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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.

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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

Featured Image: Women and the power to fight breast cancer Courtesy: © 2017. Fotolia. Used with permission.

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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Interim Phase II Results with Sacituzumab Govitecan in Pretreated Metastatic Urothelial Cancer Shows Confirmed Objective Response Rate (ORR) of 34%

Results from an interim Phase II study with sacituzumab govitecan (IMMU-132) shows that the investigational agent is active in patients with metastatic urothelial cancer (mUC) who have relapsed or are refractory to chemotherapies and immune checkpoint inhibitors or IOs.

Metastatic or unresectable disease is identified in approximately 20% of patients presenting with invasive urothelial cancer. [1] This makes the disease the sixth most common cancer in the United States after lung cancer, prostate cancer, breast cancer, colon cancer, and lymphoma. According to the American Cancer Society, the estimated number of new cases in 2017 is 79.030 and deaths from bladder cancer will reach 16,870. [2]


The results [sacituzumab govitecan] in patients relapsed or refractory to both chemotherapy and therapy with immune checkpoint inhibitors are particularly encouraging, since few options are available for these patients after they become refractory…


ESMO 2017
“The results in patients relapsed or refractory to both chemotherapy and IO therapies are particularly encouraging, since few options are available after they become refractory,” noted Scott T. Tagawa, the Richard A. Stratton Associate Professor in Hematology and Oncology, and an Associate Professor of Clinical Medicine and of Clinical Urology at Weill Cornell Medicine, who presented the results at the ESMO 2017 Congress held September 8 – 12, 2017 in Madrid, Spain.

Despite the fact that five IOs have been approved in the U.S. for patients with advanced bladder cancer following platinum chemotherapy, only about 15% to 25% of patients respond to the new treatments. I believe sacituzumab govitecan has the potential to become a second or later line treatment to platinum- or IO-based therapy,” Tagawa added. [2]

In the single-arm Phase II study with sacituzumab govitecan, the confirmed Objective Response Rate (ORR) among forty-one intention-to-treat patients was 34% (14/41), including two confirmed Complete Responses (CRs) and twelve confirmed Partial Responses (PRs). While eight of the fourteen responders are ongoing and are still receiving treatment, including four long-term responses greater than 1 year and two currently ongoing at 15 and 22 months, the median Duration of Response (DOR) at the time of data cutoff was 12.6 months (95% confidence interval [CI], 7.5 to 12.9 months).

Median PFS at 80% data maturity was 7.1 months (95% CI, 5.0 to 10.7 months).

The enrolled cohort included fourteen patients who progressed after prior IO therapy, eleven of whom received IMMU-132 as the fourth or later line of therapies.

Despite the late-stage setting, the confirmed ORR in this subset of patients was 29% (4/14), with median PFS of 5.4 months (95% CI, 1.9 to 7.2 months) but median OS was not met.

All four responders in this subgroup had three or more prior therapies before being treated with sacituzumab govitecan.

“In light of these favorable interim results with sacituzumab govitecan in metastatic urothelial cancer, we will approach the regulatory authorities to discuss the appropriate path forward in this disease with continued unmet medical need,” concluded Behzad Aghazadeh, Chairman of the Board of Immunomedics.

A total of 41 patients with mUC were enrolled into this open-label multicenter study to receive 10 mg/kg of sacituzumab govitecan on days 1 and 8 of 3-week cycles. Median number of doses received was 3 (range, 1-6). Despite repeated dosing, grade 3 or higher adverse events were limited to neutropenia (39%), anemia (10%), diarrhea (7%), and fatigue (7%).

Tagawa has served as a consultant to and receives research funding from Immunomedics.


Last Editorial Review: September 11, 2017

Featured Image: ESMO 2017 | Special Seassion Clinical Practice Demands. Courtesy: © 2017. European Society of Medical Oncology | ESMO. Used with permission.

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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Sacituzumab govitecan (IMMU-132) Demonstrates Therapeutic Potential in the Treatment of Metastatic Solid Cancers

Two prominent cancer journals have published phase II clinical trial results with sacituzumab govitecan (IMMU-132; Immunomedics) in a total of 104 patients with lung cancer, including advanced small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC) patients who relapsed after, or were refractory to, prior treatment with standard chemotherapy or immune checkpoint inhibitors.

Lung cancer is the most prevalent cancer worldwide; 1.8 million patients were diagnosed in 2012. It is also the leading cause of cancer deaths, taking 1.6 million lives annually. The vast majority of lung cancer cases (85%) comprise the NSCLC type, which has had a median life expectancy of 10 months when standard chemotherapy is used. With the introduction of immune checkpoint inhibitors, median survival has increased to almost 15 months when at least 50% of cells were positive for PD-L1.

Pembrolizumab (Keytruda®; Merck & Co) was reported to be more effective than chemotherapy in the frontline setting of patients with metastatic NSCLC at high levels of PD-L1 positivity (progression-free survival 10.3 months vs. 6.0 months for those given platinum-based chemotherapy), but this population only constituted about one-quarter of metastatic NSCLC patients.

In pretreated patients with metastatic NSCLC, the objective response rates for the immune checkpoint inhibitors generally range from 14% to 20%.

Aggressive nature
SCLC comprises approximately 15% of all lung cancers, and has the worst prognosis. This is because of its highly aggressive nature, with about two-thirds of patients already having metastatic disease at diagnosis. While palliative first-line therapy of stage IV SCLC (mSCLC) has a high initial response rate of 60% to 75%, the outcome is poor, with a median progression-free survival of only 5.5 months and a median overall survival of <10 months with platinum-based chemotherapy. Responses to second-line therapy have been poorer, such as <10%, with a median survival of only 4 to 5 months following second- or third-line chemotherapy.

Unfortunately, those patients with platinum-resistant mSCLC (i.e., response duration <3 months) fare even worse.

In the United States, the only approved drug in this second-line setting of chemosensitive patients (duration of response exceeding 3 months), since 1998, is topotecan.  This agent, which is reasonably well tolerated, is indicated for recurrent patients who were sensitive to frontline chemotherapy with platinum-containing regimens.[1]

Topotecan, a water-soluble analog, originates from a family of chemotherapeutic agents, including the parent drug Camptothecin, a plant alkaloid extract derived from the oriental tree Camptothecan acuminate, that inhibit the DNA topoisomerase I enzyme, which is responsible for relaxing a supercoiled DNA helix during DNA synthesis. The agent inhibits the religation step of the enzymatic reaction by stabilizing the DNA enzyme complex.  Following this step, it causes accumulation of persistent single strand DNA breaks.

Although is Topotecan the only approved drug,  irinotecan, taxanes, vinorelbine, gemcitabine, and pemetrexed are given frequently to patients with chemosensitive recurrent disease. Even when patients respond to second-line therapies, there is usually no improved survival. Immune checkpoint inhibitors have not gained a role in the management of mSCLC.

Sacituzumab govitecan and Small-cell Lung Cancer
A study advanced small-cell lung cancer published online in Clinical Cancer Research. In this article the authors [2] evaluated sacituzumab govitecan, a second-generation antibody-drug conjugate or ADC, composed of the humanized anti-Trop-2 antibody linked to SN-38, a payload of the active metabolite of irinotecan with a drug-to-antibody ratio (DAR) of 7.6.

Irinotecan and SN-38 inhibit the nuclear enzyme, topoisomerase- 1, resulting in double-strand DNA breaks and death of the affected cells. However, SN-38 is about 1,000- fold more potent than its parental prodrug, irinotecan.

Because SN-38 is delivered selectively by the anti-Trop-2 antibody, it is believed this toxicity is selective for cancer cells having higher levels of Trop-2 than normal cells. This results in a selective targeting and killing of cancer cells having Trop-2, which includes a large number of cancer types.

Because of the way SN-38 is attached to the cancer-targeting antibody, sacituzumab therapy avoids the debilitating diarrhea caused by irinotecan therapy. However, like irinotecan, the major adverse effect is neutropenia, which is manageable either by reducing or delaying therapy, or treating the patient with a drug that stimulates production of neutrophils.

The study published in Clinical Cancer Research  included 50 patients with small-cell lung cancer with metastatic (stage IV) disease who had a median of 2 prior therapies.

The authors noted:

  • Ninety-two percent of the patients evaluated for expression of the target for sacituzumab govitecan, Trop-2, had elevated levels in their archived tumor specimens.
  • Patients given repeated treatment cycles had manageable toxicity, mostly Grade >3 neutropenia (34%), and 60% of those patients experienced tumor shrinkage from baseline CT measurements.
  • The objective response rate was 17% at the optimal dose schedule; the median duration of response and overall survival were 5.7 and 7.5 months, respectively.
  • Activity was observed in patients who were chemosensitive or chemoresistant to frontline chemotherapy, in patients who failed second-line topotecan, and in a subset who relapsed after immune checkpoint inhibitor therapy.

“In contrast, to topotecan, sacituzumab govitecan showed activity in patients who were either responsive or refractive to frontline therapy, and also to those who relapsed to topotecan. A randomized, controlled trial comparing these two agents in second-line therapy, as well as sacituzumab in the frontline setting, should be undertaken,” noted Jhanelle Gray, MD, of the Moffitt Cancer Center, Tampa, FL, the article’s first author.

