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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.


Immune Checkpoint Inhibitor Nivolumab: Five-year Survival Rate in Advanced Lung Cancer

Data from a phase I clincal trial presented at the Annual Meeting of American Association for Cancer Research (AACR), beimg held April 1-5, 2017 confirms that treatment with the immune checkpoint inhibitor nivolumab (Opdivo®; Bristol-Myers Squibb) yielded durable responses in some patients with advanced non-small cell lung cancer (NSCLC), with a five-year survival rate of 16%,

Approved Indication
Nivolumab is indicated for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Nivolumab.

Five-year survival
According to the National Cancer Institute’s SEER data, five-year survival rate for patients with advanced lung and bronchus cancer is 4.3%, and for those with advanced NSCLC, it is 4.9%.

“This is the first report of the long-term survival rate in patients with metastatic NSCLC treated with an immune checkpoint inhibitor. Our study results show that for a small subset of patients, immunotherapy can work for a very long time,” noted Julie Brahmer, MD, associate professor of oncology at the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins.

Higher Than Historical Rate
“The five-year overall survival rate reported in this study is much higher than what is reported for this population of patients receiving standard-of-care treatment. Statistics show that most patients with advanced disease die within a year of diagnosis, and the five-year survival rate for metastatic NSCLC is about 4 percent,” Brahmer added.

Brahmer and colleagues used data from a cohort of the phase I clinical trial CA209-003, in which patients with heavily pretreated, advanced NSCLC were enrolled regardless of their tumor PD-L1 status and randomly assigned to three different dose levels of nivolumab. Prior analysis of data from this trial showed nivolumab had promising clinical activity in this patient population, and data from subsequent clinical trials led to the U.S. Food and Drug Administration (FDA) approving nivolumab for second-line treatment of patients with advanced NSCLC.

Trial results
After following 129 patients in the phase I trial for a minimum of about 58 months, overall survival rates in patients with squamous and non-squamous NSCLC were 16% and 15%, respectively.

Of the 16 patients who survived for five years or longer, nine were male, and 12 were current smokers when they enrolled in the trial. Twelve had a partial response, and two patients each had stable disease and progressive disease as best response to treatment.

Eight patients completed the two-year treatment without any side effects, and four stopped treatment early due to side effects. None of these 12 patients required further treatment, according to Brahmer. “While this speaks to the durability of the responses, further evaluations would be needed to ascertain if the cancers were completely eliminated by the immune system, because of which no further treatment was needed, or if the therapy invoked an ongoing immune memory,” Brahmer noted.

Consistent patern
“We were unable to see a consistent pattern, a clinical or tumor characteristic, to predict which metastatic lung cancer patients are going to be five-year survivors,” Brahmer noted. While baseline tumor biopsy was required for enrollment in the trial, several patients did not have adequate tumor sample to determine the PD-L1 status, she said. The presence and quantity of the protein PD-L1 is considered as a biomarker that can identify patients likely to respond to immune checkpoint inhibitors that target the PD-1/PD-L1 pathway, such as nivolumab. However, PD-L1 status was not associated clearly with long-term survival in this small group of patients.

“We are performing further studies to learn why these patients did so well for so long and better understand which patients can stop treatment at two years and which of them need to continue treatment beyond two years,” Brahmer said.

In previous phase III open-label studies, including Checkmate 057, patients with metastatic non-squamous NSCLC who had experienced disease progression during or after one prior platinum doublet-based chemotherapy regimen received nivolumab vs docetaxel. [1][2][3]

The primary endpoint for the Checkmate 057 study was overall survival (OS) [a], showing 12.2 months (95% CI: 9.7-15.0) for nivolumab and 9.4 months (95% CI: 8.0-10.7) for docetaxel. Secondary endpoints included investigator-assessed objective response rate (ORR) and progression-free survival (PFS).

ORR with nivolumab was 19% ([95% CI: 15-24]) vs 12% with docetaxel  [95% CI: 9-17; P=0.02]). In this rial, the median duration of response was 17 months in the nivolumab arm (95% CI: 8.4-NR) and 6 months in the docetaxel arm (95% CI: 4.4-7.0). Finally, the median PFS with nivolumab was 2.3 months vs 4.2 months with docetaxel; HR=0.92 (95% CI: 0.77-1.11; P=0.39)[1]

A limitation of Brahmer’s study is that this was not a randomized trial, hence, survival rate could only be compared with historical rates, Brahmer said.

