituzumab govitecan, as a single agent demonstrated, had significant clinical activity in heavily pre-treated patients with HR-positive, HER-2-negative metastatic breast cancer and has a predictable and manageable safety profile.

However, regardless of the results of clinical results, on february 17, 2019 Immunimedics confirmed that it has received a Complete Response Letter from the FDA for the Biologics License Application in which the FDA rejected the drugs.

Concern
Although the FDA did not raise concerns about the safety or efficacy of sacituzumab govitecan, the disappointing outcome follows serious manufacturing problems identified in the FDA inspection between August 6 and 14, 2018.

“The issues related to approvability in the Complete Response Letter were exclusively focused on Chemistry, Manufacturing and Control matters and no new clinical or preclinical data need to be generated,” Pehl noted.

This investigation revealed that Immunomedics’s quality control unit at the company’s Morris Plains, New Jersey, drug substance manufacturing facility didn’t have the authority to investigate a February 2018 data integrity breach, which didn’t trigger a deviation. This breach included manipulated bioburden samples, misrepresentation of an integrity test procedure in the batch record, and backdating of batch records, such as dates of analytical results.

According to the FDA, Immunomedics did not give an assurance that samples and batch records from commercial batches it manufactured before the data integrity breach were not impacted by it, and the agency was unable to conduct a proper assessment.

As a result of the problems, the FDA cited Immunomedics for multiple violations. However, according to statements to investors in December 2018 made by the company, the identified problems for which the company has been penalized have been addressed and are now (completely) resolved.

Next steps
“We are going to request a meeting with the FDA as soon as possible to gain a full understanding of the Agency’s requirements and timelines for approval and we will work closely with the FDA,” Pehl said.

“The goal [is to bring] this important medicine to patients as soon as possible,” he concluded.


Last Editorial Review: January 18, 2019

Featured Image: Pink ribbon for the breast cancer awareness. Courtesy: © Fotolia. Used with permission.

Copyright © 2010 – 2019 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 of DS-1062 in Patients with Advanced Non-Small Cell Lung Cancer Initiated

The first patient has been dosed in a phase I study assessing the safety and tolerability of DS-1062, an investigational trophoblast cell-surface antigen 2 or TROP2-targeting antibody-drug conjugate or ADC, in patients with unresectable advanced non-small cell lung cancer (NSCLC) who are refractory to or have relapsed following standard treatment or for whom no standard treatment is available.[1]

The novel agent is being developed by Japanese drug-maker Daiichi Sankyo. It’s the third ADC in clinical development based on Daiichi Sankyo’s proprietary linker and payload technology.


With the initiation of this study … Daiichi Sankyo moves a third Antibody-drug Conjugate into the clinic …  investigating the potential of the smart delivery of chemotherapeutic agents in various cancers including lung, breast and gastric cancer.


Antibody-drug conjugates are targeted cancer medicines that deliver cytotoxic chemotherapeutic payload to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

Proprietary ADC technology
Designed using Daiichi Sankyo’s proprietary ADC technology, DS-1062 is a smart chemotherapy comprised of a humanized anti-TROP2 monoclonal 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 (or chemotherapy) compared to the way chemotherapy is commonly delivered.

Trial design
The phase I, open-label study is a first-in-human study investigates the safety and tolerability of DS-1062 in patients with unresectable advanced NSCLC who are refractory to or have relapsed following standard treatment or for whom no standard treatment is available.

The first part of the study, know as the dose escalation phase, assesses the safety and tolerability of increasing doses of DS-1062 to determine the maximum tolerated dose and recommended dose for expansion. The second part of the study (dose expansion) will evaluate the safety and tolerability of DS-1062 at the recommended dose for expansion.

Study endpoints include safety, pharmacokinetics, objective response rate, duration of response, disease control rate, time to response, progression-free survival, overall survival, biomarker analysis and immunogenicity. This portion of the study is expected to enroll approximately 40 patients with unresectable advanced NSCLC in the United States and Japan.

Following the outcome of both the dose escalation and dose expansion parts of the study in patients with unresectable advanced NSCLC, there may be two additional expansion cohorts opened for other solid tumors where high expression of TROP2 is frequently observed.

Improved patient outcome
With the discovery of driver genes and introduction of targeted therapies, there has been improvement in patient outcomes for certain types of NSCLC. However, for patients with unresectable advanced NSCLC, there is still a need for new therapeutic strategies as the five-year survival rates for patients with advanced stages of NSCLC are low.[2]

DS-1062 is designed to target and deliver chemotherapy inside cancer cells expressing trophoblast cell-surface antigen 2 (TROP2), which is overexpressed in many cancers including NSCLC.[3] Overexpression of TROP2 is a driver in cancer growth and has been associated with decreased patient survival, increased tumor aggressiveness, metastasis, and drug resistance in several tumor types.[4]

“We are initially focusing on evaluating DS-1062 in patients with advanced NSCLC with potential expansion into other tumor types depending on the results of this early critical test in a study designed to provide evidence supporting unique properties of this particular TROP2 ADC construct,” noted Antoine Yver, MD, MSc, Executive Vice President and Global Head, Oncology Research and Development, Daiichi Sankyo.

“With the initiation of this study of DS-1062, we move our third ADC into the clinic and continue to investigate the potential of the smart delivery of chemotherapy in various cancers including lung, breast and gastric cancer,” Yver concluded.


Last editorial review: February 23, 2018

Featured Image: Life scientists researching in laboratory. Courtesy: © 2010 – 2018 Fotolia. Used with Permission.

Copyright © 2010 – 2018 InPress Media Group, LLC. 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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