Promising new therapeutic candidate
“Sacituzumab govitecan represents a promising new therapeutic candidate for advanced mSCLC, a very lethal cancer with a five-year survival rate of only 6 percent,” commented David M. Goldenberg, Immunomedics’ founder.

“Importantly, this candidate potentially could be the first new therapeutic approved for the treatment of metastatic (stage IV) small-cell lung cancer (mSCLC) in twenty years,” he added.

Sacituzumab govitecan and Non-small Cell Lung Cancer
In the second article published online on May 26, 2017, in the Journal of Clinical Oncology, the authors [3] reported the results of the phase II, multicenter trial of 54 heavily-pretreated patients with metastatic NSCLC who received either 8 or 10 mg/kg sacituzumab govitecan on days 1 and 8 of 21-day cycles. The primary endpoints were safety and objective response rate (ORR). Progression- free survival (PFS) and overall survival (OS) were secondary endpoints.

  • Some of the key findings reported in this article included:
    In the response-assessable study population (N = 47), which had a median of 3 prior therapies (range, 2-7), 67% of patients showed a shrinkage from baseline CT measurements.
  • The confirmed objective response rate was 19.1%, the median response duration 6.0 months (95% CI, 4.8, 8.3), and the clinical benefit rate (CR+PR+SD>4 months) was 43%. Responses occurred with a median onset of 3.8 months, including patients who had relapsed or progressed after immune checkpoint inhibitor therapy.
  • Median intention-to-treat (ITT) PFS was 5.2 months (95% CI, 3.2, 7.1), and median ITT OS was 9.5 months (95% CI, 5.9, 16.7).
  • Grade 3 or higher adverse events included neutropenia (28%), diarrhea (7%), nausea (7%), fatigue (6%), and febrile neutropenia (4%).
  • Over 90% of 26 assessable archival tumor specimens were highly positive for Trop-2 by immunohistochemistry.

“In a heavily pretreated population like this, the results with sacituzumab govitecan are quite encouraging, suggesting further trials both alone and in combination with other drugs, potentially including immunotherapy, should be strongly considered,” D. Ross Camidge, Director of Thoracic Oncology at the University of Colorado Cancer Center and senior author of this study, explained

“Non-small-cell lung cancer patients will always benefit from additional therapeutic choices, and while immunotherapy and oncogene targeted therapy have certainly revolutionized the treatment for subsets of the disease, the use of ‘smarter’ chemotherapy in the form of an effective antibody-drug conjugate such as sacituzumab govitecan may well be the next major advance we see,” Camidge added.

More promising results
“These promising results in two lung cancer indications, comprising the major cancer killers, attest to the breadth of the therapeutic potential for IMMU-132 in the treatment of metastatic solid cancers. Our principal focus is to seek accelerated approval for this ADC in patients with advanced, heavily-pretreated triple-negative breast cancer (TNBC), for which there is no approved therapy and significant patient unmet need,” noted Behzad Aghazadeh, MD, Chairman of the Board of Immunomedics.

“We have also reported that sacituzumab govitecan, in addition to TNBC, SCLC, and NSCLC, is active in patients with metastatic urothelial cancers, where we hope to update results at a future medical meeting, so we now know it is active in at least four different major solid cancers, Aghazadeh concluded.


Last Editorial Review: July 11, 2017

Featured Image: Lung Cancer Courtesy: © 2017. Fotolia Used with permission.

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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Antitumor Effect of Sacituzumab Govitecan in Triple-Negative Breast Cancer Can be Enhanced With DNA-Repair Inhibitors

Based on a pre-clinical study, treatment of patients sacituzumab govitecan, also known as  IMMU-132 (Immunomedics), in patients with metastatic triple-negative breast cancer (mTNBC) has the potential to be further improved when combined with agents that inhibit DNA repair pathways both in patients with mutated and wild-type BRCA1/2.

Results from this pre-clinical study were published online in Clinical Cancer Research, which is the official publication of the American Association for Cancer Research (AACR).

“This preclinical study is part of our ongoing strategy to broaden the applicability of this important asset for the treatment of patients with solid cancers and the positive results we have achieved thus far are a testament to the strength of our talented team. The progress we have made affirms our commitment to continued product development,” remarked Cynthia L. Sullivan, Immunomedics’ President and Chief Executive Officer.

IMMU-132 is a first-in-class antibody-drug conjugate or ADC developed by Immunomedics, is a clinical-stage biopharmaceutical company by conjugating the moderately-toxic drug, SN-38, site-specifically and at a high drug-to-antibody ratio (DAR) to a humanized antibody that targets the Trop-2 receptor expressed by many solid cancers. In a single-arm Phase 2 study, this ADC has produced rapid and durable responses in metastatic TNBC patients, with only limited and manageable Grade 3 or 4 toxicity, and has received a Breakthrough Therapy Designation from the FDA in this cancer setting.

Active metabolite of irinotecan
SN-38 is the active metabolite of irinotecan (Camptosar), which is used to treat certain solid cancers as a part of combination therapies. It exerts its cell-killing activity by inhibiting topoisomerase I, an enzyme needed by the cell for normal DNA replication. This inhibition results in breaks in the DNA during replication, leading ultimately to the cell’s death if left unrepaired by the cell. The goal of this preclinical study was to determine whether the DNA-damaging property of IMMU-132 can be augmented by agents that inhibit the repair of DNA.

Poly (adenosine diphosphoribose) polymerase or PARP is a family of enzymes whose primary function is to repair DNA breaks. It is one of several proteins used by cells for this purpose.  PARP inhibitors (PARPi), such as olaparib (AZD-2281; Lynparza®; AstraZeneca) and talazoparib (BMN-673; Medivation) are currently under investigation in cancers whith existing DNA-repair defects (BRCA1 and BRCA2).

BRCA1 and BRCA2 are a pair of genes that encode proteins important in a cell’s ability to repair double-stranded DNA breaks. In cell culture, the cytotoxicity of IMMU-132, when combined with one of three different PARPi’s, olaparib, talazoparib, and rucaparib (AG-014699, PF-01367338; Clovis Oncology), produced synergistic growth inhibition in BRCA1 and BRCA2-defective human TNBC tumor lines.

Furthermore, combining IMMU-132 with these PARPi’s also demonstrated synergy in BRCA1 and BRCA2 wild-type tumor lines in which the DNA-repair pathways are not defective. In mice bearing human TNBC tumors with mutated BRCA1 and BRCA2, a combination of IMMU-132 plus olaparib or talazoparib produced significantly improved antitumor effects and delay in time-to-tumor-progression, compared to monotherapy. Most importantly, in mice bearing tumors that are not defective in DNA repair (BRCA1 and BRCA2 wild-type), the combination of IMMU-132 plus olaparib imparted a significant antitumor effect and survival benefit above that achieved with monotherapy. Noteworthy, this combination was well tolerated, with no substantial changes in hematologic parameters.

“These preclinical results indicate that the combination of PARPi and IMMU-132 could broaden the range of tumors that are usually treated with the former to a TNBC patient population that includes BRCA1/2 wild-type tumors. Given the promising results obtained thus far with IMMU-132 in patients with TNBC, the logical next step is to combine this therapy with PARPi to further improve clinical outcome,” Ms. Sullivan noted.


Treatment Groups N Time-To-Tumor (TTP) Progression
Olaparib Talazoparib
  TTP (days  )   IMMU-132 vs. Control
(P-value)
  Combination vs. Control
(P-value)
  TTP (days)   IMMU-132 vs. Control
(P-value)
  Combination vs. Control
(P-value)
  IMMU-132 + PARPi  10 36.9 ± 8.1 N.A. N.A. 21.8 ± 9.6 N.A. N.A.
IMMU-132 alone 9   17.6 ± 3.9 N.A. <0.0001   7.9 ± 6.6 N.A. 0.0021
PARPi alone 9   9.1 ± 4.8 0.0009 <0.0001   5.9 ± 5.9 0.5099 0.0005
Saline Control 10   7.7 ± 5.0 <0.0001 <0.0001   4.2 ± 1.9 0.0709 0.0001

N = Number of mice per group
N.A. = Not Applicable

Table 1.0: Improved efficacy of IMMU-132 when combined with olaparib or talazoparib in mice bearing TNBC tumors that are deficient in DNA repair.


Last Editorial Review: January 9, 2017
Last Editorial Update: January 11, 2017

Featured Image: A conversation with a patient.Courtesy: © 2017 Fotolia. Used with permission.