This study was funded by Bristol-Myers Squibb (BMS). Brahmer received research funding from BMS, and is an advisor to the company.

[a] Hazard Ratio (HR) for OS=0.73 (95% CI: 0.60-0.89, P=0.0015)

Last Editorial Review: April 3, 2017

Featured Image: The Capitol Building in Washington DC at night with reflection in pond, capital of the United States of America 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.


Data Highlights the Potential to Combine Mirvetuximab Soravtansine with an Immune Checkpoint Inhibitor

Preclinical data demonstrate the potential for enhancing the activity of mirvetuximab soravtansine, also known as IMGN853, when the investigational agent is combined with and immune checkpoint inhibition.  The drug is being developed by Immunogen. [1]

Data from clinical trials was presented at the 31st Annual Meeting of the Society for Immunotherapy of Cancer (SITC), being held November 9-13, 2016 in National Harbor, Maryland.

Mirvetuximab soravtansine, in which a humanized FRα-binding M9346A antibody is linked to the tubulin-disrupting cytotoxin maytansinoid DM4, is a first-in-class folate receptor alpha (FRα)-targeting antibody-drug conjugate or ADC showing promising single-agent activity and a favorable safety profile in FRα-positive ovarian cancer patients in a phase I study.

The drug is entering a Phase III trial called FORWARD I (NCT02631876) as a single agent treatment for platinum-resistant ovarian cancer.

Ovarian cancer
Ovarian cancer ranks fifth in cancer deaths among women, accounting for more deaths than any other cancer of the female reproductive system. According to the American Cancer Society in 2016 about 22,280 women are expected to receive a new diagnosis of ovarian cancer in the United States, and about 14,240 women will die from the disease.  Ovarian cancer generally develops in older women. About half of the women who are diagnosed with ovarian cancer are 63 years or older. It is more common in white women than African-American women. [2]

The rate at which women are diagnosed with ovarian cancer has been slowly falling over the past 20 years. [2]

Mechanism of Action
Mirvetuximab soravtansine uses a FRα-binding antibody to target the antibody-drug conjugate specifically to FRα-expressing cancer cells and a potent anti-tumor agent, DM4, to kill the targeted cancer cells. After the investigational agents binds to FRα± on cancer cells and is internalized, DM4 is released through enzymatic degradation of the antibody and linker cleavage. This results in disruption of cell division and cell death.

Combination trials
Mirvetuximab soravtansine is also being assessed in combination regimens with pembrolizumab (Keytruda®; Merck Oncology/MSD, an immune checkpoint inhibitor which releases programmed death receptor-1 or PD-1 pathway–mediated inhibition of the immune response, as well as liposomal doxorubicin (Doxil®; Janssen Products), carboplatin and bevacizumab (Avastin®; Genentech) for both platinum-resistant and platinum-sensitive ovarian cancer in the Phase Ib/II FORWARD II trial.

Researchers at ImmunoGen expects initial data from FORWARD II in mid-2017.

In the poster presentation at SITC, the researchers reported in vitro data showing that treatment of FRα-expressing tumor cells with mirvetuximab soravtansine activates monocytes, a type of antigen presenting cell or APC. [1]

Monocyte activation required both the antibody component of mirvetuximab soravtansine, which interacts with Fcγ receptors on APCs and its cancer-killing agent DM4, which promotes immunogenic cell death of the tumor cells. Activation of APCs in the presence of tumor neo antigen would trigger an anti-tumor T cell response that could be enhanced by immune checkpoint inhibition. Hence, the researchers concluded that their data provided a rationale for the clinical evaluation of mirvetuximab soravtansine and a checkpoint inhibitor.

“We are committed to continuing to drive innovation in the research and development of antibody-drug conjugates for the treatment of cancer. These preclinical data reinforce the potential of combining mirvetuximab soravtansine with an immune checkpoint inhibitor, which we are evaluating as part of our FORWARD II trial,” explained Richard Gregory, Ph.D., executive vice president and chief scientific officer of ImmunoGen.

“More broadly, these data suggest that ADCs using ImmunoGen’s maytansinoid technology may have an important role in promoting anti-tumor immunity in conjunction with immune-oncology drugs,” Gregory added.

Last Editorial Review: November 14, 2016

Featured Image: Female Reproductive System Anatomy with nervous sysyem and Urinary bladder. 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.


First of Two Planned Trials Combining Brentuximab Vedotin and Nivolumab Start Under Clinical Collaboration Agreement between Bristol-Myers Squibb and Seattle Genetics

Seattle Genetics, a biotechnology company focused on the development and commercialization of innovative antibody-based therapies for the treatment of cancer, has initiated a phase 1/2 clinical trial of brentuximab vedotin (Adcetris®) in combination with nivolumab (Opdivo®) for patients with relapsed or refractory Hodgkin lymphoma (HL) after failure of frontline treatment. The trial is being conducted as part of a clinical trial collaboration agreed between Bristol-Myers Squibb Company and Seattle Genetics.

A second trial under the collaboration is planned to begin later in 2015 for relapsed or refractory B-cell and T-cell non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL).

Lymphatic system
Lymphoma is a general term for a group of cancers that originate in the lymphatic system. There are two major categories of lymphoma: Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). HL is distinguished from other types of lymphoma by the presence of one characteristic type of cell, known as the Reed-Sternberg cell. The Reed-Sternberg cell generally expresses CD30. NHL is further categorized into indolent (low-grade) or aggressive, including DLBCL. DLBCL is the most common type of non-Hodgkin lymphoma or NHL.

Antibody-drug Conjugate
Brentuximab vedotin is an antibody-drug conjugate or ADC directed to CD30, a defining marker of classical HL, which combines the targeting ability of a monoclonal antibody via a protease-cleavable linker to a highly potent, microtubule disrupting, cell-killing, agent called monomethyl auristatin E (MMAE). The antibody-drug conjugate employs a linker system that is designed to be stable in the bloodstream but to release MMAE upon internalization into CD30-expressing tumor cells.

Checkpoint inhibitors
Nivolumab is a human antibody that targets and inhibits the programmed death receptor-1 or PD-1, resulting in T-cell activation. The drug is part of a new class of cancer immunotherapy treatments known as immune checkpoint inhibitors, which are designed to harness the body’s own immune system in fighting cancer by targeting distinct regulatory components of the immune system.

Among the most exciting features of these immune checkpoint inhibitors is that they provide impressive tumor responses in metastatic cancers of different histologies.  Furthermore, the remarkable antitumor activity of these novel agents has generated an unprecedented wave of interest for immune checkpoint inhibitors in the field of oncology and hematology.  The potential of these compounds given alone or in combination with existing therapeutics is, according to a number of experts, enormous.

The strategy to harness the host’s immune system to fight cancer and hematological disorders has been a cornerstone of immunotherapy in oncology and hematology. This strategy has, with the emergence of immune checkpoint inhibitors, gained substantial momentum These agents block inhibitory receptors such as cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), programmed death receptor-1 (PD-1) and its ligand PD-L1, and thus liberate tumour-specific T cells to exert their effector function against tumor cells.

Combination therapy
“This is the first corporate-sponsored clinical trial to evaluate brentuximab vedotin combined with an immune checkpoint inhibitor to determine if the combination can improve patient outcomes,” noted Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development.

“The trial supports our strategy to establish brentuximab vedotin as the foundation of care for CD30-expressing malignancies, and to test novel combinations that could benefit patients. We are executing a broad clinical program with brentuximab vedotin to potentially expand into earlier lines of therapy and new indications, including the ECHELON-1 trial in frontline Hodgkin lymphoma, the ECHELON-2 trial in frontline mature T-cell lymphoma, the ALCANZA trial in cutaneous T-cell lymphoma and both ongoing and planned trials in diffuse large B-cell lymphoma,” Drachman further noted.

Trial design
The phase 1/2 open-label trial will enroll relapsed or refractory HL patients who have failed frontline therapy. The primary objective is to assess the safety and antitumor activity of brentuximab vedotin in combination with nivolumab. After completion of four cycles of combination therapy, patients are eligible to undergo autologous stem cell transplant (ASCT). Patients at high risk of relapse or progression following ASCT will be eligible to receive brentuximab vedotin in the commercial setting. All patients will be assessed for progression-free survival after ASCT. The trial is being conducted at multiple centers in the United States and is designed to enroll up to approximately 60 patients.

Brentuximab vedotin is not currently approved for the treatment of second-line, transplant eligible HL or for the treatment of NHL other than relapsed systemic anaplastic large cell lymphoma. Nivolumab is currently not approved for the treatment of lymphoma.

Last Editorial Review: October 7, 2015

Feature Image: A senior researchers at Seattle Genetics. Feature image Courtesy:Seattle Genetics.

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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