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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Enhancing Activity of Sacituzumab Govitecan in SN-38-Resistant Cancer

Adding an inhibitor of ATP-binding cassette (ABC) transporters to sacituzumab govitecan increased the median survival of mice bearing a SN-38-resistant human gastric cancer cell line. Results from this preclinical study were published in Molecular Cancer Therapeutics.[1]

ATP-binding cassette transporters are ubiquitous membrane proteins.  They are characterized by active ATP-dependent movement of a range of substrates, including ions, lipids, peptides, steroids. Individual subunits are typically made up of two groups of 6TM-spanning domains, with two nucleotide-binding domains (NBD).[2]

Sacituzumab govitecan, being developed by Immunomedics, a clinical-stage biopharmaceutical company developing monoclonal antibody-based products for the targeted treatment of cancer, is a first-in-class antibody-drug conjugate or ADC developed by conjugating the moderately-toxic drug, SN-38, site-specifically and at a high ratio of drug to hRS7, a humanized antibody that targets the Trop-2 receptor expressed by many solid cancers.

Promising results
This novel drug candidate, Immunimedics lead antibody-drug conjugate for solid cancer therapy,  has produced promising therapeutic results in some patients with metastatic solid cancers in an open-label, single arm Phase II study. Based on results from this mid-stage trial, the U.S. Food and Drug Administration (FDA) has granted sacituzumab govitecan Breakthrough Therapy designation for the treatment of patients with triple-negative breast cancer, a disease which is negative for estrogen receptors (ER-), progesterone receptors (PR-), and HER2 (HER2-), who have failed prior therapies for metastatic disease. Following this initial designation, Immunomedics is working with the FDA toward a potential accelerated approval in this disease setting.

Multidrug resistance
A common cause of treatment failure in cancer therapy is multidrug resistance. In general, the occurrence of drug resistance in cancer cells can be intrinsic or acquired, with each type resulting from a variety of factors, such as decreased uptake of soluble drugs, activation of drug-detoxifying systems, modulation or mutation of drug targets, defective apoptosis pathways, and, above all, overexpression of the ABC transporters, which act by expelling drugs from the cell, thereby lowering the amount of drugs inside the cancer cells.

Preclinical Study
The objective of this preclinical study was to explore the use of known inhibitors of ABC transporters for improving the therapeutic efficacy of sacituzumab govitecan by overcoming SN-38-resistance. Human breast and gastric cancer cell lines were first made resistant to SN-38 by continuously exposing them to increased concentrations of SN-38 over a period of approximately 2 years. The two SN-38-resistant cell lines were shown to be 50-fold less responsive to SN-38 than their parental cells.

Restored toxicity
Treatment of both SN-38-resistant human cancer cell lines with known inhibitors of ABC transporters restored toxicity of SN-38. More importantly, when sacituzumab govitecan was combined with YHO-13351, an inhibitor of ABC transporter, in mice bearing SN-38-resistant human gastric cancer cell line, a statistically significant 64% improvement in median survival was achieved in comparison with untreated animals (P = 0.0278). Sacituzumab govitecan alone had a 29% improvement in median survival, while the water-soluble diethylaminoacetate prodrug YHO-13351 showed no effect on its own. Although irinotecan plus YHO-13551 improved the survival of the mice, it did not reach significance (P = 0.0852).

“These in vivo results suggest that suitable inhibitors that are tolerated well by the host animals can overcome ABC resistance and that the resistant tumor lines can become appreciably responsive to IMMU-132 and to a lesser extent to irinotecan,” noted Cynthia L. Sullivan, President and Chief Executive Officer of Immunomedics.

“We are pursuing further work to address the feasibility of preclinical testing for such drug resistance as a predictive bioassay to select patients who should receive ABC-blocking therapy with IMMU-132, in order to enhance the potency of IMMU-132 in cancer cells that are intrinsically or become resistant to SN-38,” Sullivan added.


Last Editorial Review: August 22, 2016

Featured Image: Close up of Doctor reviewing mammography results on x-ray and typing results on laptop. Courtesy: © Fotolia. Used with permission.

Copyright © 2016 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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ASCO 2016 Emphasizes Collective Wisdom: The Future of Patient-Centered Care and Research

Only a few weeks until the start of the 2016 annual meeting of the American Society of Clinical Oncology (ASCO). This year’s ASCO, taking place in the McCormick Place convention center in Chicago, Illinois, June 3-7, is expected to attract as many as 30,000 oncology professionals from the United States and around the world.

The theme of the annual meeting is Collective Wisdom: The Future of Patient-Centered Care and Research, emphasizing that the combined knowledge from various disciplines, cancer types, treatment approaches, and big data technologies is essential to progress. The theme is noticeable throughout the entire annual meeting and reinforces the inextricable link – a necessity – between ongoing research and advances in patient-centered care. The 2016 theme is also evident as the latest, most exciting discoveries, based on a better understanding of cancer biology and chemistry, will be presented.

ASCOIn preparation of the meeting, the program coordinators have accepted more than 5,200 abstracts to the ASCO Annual Meeting. Additional Late-Breaking Abstracts (LBAs), including Plenary abstracts, will be released on-site throughout the Annual Meeting.

Quality and access to care
Improving quality as well as access to appropriate care is a key subject being discussed during the 2016 annual meeting. Care may come in different forms, and researchers will discuss a phase III trial exploring whether using a mobile device-friendly web application for symptom monitoring improves survival of patients with lung cancer (Abstract LBA9006). Another study discusses a large analysis examining use of aggressive medical care and hospice for patients younger than age 65 in the last 30 days of life (Abstract LBA10033). Another study exploring racial disparities in receipt of breast and ovarian cancer risk-reducing procedures among younger breast cancer survivors with BRCA mutations (Abstract LBA1504).  Cost of novel cancer therapeutics plays a role in access to these drugs. An analysis of cancer drug prices around the world (Abstract LBA6500) is expected to shine some light on the discrepancy in the availability of care.

Immunotherapy
One of the exciting development in the treatment of cancer includes immunotherapy.  During the upcoming annual meeting, researchers will highlight studies representing the range of research topics, discuss survival data from early pre-clinical to phase III trials with a number of (novel) antibody-drug conjugates (ADCs) and other targeted therapies, include PD-1’s and BiTe’s.

Antibody-drug conjugates have, over the last decade, revolutionized the field of cancer chemotherapy. Unlike conventional treatments that damage healthy tissues upon dose escalation, ADCs utilize monoclonal antibodies (mAbs) to specifically bind tumor-associated target antigens and deliver a highly potent cytotoxic agent.[1]

Today there are multiple ADCs in clinical trials, targeting varied antigens using different linker chemistries and cytotoxic payloads. In the development novel ADCs, scientists have met a number of challenges including how to improve the therapeutic index, the selection of the optimal target, a better understanding of mechanism of action (MOA), how to manage and understand off-target toxicities, as well as the selection of appropriate clinical settings where these novel drugs may have the highest clinical benefit. [2]

Optimal target selection
The identification of optimal target is key to the clinical advancement of new antibody-drug conjugates. The possibilities of these novel targeted drugs used in the treatment of a wide range of solid cancers and hematological malignancies is limited by the discovery of suitable targets. Optimal targets are highly expressed on cancer cells and not, or minimally, on normal, healthy, tissues.[1]

Photo 1.0: Howard A. Burris, MD, during the Annual Business Meeting at the American Society for Clinical Oncology (ASCO) Annual Meeting , Monday June 3, 2013.

On Sunday morning, June 5, Howard A. Burris, MD (Sarah Cannon Research Institute) will be discussing the importance of the discovery of unique targets for antibody-drug conjugates designed to “make chemotherapy great again.”

Brentuximab vedotin
Brentuximab vedotin (also known as SGN-035; Adcetris® by Seattle Genetics Inc.) is an antibody-drug conjugate (ADC) or immunoconjugate directed to CD30, which is expressed in classical hodgkin lymphoma and systemic anaplastic large cell lymphoma.

This year, as part of ASCO’s oral abstract session “Hematologic Malignancies—Lymphoma and Chronic Lymphocytic Leukemia,” on Saturday June 4,  Steven I. Park, MD (University of North Carolina Lineberger Comprehensive Cancer Center) will present data from phase II trial of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) followed by brentuximab vedotin consolidation in limited stage non-bulky Hodgkin lymphoma (Abstract 7508).

During the poster discussion session on Monday, June 6, Anas Younes, MD  (Memorial Sloan Kettering Cancer Center) will discuss results from Checkmate 205,  a phase II study comparing safety and efficacy of nivolumab (Opdivo®; Bristol-Myers Squibb), a programmed death-1 (or PD-1) inhibitor approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency for the treatment of melanoma and advanced non-small cell lung cancer, in classical Hodgkin lymphoma after autologous stem cell transplant (ASCT) and brentuximab vedotin. (Abstract 7535, Poster Board: #91).

On Monday, Philippe Armand, MD, PhD (Dana-Farber Cancer Institute) will share an update of a phase I/II study to evaluate safety and efficacy of nivolumab plus brentuximab vedotin in patients with CD30-expressing relapsed/refractory non-Hodgkin lymphomas. (Abstract TPS7576; Poster Board: #130a).

Another poster, presented by Somali C. Gavane, MBBS (Memorial Sloan Kettering Cancer Center) on Monday, includes an update of metabolic tumor volume to predict event-free survival in patients with relapsed/refractory Hodgkin lymphomas treated with brentuximab vedotin-based salvage therapy (Abstract 11566, Poster Board: #263).

Ado-trastuzumab emtansine
Ado-trastuzumab emtansine, also know all T-DM1 (Kadcyla®; Genentech/Roche) is an antibody-drug conjugate consisting of the recombinant anti-epidermal growth factor receptor 2 (HER2) antibody trastuzumab conjugated to the maytansinoid DM1 via a nonreducible thioether linkage (MCC). The trastuzumab moiety binds to HER2 on tumor cell surface surfaces.  Following internalization, the DM1 is released and binds to tubulin, thereby disrupting microtubule assembly/disassembly dynamics and inhibiting cell division and the proliferation of cancer cells that overexpress HER2.

The linkage of antibody and drug through a nonreducible linker has shown to contribute to the improved efficacy and reduced toxicity of ado-trastuzumab emtansine compared to similar ADCs constructed with reducible linkers.

During the 2016 annual meeting, results from a large number of studies with ado-trastuzumab emtansine will be presented:

  • On Sunday, June 5, Carlos H. Barrios (PUCRS School of Medicine) will present a poster covering patient-reported outcomes from MARIANNE: A phase III study of trastuzumab emtansine (T-DM1) +/- pertuzumab vs. trastuzumab + taxane for the treatment of HER2-positive advanced breast cancer (Abstract 593, Poster Board: #81);
  • The same day Audrey Mailliez, MD (Centre Oscar Lambert) will present response to ado-trastuzumab emtansine according to RANO criteria in central nervous system metastases of HER2 positive breast cancers (Abstract 605, Poster Board: #93);
  • Sunil S. Badve, MD (Indiana University) will present an update from the EMILIA trial discussing the role of tumor infiltrating lymphocytes (TILs) in HER2+ metastatic breast cancers (MBC) treated with ado-trastuzumab emtansine (T-DM1) or lapatinib plus capecitabine (Abstract 607, Poster Board: #95);
  • During the same poster session, Rachel A. Freedman, MD, MPH (Dana-Farber Cancer Institute) will present data about adjuvant ado-trastuzumab emtansine (T-DM1) for older patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. (Abstract TPS629,  Poster Board: #109a).
  • Finally, Kathy Miller, MD (Indiana University Melvin and Bren Simon Cancer Center) will present results from the HERMIONE-trial,  a phase II randomized, open label trial comparing MM-302 + trastuzumab with chemotherapy of physician’s choice plus trastuzumab, in anthracycline naive HER2-positive, locally advanced/metastatic breast cancer patients previously treated with pertuzumab and ado-trastuzumab emtansine. (Abstract TPS631, Poster Board: #110a)

During an oral abstract session on Monday, June 6 (breast cancer—HER2/ER), Sara A. Hurvitz (David Geffen School of Medicine, University of California Los Angeles) will discuss pathologic complete response (pCR) rates after neoadjuvant ado-trastuzumab emtansine + pertuzumab vs. docetaxel + carboplatin + trastuzumab + pertuzumab (TCHP) treatment in patients with HER2-positive (HER2+) early breast cancer (KRISTINE). (Abstract 500)

Sacituzumab govitecan
The anti-Trop-2-SN-38 antibody-drug conjugate (ADC)  sacituzumab govitecan (IMMU-132), being developed by Immunomedics (Morris Plains, NJ 07950), is designed to deliver the moderately-toxic conventional chemotherapeutic drug, SN-38, the active metabolite of irinotecan (Camptosar®, Pfizer), site-specifically and at a high drug to antibody ratio (DAR), to a humanized antibody that targets the Trop-2 receptor, expressed by many solid cancers, while reducing overall toxic effects that are usually found with conventional administration of these chemotherapeutic agents.

During the clinical science symposium “Future directions in breast cancer treatment: new drugs, new markers,” on Friday, June 3, Aditya Bardia, MD, MPH (Massachusetts General Hospital Cancer Center) will present results from a phase II study of sacituzumab govitecan, for the treatment relapsed/refractory metastatic triple-negative breast cancer (mTNBC) (Abstract LBA509).

Results with the first-in-class antibody-drug conjugate sacituzumab govitecan in patients with previously treated metastatic small-cell lung cancer (mSCLC) will be presented in a poster session by Alexander Starodub, MD, PhD (Indiana University Health Goshen Center for Cancer Care) on Saturday, June 4, discussing “Lung Cancer—Non-Small Cell Local-Regional, Small Cell and Other Thoracic Cancers” (Abstract 8559; Poster Board: #187)

On Monday, June 6, during the clinical science symposium “Raising the bar for targeted therapies for lung cancers,” D. Ross Camidge, MD, PhD (University of Colorado), will present new approaches to the treatment of metastatic, non-small cell lung cancer (mNSCLC) with sacituzumab govitecan (Abstract 9011).

In early 2016 sacituzumab govitecan received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with triple-negative breast cancer or TNBC who have failed at least 2 prior therapies for metastatic disease.

Rovalpituzumab tesirine
Rovalpituzumab tesirine combines a novel targeted drug (anti-DLL3 antibody) with a toxin, D6.5 pyrrolobenzodiazepine (PBD), which is conjugated to cysteine residues on the SC16 antibody via a maleimide-containing linker with an eight-carbon polyethylene glycol spacer, cathepsin B–cleavable valine-alanine dipeptide, and self-immolating group, with a mean drug-to-antibody ratio (DAR) of 2. [3]

Photo 2.0: Charles Rudin, MD, PhD, during the Grant Writing Workshop at the American Society for Clinical Oncology (ASCO) Annual Meeting on Friday June 1, 2012.

On Sunday, June 5, Charles M. Rudin, MD, PhD (Memorial Sloan Kettering Cancer Center) will present results from a phase I/II study investigating the safety and efficacy of antibody-drug conjugate rovalpituzumab tesirine (SC16LD6.5), a delta-like protein 3 (DLL3)-targeted antibody-drug conjugate, for the treatment of recurrent or refractory small cell lung cancer (SCLC) (Abstract LBA8505).

New indication of rovalpituzumab tesirine also include the potential treatment of metastatic melanoma, glioblastoma and high-grade extrapulmonary neuroendocrine carcinomas (NECs).  Initial results are presented in a poster presentation on June 6 by Stemcentrx‘s Stanford L. Peng, MD, PhD will present (Abstract 11611, Poster Board: #308).

PSMA ADC
Prostrate-specific membrane antigen or PSMA is a protein that is highly expressed on most of the tumor cells in prostate cancer.  The protein is also expressed on the (neo)vasculature that supplies blood to many other tumors.  Researchers at Ambrx (La Jolla, CA 92037) have developed a site specific antibody-drug conjugate using the company’s proprietary drug payload.  The trial drug,  which is being evaluating for efficacy and overall toxicity compared with conventional antibody-drug conjugates, may have the potential to demonstrate increased potency in cancer patients while decreasing the toxicity that is usually seen in other antibody-drug conjugates due to the heterogeneity of the random conjugation approach used to generate these molecules.  The anti-PSMA ADC is being developed for the treatment of patients with prostate cancer and glioblastoma multiforme.

On Saturday, June 4, Heinrich Elinzano, MD (Rhode Island Hospital) will present results of the Phase II Brown University Oncology Research Group Study investigation the novel PSMA ADC in patients with progressive glioblastoma (Abstract 2065; Poster Board: #252)

The potential treatment of glioblastoma (GBM), the most common malignant primary brain tumor, is also presented by Martin J. Van Den Bent, MD (Erasmus MC Cancer Center) in a poster presentation reviewing the efficacy of ABT-414 (AbbVie), composed of the antibody ABT-806 targeting active EGFR/mutant EGFRvIII linked to the anti-microtubule agent monomethyl auristatin F, as monotherapy in epidermal growth factor receptor (EGFR) amplified, recurrent glioblastoma (Abstract 2542; Poster Board: #242).

Scientists have identified aberrant EGFR expression and signaling as a hallmark of cancer growth and survival. In several EGFR-overexpressing tumor xenografts ABT-414 has shown potent anti tumor activity.

Enfortumab vedotin
The antibody-drug conjugates enfortumab vedotin comprises the human anti-nectin-4 antibody conjugated to the highly potent microtubule disrupting agent monomethyl auristatin E (MMAE). Scientists at Agensys (Santa Monica, CA, 90404) prepared hybridoma (AGS-22M6E) and CHO (ASG-22CE) versions of enfortumab vedotin (also known as ASG-22ME).  They were able to bind the the versions of enfortumab vedotin to cell surface expressed nectin-4, a type I transmembrane protein and member of a family of related immunoglobulin-like adhesion molecules and reported high affinity and induced cell death in vitro in a dose-dependent manner. [4]

Using mouse xenograft models of human breast, bladder, pancreatic, and lung cancers, scientists found that treatment with enfortumab vedotin significantly inhibited the growth these tumor types.  They also noted tumor regression of breast and bladder xenografts. Overall, these findings validate nectin-4 as an attractive therapeutic target in multiple solid tumors, and support further clinical development, investigation, and application of nectin-4-targeting ADCs.[4]

Photo 3.0: Jonathan E. Rosenberg, MD, during the 2014 Genitourinary Cancers Symposium in San Francisco, Friday January 31, 2014.

On Monday, June 6, during a poster session covering genitourinary (non-prostate) cancers, Jonathan E. Rosenberg, MD (Memorial Sloan Kettering Cancer Center) will present data of the anti-tumor activity, safety and pharmacokinetics of ASG-22CE (ASG-22ME; enfortumab vedotin) in a phase I dose escalation trial in patients with metastatic urothelial cancer. (Abstract 4533, Poster Board: #156).

Inotuzumab ozogamicin
Inotuzumab ozogamicin is an investigational ADC comprised of a humanized IgG4 anti-CD22 antibody targeting CD22, a cell surface antigen expressed on approximately 90% of B-cell malignancies, covalently linked to N-acetyl-gamma-calicheamicin dimethyl hydrazine or calichDMH, a derivative of gamma calicheamicin, a cytotoxic antibiotic produced by the bacterium Micromonospora echinospora, with potential antineoplastic activity.

When inotuzumab ozogamicin binds to the CD22 antigen on malignant B-cells, it is rapidly internalized, delivering the conjugated CalichDMH intracellularly. The CalichDMH moiety then binds to the minor groove of DNA in a sequence-specific manner, resulting in double-strand DNA breaks and apoptosis.

The trial drug originates from a collaboration between Pfizer and Celltech (now part of UCB).

During the poster session “Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant” on Monday, June 6, a total of 3 posters with trial updates covering inotuzumab ozogamicin will be presented:

  • Hagop M Kantarjian, MD (The University of Texas MD Anderson Cancer Center, Department of Leukemia) will present patient-reported outcomes from a global phase III randomized controlled trial of inotuzumab ozogamicin vs. standard care for relapsed/refractory (R/R) acute lymphoblastic leukemia or ALL. (Abstract 7027, Poster Board: #19);
  • Daniel J. DeAngelo, MD, PhD (Dana-Farber Cancer Institute) will present the efficacy and safety by prior therapy of inotuzumab ozogamicin for the treatment of patients with relapsed/refractory acute lymphoblastic leukemia in the phase III INO-VATE trial.(Abstract 7028, Poster Board: #20), and
  • Elias Jabbour, MD (The University of Texas MD Anderson Cancer Center) will follow with data of the efficacy and safety of inotuzumab ozogamicin in older patients with relapsed/refractory acute lymphoblastic leukemia (ALL) who were enrolled in the phase III INO-VATE trial.(Abstract 7029,Poster Board: #21).

The presented results stem from the INO-VATE trial, is an open-label, randomized, Phase III study evaluating the safety and efficacy of inotuzumab ozogamicin as compared with a defined set of chemotherapy choices in adult patients with relapsed or refractory CD22-positive acute lymphoblastic leukemia (ALL).

The two primary endpoints in this trial are hematologic remission, defined as a complete response with or without platelet and/or neutrophil recovery (CR/CRi), and overall survival. Secondary endpoints include progression-free survival, volume of distribution and systemic clearance for inotuzumab ozogamicin in serum, duration of response, rate of stem-cell transplantation, minimal residual disease, cytogenetics, safety and quality of life based on the EORTC’s Quality of Life Questionnaire.

More studies
A (poster) presentation by George R. Blumenschein, M.D., Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, presents the results of a phase I study of anti-mesothelin antibody drug conjugate anetumab ravtansine, also known as BAY 94-9343, being developed by Bayer HealthCare under an agreement with ImmunoGen, consists of a human anti-mesothelin antibody conjugated to the maytansinoid tubulin inhibitor DM4 via a disulfide-containing linker (Abstract 2509; Poster Board: #209). [5]

Upon internalization, the DM4 moiety in anetumab ravtansine binds to tubulin and disrupts microtubule assembly/disassembly dynamics, resulting in inhibition of cell division and cell growth of mesothelin-expressing tumor cells. Mesothelin is overexpressed on all mesotheliomas as well as many ovarian and pancreatic cancers while minimally expressed on normal tissue. [6]

Results from a number of studies with antibody-drug conjugates presented during ASCO include:

  • Results from a phase I, open-label, dose-escalation and expansion study of ABBV-399 (AbbVie), an antibody drug conjugate targeting c-Met, in patients with advanced solid tumors. (Abstract 2510; Poster Board: #210), presented by John H. Strickler, MD (Duke University Medical Center)[7]
  • A poster presentation by Carlos Alberto Gomez-Roca, MD (Institut Universitaire du Cancer de Toulouse) detailing the results of a phase I study of SAR566658, an anti CA6-antibody-drug conjugate created by ImmunoGen and licensed preclinically to Sanofi, in patients with CA6-positive advanced solid tumors (STs)(NCT01156870). SAR566658 comprises of ImmunoGen’s huDS6 CA6-targeting antibody conjugated to DM4 via one of the compansy’s engineered linkers (SPDB). (Abstract 2511; Poster Board: #211)[8]
  • Results from mirvetuximab soravtansine (IMGN853), a folate receptor alpha (FRα)-targeting antibody-drug conjugate in clinical trials as single agent activity in platinum-resistant epithelial ovarian cancer patients will be presented by Kathleen N. Moore, MD (University of Oklahoma Health Sciences Center) (Abstract 5567; Poster Board: #390)
  • Data from a randomized, open-label, phase II study of the anti-NaPi2b antibody-drug conjugate Lifastuzumab (Lifa) Vedotin, also known as DNIB0600A and RG-7599, being developed by Genentech/Roche, compared to pegylated liposomal doxorubicin in patients with platinum-resistant ovarian cancer, will be presented by Susana N. Banerjee, MBBS, MA, PhD, MRCP (Royal Marsden Hospital). (Abstract 5569; Poster Board: #392).[9]

Nanoparticle-drug conjugate
Nanotechnology is a multidisciplinary field opening the door to a new generation of devices for cancer diagnosis, treatment and prevention. Drug-loaded nanoparticles offer considerable potential to provide a potentially ideal solution to solve some of the problems seen with traditional chemotherapy.

Although nanoparticles can become concentrated preferentially to tumors by virtue of the enhanced permeability and retention (EPR) effect of the vasculature, the low selectivity of nanoparticles towards the cancer cells hinders the advantages of the nanoparticle formulation for efficient chemotherapy.  One reason is that a therapeutic agents such as docetaxel, a commercially successful oncology drug that suffers from a poor safety profile limiting its clinical utility, also kills healthy cells.  To solve this problem, scientist have been working on the development of novel drugs containing docetaxel.

CRLX301 is a novel nanoparticle-drug conjugate (NDC) containing a docetaxel payload being developed by Cerulean Pharma (Waltham, MA 02451) for the treatment of patients with refractory solid tumors. The trial drug is expected to be differentiated from standard docetaxel because it is designed to concentrate more docetaxel in tumor cells and spare healthy tissue. Preclinical data show that CRLX301 had lower toxicity than has been reported with docetaxel in preclinical studies.

Ben Markman, MBBS, FRACP (Monash Cancer Center) will presents phase I trial results of CRLX301. (Abstract 2526; Poster Board: #226).

ASCO’s iPlanner
It’s just a few more weeks until the start of the 2016 annual meeting of American Society of Clinical Oncology. To help attendees plan their meeting, ASCO has developed a a new scheduling tool – the iPlanner – to browse abstract titles, search for sessions, or create a customized schedule.  In addition, the organizers have developed a new ‘Insiders Guide‘  designed to help meeting attendees navigate the ASCO and make the best of their time during the 2016 annual meeting.

Every year, in addition to offering a forum to share clinical updates in all areas of oncology, ASCO offers it’s audience a valuable opportunity to actively participate in discussions with colleagues, conforming it’s standing among the leading oncology meetings around the globe.


Last Editorial Review: May 7, 2016
Last Editorial update: May 8, 2016

Featured Image:Escalators in the McCormick Place convention center in Chicago, Illinois during the 51st annual meeting of the American Society of Clinical Oncology. Courtesy: © ASCO/Rodney White 2015 . Used with permission. Photo 1.0: Howard A. Burris, M.D., during the Annual Business Meeting at the American Society for Clinical Oncology (ASCO) Annual Meeting , Monday June 3, 2013. Courtesy © ASCO/Phil McCarten. Used with permission. Photo 2.0: Charles Rudin, M.D., Ph.,D., during the Grant Writing Workshop at the American Society for Clinical Oncology (ASCO) Annual Meeting on Friday June 1, 2012. Courtesy © ASCO/Phil McCarten. Used with permission. Photo 3.0: Jonathan E. Rosenberg, MD during the 2014 Genitourinary Cancers Symposium in San Francisco, Friday January 31, 2014. Courtesy © ASCO/Todd Buchanan. Used with permission.

Copyright © 2016 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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American Association for Cancer Research (AACR) – What to Expect at the 2016 Annual Meeting?

This year, the American Association for Cancer Research (AACR) will host their annual meeting from April 16 to 20, 2016 in the Ernest N. Morial Convention Center in New Orleans, LA. The meeting is expected to draw approximately 19,000 scientists, clinicians, advocates, and others to discuss advances in the field of cancer science. The multidisciplinary program will include an outstanding roster of speakers, hundreds of invited talks, and more than 6,000 proffered papers.

imagesThis year, among the thousands of oral sessions, papers and poster to be presented, nearly 100 will cover all aspects of antibody-drug conjugates – from early discovery to preclinical and clinical trials. Here is a short overview of what can be expected.

Importance of ADCs
Although the global market for antibody drug conjugates is still considered to be in an infancy stage – with only three antibody drug conjugates ever to have received market approval from the United States Food and Drug Administration (FDA) they have emerged as important therapeutics for treating cancer and hematological malignancies. Their importance is confirmed by the approval of brentuximab vedotin (Adcetris™, Seattle Genetics) and ado-trastuzumab emtansine (Kadcyla™, Genentech/Roche) and the large number of ADCs (>35) currently in clinical trials.

In a CME-designated Educational Session during the annual meeting of the AACR  (“From Chemistry to the Clinic: Pathways for Drug Discovery and Development, Part 1– Optimizing Drug Discovery: Insights on an Important Process”) on Saturday, April 16 (8:00 AM -10:00 AM; Location: Room 271, Morial Convention Center), the invited presenters discuss that all potential chemically modified agents, including antibody-drug conjugates, will realize improved anticancer activity, utilizing ADME, toxicology, and pharmacology data as the drivers towards further compound optimization towards finding effective agents with minimal toxicities and significantly improved anticancer activities.

Linker chemistry
The combination of a highly potent cytotoxic drugs linked to the targeting capacity of monoclonal antibodies allows sensitive discrimination between cancerous tissues and healthy tissues. The conditionally cleavable linker, which is stable in circulation, is designed to release the cytotoxic payload upon internalization into a target cell.

The development of an antibody-drug conjugate involves a variety of factors, including the presence of a ‘functional’ conjugation handle on the cytotoxic drug payload which is required to attach the drug to the linker, the linker chemistry to attach the cytotoxic drug to the antibody.

In the development of ADCs, these ‘functional conjugation handles’ being used include amines (both primary and secondary), thiols, and carboxylic acids. However, the majority of payloads used in the development of antibody-drug conjugates do not possess appropriate ‘handles’ that allow for stable conjugation and release of the cytotoxic drug in an unmodified form. In most cases, these drugs have been considered unsuitable for use as part of an ADC. While scientists can modify the drug structure to introduce a handle for conjugation, such modifications generally interfere negatively with the drug’s activity profile, which, in turn, can result in reduced potency, insufficient immunologic specificity of the antibody-drug conjugate and, due to non-specific release of the drug from the conjugate, increased toxicity.[1]

To avoid this problem, scientists at Seattle Genetics have developed new linker chemistry, the methylene-alkoxy-carbamate (MAC) [1]. Their novel approach enables direct conjugation of drugs through alcohol functional groups. Because these groups are present on a diverse range of synthetic drugs as well as cytotoxic natural products, scientist have effectively expanded the potential of available cytotoxic payloads. During the upcoming meeting, scientists from Seattle Genetics will present the proof-of-concept in which they have linked monomethyl auristatin E (MMAE) through the secondary alcohol of the norephedrine residue and characterized the stability and in vivo activity of the resulting ADCs.[2]

The data from Seattle Genetics’ novel  MMAE linker technology will be highlighted in a poster presentation on Tuesday, April 19, 2016 (Abstract 2956). By incorporating a short polyethylene glycol (PEG) unit, a self-hydrolysing maleimide and a glucuronidase release mechanism, the new MMAE drug-linker demonstrates pronounced activity with an increased therapeutic index in preclinical models.

“[These] data presentations … illustrate novel linker systems and cell-killing payloads as well as continued progress in understanding the chemical and biological properties of ADCs …. We believe [that] ADCs will continue to play an increasingly important role in cancer treatment,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

Thrombocytopenia and neutropenia
During the upcoming meeting, scientists from Agensys (Santa Monica, CA) will present results from their investigation of the potential mechanisms of thrombocytopenia and neutropenia as common adverse events in cancer patients treated with antibody-drug conjugates (ADCs).  The investigators used (HSC) in vitro and two ADCs, AGS-16C3F and ado-trastuzumab emtansine (T-DM1) to investigate the underlying mechanisms.

Breast Cancer
One Saturday, April 16, the educational session “Breast Cancer Targets in 2016,” will address targetable and potentially targetable abnormalities in breast cancer as well as potential opportunities for targeting the HER2 pathway in clinically HER2 negative breast cancer. During this session, Ron Bose  from the Washington University School of Medicine in Saint Louis, MO, will discuss “Targeting HER2/3 in breast cancer: An overview of genomic changes, drug development and clinical trials (10:45 AM -11:10 AM, Location: Room 291, Morial Convention Center).

Foto 1.0 – The main hall of the convention center, late Friday afternoon, April 15, awaiting more than 19,000 attendees to the 2016 annual meeting of the American Association for Cancer Research.

Thomas M. Cardillo, Serengulam V. Govindan, Maria Zalath and their colleagues at Immunomedics, Inc., Morris Plains, NJ show that the combining the  anti-Trop-2-SN-38 antibody-drug conjugate, sacituzumab govitecan (IMMU-132) with a poly(adenosine diphosphoribose) polymerase (PARP) inhibitor achieves synergistic growth inhibition in the treatment of patients with triple-negative breast cancer (TNBC), regardless of BRCA1/2 status.

The researchers found that the combination of IMMU-132 therapy with either microtubule or PARP inhibitors resulted in significant anti-tumor effects in TNBC disease models with no observable toxicity.  According to the scientists, the trial data provide the rationale for the clinical evaluation of IMMU-132 in combination with these chemotherapeutics in TNBC patients (Significant enhancement of efficacy of an anti-Trop-2 antibody-drug conjugate, sacituzumab govitecan (IMMU-132), in experimental triple-negative breast cancer (TNBC) when combined with microtubule or PARP inhibitors; Presentation Time: Sunday, April 17, 2016, 1:00 PM – 5:00 PM; Abstract 584).

Earlier this year Immunomedics lead antibody-drug conjugate, sacituzumab govitecan has received Breakthrough Therapy Designation from the FDA for the treatment of patients with triple-negative breast cancer (TNBC) who have failed at least 2 prior therapies for metastatic disease.

Lymphoma & Leukemia
Nandini Rudra-Ganguly, Pia M. Challita-Eid, Christine Lowe, Mike Mattie, et al. (Agensys Inc., an Affiliate of Astellas Pharma Inc., Santa Monica, CA), in a poster (Therapeutic Antibodies, Section 27, Immunology, Sunday, April 17, 2016, 1:00 PM – 5:00 PM; Abstract 574) present the developed a site-specific ADC targeting FLT3 that exhibits potent anti-tumor activity in xenograft models regardless of FLT3 activation status.  FLT3, a member of the class III receptor tyrosine kinase family that includes C-KIT, C-FMS and platelet derived growth factor receptor (PDGFR), is primarily expressed in early myeloid and lymphoid progenitors and plays an important role in their proliferation and differentiation.  The researchers show that the trial drug can potentially offer a new and more versatile approach in targeting FLT3-expressing leukemia through a mechanism independent of FLT3 genetic aberration.

During the same poster presentation (Abstract 579), Aradhana Awasthi Tiwari, Janet Ayello, Carmella van de Ven, Lisa Kurien, et al. from New York Medical College, Elsmford, NY, present  preliminary data that indicates that the antibody-drug conjugate anti-CD79b-vc-MMAE  (Polatuzumab Vedotin; Genentech/Roche) exhibit enhanced cell death when targeted to CD79b+ Burkitt lymphoma and Primary Mediastinal large B-cell Lymphoma (PMBL). They conclude that Polatuzumab Vedotin may be a novel agent to investigate as immunotherapeutic agent in patients with relapsed refractory CD79b+ BL and/or PMBL.

Gastric cancer
Natasha Bodyak, Alex Yurkovetskiy, Dmitry R. Gumerov from Mersana Therapeutics, Cambridge, MA and their partners at Adimab LLC, Lebanon, NH, show that XMT-1522, an anti-HER2 ADC that incorporates HT-19, a human anti-HER2 antibody optimized for cytotoxic payload delivery, is consistent with their hypothesis that a non-competitive ADC can be combined with current anti-HER2 regimens.  The initial results confirm that the combination of XMT-1522 with trastuzumab and/or pertuzumab offers a more rapid internalization, more complete HER2 degradation, and significantly great anti-tumor activity in the NCI-N87 gastric cancer xenograft model relative to XMT-1522 alone or the combination of pertuzumab + trastuzumab (Optimization of lead antibody selection for XMT-1522, a novel, highly potent HER2-targeted antibody-drug conjugate (ADC); Presentation Time: Sunday, April 17, 2016, 1:00 PM – 5:00 PM
Location: Section 27; Abstract 596).

Neuroblastoma
During the CME-designated minisymposium “New Molecular Advances in Pediatric Cancer” (Monday, April 18, 2016, 3:00 PM – 5:00 PM; Location: Room 354, Morial Convention Center; Abstract 2690) Renata Sano, Kateryna Krytska, Colleen Larmour from the Children’s Hospital of Philadelphia, Philadelphia, PA and their collaborators at Kolltan Pharmaceuticals, New Haven, CT and Nerviano Medical Sciences, Nerviano, Italy evaluate the therapeutic potential of ALK2-ADC in vivo, mice bearing Felix-patient-derived xenograft (PDX) tumors, containing the third most common ALK mutation (R1245C), to demonstrate that ALK2-ADC led to a significant reduction in tumor growth compared to unconjugated antibody and a control ADC (p<0.0001).

Their work was based on the hypothesis that ALK-targeted antibodies may be useful in neuroblastoma as single-agent immunotherapy or in combination with small-molecule ALK inhibitors – especially where mutations reduce kinase inhibitor sensitivity. Their research demonstrated that targeting human ALK-expressing with an ALK antibody-drug conjugate shows early signs of favorable efficacy and tolerability supporting future development of this approach as a potential novel therapeutic for patients with neuroblastoma.

More payloads
On Tuesday, Manami Shizuka, Alan Wilhelm, Katie Archer, Emily Reid,  et al,  ImmunoGen, Inc., Waltham, MA present results of their of on the ongoing effort to expand the cytotoxic payloads for use in ADCs.  The development of the mono-imine-containing indolino-benzodiazepine dimer, IGN-P1, conjugated via a protease-cleavable peptidic L-alanine-L-alanine linker to a folate receptor α (FRα)-binding antibody, and an EGFR-binding antibody resulted in  a novel ADCs demonstrating high in vitro potency (IC50 ~4-100 pM) and specificity towards several cancer cell line.

The researchers found that the stereochemistry of the peptide linker was crucial for bystander activity and in vivo efficacy and that  IGN-P1 ADC exhibited strong bystander activity, which, they believe is dictating strong antitumor activity in vivo. Furthermore, treatment of low to moderate antigen-expressing models with Ab-IGN-P1 showed  tumor regressions at doses as low as 3-10 µg/kg linked payload.

Based on the initial results of their study, the researchers conclude that there is a potential therapeutic benefit of highly active and specific IGN-P1 conjugates, even for the challenging subset of patients with solid tumors where the target antigen is expressed at lower levels (Peptide-linked indolino-benzodiazepine DNA-alkylating agents for use in antibody-drug conjugates; Tuesday, Apr 19, 2016, 8:00 AM -12:00 PM; Abstract 2959)

Late breaking 
During a late breaking session on Sunday, Marie-Priscille Brun, Hervé Bouchard, François Clerc, and their collegues from Sanofi R&D, Vitry-sur-Seine, France, present  “Towards new cryptophycins as promising payloads for ADC.” (LB-053). Cryptophycins, a potent, cytotoxic dioxadiazacyclohexadecenetetrone isolated from cyanobacteria of the genus Nostoc, have been evaluated as payloads in ADCs.  Scientists have found that free cryptophycin analog 1 displayed cell activity an order of magnitude more potent than te currently approved payloads MMAE (in brentuximab vedotin) and DM1 (in ado-trastuzumab emtansine). The observed potency increase was also reflected in the activity of a cryptophycin based ADC, attached via a either cleavable or non-cleavable linker. [3]

Worth mentioning

  • In a Late Breaking poster (LB-062), Rosa Cardoso, Shalom Goldberg, Tricia Lin, Tracy Spinka-Doms,  et al from Janssen Research & Development, LLC, Spring House, PA, present Evaluation of drug conjugation sites in an anti-EGFR Centyrin.
  • During the session “HDAC, Methyltransferase Inhibitors, and Novel Anticancer Agents (Designing novel warheads for targeted therapies: SAR and efficient strategies for the synthesis of analogues of tubulysin; Wednesday, Apr 20, 2016, 7:30 AM -11:00 AM; Abstract 4735) Iontcho Vlahov, Fei You, Paul Kleindl, and their colleagues at Endocyte, W. Lafayette, IN, will discuss the synthesizing novel tubulysin analogs which are less prone to degradation under acidic and basic conditions, as well as enzymic influences, which were used as warheads for folate receptor(FR)-targeted therapy.

Clinical Trials Minisymposium
On Monday afternoon, during the “Early Clinical Trials of Novel Agents” CME-designated clinical trials minisymposium (Monday, Apr 18, 2016, 3:00 PM – 5:00 PM; Location: Room 391, Morial Convention Center; Abstract CT064), Scott T. Tarawa and Bishoy Faltas (Weill Cornell Medicine, New York, NY), Elaine Lam and Wells A. Messersmith (University of Colorado Cancer Center, Aurora, CO), Philip Saylor, Aditya Bardia (Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA) and their collaborating partners at UF Health Cancer Center-Orlando Health, Orlando, FL, Vanderbilt Ingram Cancer Center, Nashville, TN, Columbia University-Herbert Irving Comprehensive Cancer Center, New York, NY and Immunomedics, Inc., Morris Plains, NJ, present their phase I/II clinical experience in the the treatment of patients with metastatic platinum-resistant urothelial cancer (PRUC) with an anti-Trop-2-SN-38 antibody-drug conjugate, sacituzumab govitecan (IMMU-132).

Results from a phase II trial of the anti-CEACAM5/SN-38 ADC, the company’s second ADC labetuzumab govitecan or IMMU-130,  in patients with metastatic colorectal cancer also will be presented in the same minisymposium session. (Labetuzumab govitecan (IMMU-130), an anti-CEACAM5/SN-38 antibody-drug conjugate, is active in patients with heavily pretreated metastatic colorectal cancer (mCRC): phase II results Presentation Time: Monday, Apr 18, 2016, 3:15 PM – 3:30 PM Location: Room 391, Morial Convention Center; Abstract CT065).

Moonshot
One of the highlights of the annual meeting is the presentation by Vice President Joe Biden on Wednesday, April 20, at the beginning of the Wrap-Up Plenary Session, entitled the “AACR Annual Meeting 2016 Highlights: Vision for the Future.”

Commenting on the upcoming visit of the Vice President to the last day of the annual meeting, AACR’s Chief Executive Officer Margaret Foti, PhD, MD (hc) said: “This is really a monumental moment in the field of cancer research and it is an extraordinary honor for the AACR to welcome the Vice President.”

Foti continued “[The Vice President] has chosen our Annual Meeting… to provide us with the latest information about the National Cancer Moonshot Initiative, which President Obama announced during his 2016 State of the Union address, including sharing additional details about the Blue Ribbon Panel of scientific experts, cancer leaders, and patient advocates that was established last week to help guide the National Cancer Moonshot Initiative.”

This years the annual meeting of the American Association for Cancer Research is again confirming its standing among the most important medical meetings around the globe.


Last Editorial Review: April 15, 2016

Featured Image: AACR Annual Meeting. Foto 1.0: Inside the Ernest N. Morial Convention Center in New Orleans, LA. Courtesy: © Sunvalley Communication, LLC. Used with permission. Logo: © AACR/Used with permission

Copyright © 2016 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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Breakthrough Therapy Designation for Sacituzumab Govitecan in Triple-negative Breast Cancer

Sacituzumab govitecan, also known as IMMU-132, has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with triple-negative breast cancer (TNBC) who have failed at least 2 prior therapies for metastatic disease. The trial-drug is Immunomedics novel investigational antibody-drug conjugate.

Triple-Negative Breast Cancer or TNBC, is a serious disease. Its includes about 15% of all breast cancer types and according to the American Cancer Society, the an annual incidence is estimated to be about 40,000 people, with 20,000 diagnosed with metastatic TNBC, in the United States alone. [1] As the name implies, Triple-Negative Breast Cancer does not express estrogen, progesterone or the HER2 receptor, and is, therefore, insensitive to most of the available targeted therapies for breast cancer treatment, including HER2-directed therapy, including  trastuzumab (Herceptin®; Genentech/Roche), and endocrine therapies (such as tamoxifen or the aromatase inhibitors).

TNBC has a particularly aggressive course. Following first-line therapy, the median overall survival is 6-13 months and the median progression-free survival (PFS) is usually 3-4 months. Currently there is no single standard chemotherapy to treat patients with relapsed/refractory metastatic TNBC. Rapid relapse, with visceral and brain metastases, is very common.

Therefore, new treatment strategies are needed. Because Trop-2 is expressed in >90% of TNBC, as measured by immunohistochemical (IHC) assay, researchers conducted a trial to evaluate the safety and efficacy of an anti-Trop-2 monoclonal antibody conjugated to SN-38.[1]

This novel drug, sacituzumab govitecan, is an investigational and first-in-class antibody-drug conjugate being developed by the clinical-stage biopharmaceutical company Immunomedics, conjugates the moderately-toxic drug, SN-38, site-specifically and at a high ratio of drug to antibody, to a humanized antibody that targets the Trop-2 receptor expressed by many solid cancers and may be beneficial for the treatment of patients with TNBC.

SN-38 is a topoisomerase I inhibitor and the active metabolite of the prodrug irinotecan  (Camptosar®, CPT-11; Pfizer), which is used to treat certain solid cancers as a part of combination therapies. SN-38 has a 2-3 logs higher potency than the prodrug.  The pharmacology and properties of the drug are well- known.

Fast Track designation
Sacituzumab govitecan has received Fast Track designation from the FDA 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.

Breakthrough Therapy
The Breakthrough Therapy Designation received earlier this year was supported by a Phase II study in patients with metastatic TNBC who had received a median of 5 prior therapies, with a minimum of 2 therapies (range, 2 – 12).

The FDA created the Breakthrough Therapy Designation as part of the 2012 FDA Safety and Innovation Act (FDASIA) to expedite the development and review of a drug that is intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

Validation
“We believe Breakthrough Therapy Designation for IMMU-132 further validates this potential therapeutic for patients with TNBC, and we are delighted to receive this important recognition,” noted  Cynthia L. Sullivan, President and Chief Executive Officer. “We continue to assess partnering opportunities while completing the scale-up manufacturing and regulatory activities for an international, randomized, controlled, registration trial in TNBC, based on the Special Protocol Assessment agreement that was already granted by the FDA,” she added.

“[Sacituzumab govitecan] is also in Phase II trials in patients with advanced, heavily-pretreated, non-small-cell lung cancer, small-cell lung cancer, and urothelial cancers, where encouraging results have been observed. The Trop-2 receptor targeted by this antibody- drug conjugate has increased expression in a large number of solid cancers. To date, we have enrolled about 300 patients with diverse cancer types,” Sullivan further stated.

Clinical trials
Following the establishment  of the optimal repeated dose in a Phase I trial (ClinicalTrials.gov, NCT01631552) involving many different solid cancer types, an expanded Phase II was undertaken in a number of cancers, including TNBC.

The primary objective of the multi-center trial was to evaluate the safety and tolerability of sacituzumab govitecan as a single agent administered in 3-week treatment cycles for up to 8 cycles, in previously treated patients with advanced epithelial cancer. The secondary objectives are to obtain initial data concerning pharmacokinetics, immunogenicity, and efficacy with this dosing regimen.

In this trial, patients received 8 or 10 mg/kg sacituzumab govitecan i.v. on days 1 and 8 of 21-day repeated cycles. Assessments of safety and response by RECIST 1.1 were made weekly and bimonthly, respectively. Tumor biopsies (archival, at baseline prior to treatment, and at disease progression) were obtained when safe and feasible.

As of May 10, 2015, 58 patients with Tripple-negative Breast Cancer, with a median of 4 prior therapies (range, 1-11), were treated with sacituzumab govitecan.

Observed grade 3-4 toxicities included neutropenia (26%), febrile neutropenia (2%), diarrhea (2%), anemia (4%), and fatigue (4%).  The participating patients did not developed antibodies to SN-38 or the anti-Trop-2 antibody RS7. Non of the participating patients had to discontinued therapy due to toxicity.

Tumor responses were defined as Objective Response Rate (Complete Response +Partial Response) in 31% of 49 evaluated patients, including 2 with Complete Response (CR), and a clinical benefit ratio (CR+PR+ Stable Disease)>6 months) of 49% (63% with SD>4 months. A total of 23 patients are continuing treatment after 1st assessment.

Trial results
The current median progression-free survival is 7.3 months with 44% maturity in 50 patients treated at the 8 or 10 mg/kg dose level. Overall survival data are still not mature 20 months after enrollment of first patient.

Clinical efficacy correlated to biomarker studies, including Trop-2 expression (target of antibody), topoisomerase-1 expression (target of SN-38), and homologous recombinant deficiency (HRD) assay (marker of DNA repair), is being studied. Immunohistochemistry results in archival specimens currently show 97% positivity of Trop-2 among 34 specimens evaluated, with 79% having high intensity (2+/3+) staining.

The researchers conducting the trial concluded that sacituzumab govitecan shows manageable toxicity, and encouraging anti-tumor activity in relapsed/refractory patients with TNBC. This antibody-drug conjugate appears to have a high therapeutic index in heavily pretreated patients.


Last Editorial Review: February 6, 2016

Featured Image: X-ray mammogram Courtesy: © Fotolia. Used with permission.

Copyright © 2016 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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Sacituzumab govitecan (IMMU-132) Shows Positive Interim Phase II Results

Sacituzumab govitecan also known as IMMU-132, an antibody-drug conjugate being developed by Immunomedics, a clinical-stage biopharmaceutical company, continues to produce durable responses in patients with metastatic lung cancer who had relapsed or were refractory to their last cancer therapy.

Sacituzumab govitecan is a first-in-class antibody-drug conjugate in which the moderately-toxic drug, SN-38, site-specifically and at a high ratio of drug to antibody (DAR= 7.6), is conjugated to a humanized monoclonal antibody that targets the TROP-2 receptor which is widely expressed in most epithelial cancers, including non-small and small-cell lung cancers (NSCLC and SCLC).

SN-38 is the active metabolite of irinotecan (Camptosar®; Pfizer), which is used as a first-line therapy in combination with 5-fluorouracil and leucovorin for patients with metastatic carcinoma of the colon or rectum and in the treatment of patients with metastatic carcinoma of the colon or rectum whose disease has recurred or progressed following initial fluorouracil-based therapy. Being part of existing combination therapies, the pharmacology and properties of the active compound irinotecan are well-known.

Both in vitro and in vivo preclinical data suggest that sacituzumab govitecan delivers up to 136-fold more SN-38 than its parental drug, irinotecan, in a human cancer xenograft.

Highly tolerable
In addition to durable responses, repeated cycles of sacituzumab govitecan monotherapy are well tolerated. Sacituzumab govitecan also continues to demonstrate a highly tolerable and easily managed toxicity profile.

Objective response rate (ORR) and progression-free survival (PFS) data in previously-treated metastatic lung cancer (5.4 months in NSCLC) are encouraging and warrant further evaluation of IMMU-132 in these lung cancers.

In one study in which 31 lung cancer patients received sacituzumab govitecan at the dose of 10 mg/kg, the major toxicity reported was 10% Grades 3 and 4 neutropenia. Remarkably, there was no reported incidence of Grade 3 or 4 diarrhea, which is a major side effect with irinotecan. At 10 mg/kg 13% of lung cancer patients required a dose reduction in sacituzumab govitecan.

Clinical Trial
At the time of the interim analysis of the Phase II data, a total of 57 patients with metastatic lung cancer (28 non-small-cell lung cancer (NSCLC) and 29 small-cell lung cancer (SCLC)) had been enrolled into this multicenter study at doses ranging from 8-18 mg/kg given on days 1 and 8 every 21 days. The median number of prior lines of therapy in the NSCLC and SCLC patients was 3 and 2.5, respectively. Across all tumor types, 12 mg/kg was declared the maximal tolerated dose and 10 mg/kg declared the recommended Phase II dose. Accrual at 10 mg/kg continues. [2]

Treatment response in lung cancer patients administered doses of ≤12 mg/kg was assessed by computed tomography using the rules set by the Response Evaluation Criteria In Solid Tumors (RECIST 1.1).

Response
In NSCLC, the most common type of lung cancer, 6 of 19 patients achieved an objective response (ORR = 32%). In SCLC, 6 of 20 patients achieved an objective response (ORR = 30%). In the 10 mg/kg cohorts, the objective response (partial response) rates in NSCLC and SCLC were 3/10 (30%) and 3/5 (60%), respectively.

In NSCLC, the interim median progression-free survival (PFS), which is the length of time patients are living without their cancer progressing, was 5.4 months for those patients receiving sacituzumab govitecan at the dose level of 10 mg/kg. At the time of analysis, fifty-six percent of NSCLC patients in this dose group had experienced a PFS event. For patients with SCLC, interim median PFS was 4.6 months at the 10 mg/kg dose level. At the time of analysis, eighty- three percent of SCLC patients in this dose group had experienced a PFS event. Overall survival (OS) data were too early to report.

Early compelling results
“These results, while still early, seem to show noticeable activity of this drug in a heavily pretreated lung cancer population,” commented D. Ross Camidge, Joyce Zeff Chair in Lung Cancer Research at the University of Colorado Cancer Center, who presented these data in an Oral Session at the 16th World Conference on Lung Cancer (WCLC) being held September 6 – 9, 2015 [1]

“Based on these compelling results, we consider both NSCLC and SCLC to be of primary interest, along with triple-negative breast, esophageal, urothelial, and colorectal cancers, for further study with sacituzumab govitecan,” remarked Cynthia L. Sullivan, President and Chief Executive Officer of Immunomedics. “Updated results in these other solid cancers are expected at future national and international cancer conferences,” Sullivan added.

According to the American Cancer Society, lung cancer accounts for more deaths than any other cancer in both men and women. An estimated 158,040 deaths are expected to occur in 2015, accounting for about 27% of all cancer deaths.


Last Editorial Review: September 8, 2015

Feature Image: Denver Skyline at Sunset, Denver, Colorado. Feature image Courtesy: © Larry Johnson. This file is licensed under the Creative Commons Attribution 2.0 Generic license. CC BY-SA 2.0

Copyright © 2015 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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