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PEER-REVIEWED ARTICLES

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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Tisotumab vedotin Demonstrates Encouraging Response Rate and a Manageable Safety Profile in Cervical Cancer

Preliminary clinical data for tisotumab vedotin, also known as HuMax®-TF-ADC from a Genmab-sponsored phase I/II clinical trial (GEN 701) were featured today in an oral presentation at the ESMO 2017 Congress held September 8 – 12, 2017 in Madrid, Spain, organized by the European Society for Medical Oncology (ESMO). [1][2] A separate poster of the trial includes additional trial results.

Tisotumab vedotin is an antibody-drug conjugate (ADC) which includes a monoclonal antibody targeting tissue factor (TF), a protein involved in tumor signaling and angiogenesis expressed on a broad range of solid tumors. The ADC contains a cleavable linker and the cytotoxic drug monomethyl auristatin E or MMAE.

Based on its high expression on many solid tumors and its rapid internalization, TF was selected as a target for an ADC approach. Tisotumab vedotin is in phase I/II clinical studies for solid tumors, including cervical cancer.

Cervical cancer
Cervical cancer originates in the cells lining the cervix, which is the lower part of the uterus. Routine medical examinations and the human papillomavirus (HPV) vaccine have had a positive impact on the incidence of cervical cancer in the developed world.

However, even in developed countries, many women do not receive routine medical care or the HPV vaccine, resulting in an unmet medical need particularly for recurrent/metastatic disease. Standard therapies for recurrent/metastatic cervical cancer generally result in response rates of less than 15% and a median overall survival of 6 to 8 months.

Among patients with cervical cancer treated in the trial, tisotumab vedotin demonstrated an encouraging response rate and manageable safety profile.

Co-development
Earlier this year Seattle Genetics exercised its option to co-develop tisotumab vedotin with Genmab. The companies originally entered into a commercial license and collaboration agreement in October 2011 under which Seattle Genetics had the right to exercise a co-development option for tisotumab vedotin at the end of Phase I clinical development. As part of this process, the companies are evaluating next steps in the development of tisotumab vedotin for cervical cancer.

“Our ADC partnership with Genmab has generated promising Phase I/II data for tisotumab vedotin in patients with recurrent cervical cancer. As Seattle Genetics opts into co-development of this clinical program, we add another potential product to our strong pipeline,” said Clay Siegall, Ph.D., President and Chief Executive Officer of Seattle Genetics.

“Together with Genmab, we look forward to advancing tisotumab vedotin for the treatment of solid tumors,” Siegall further noted.

Solid Tumor Indication
The GEN 701 study (NCT02001623) is ongoing and further data, including other solid tumor indications, will be published at a later date.

“In the recurrent cervical cancer setting, there is no standard of care and response rates are limited, underscoring the unmet need. Beyond cervical cancer, we believe tisotumab vedotin may have therapeutic potential in other solid tumors, and we are collaborating with Genmab to advance this program to benefit patients,”said Jonathan Drachman, M.D., Chief Medical Officer and Executive Vice President, Research and Development at Seattle Genetics.

“The encouraging [data from this trial] reinforce our recent decision to exercise our option to co-develop tisotumab vedotin with Genmab, thereby adding another clinical-stage solid tumor ADC program to our pipeline with a potentially rapid registrational pathway.”

“In the recurrent cervical cancer setting, there is no standard of care and response rates are limited, underscoring the unmet need. Beyond cervical cancer, we believe tisotumab vedotin may have therapeutic potential in other solid tumors, and we are collaborating with Genmab to advance this program to benefit patients,” Drachman added.

Clinical trial
Tisotumab vedotin was evaluated in a phase I/II two-part trial conducted by Genmab. Part 1 assessed escalating single-agent doses ranging from 0.3 to 2.2 milligrams per kilogram (mg/kg) administered every three weeks in a variety of solid tumors. Part 2 consisted of disease-specific expansion cohorts at the recommended dose of 2.0 mg/kg.

Data were reported from an expansion cohort of 34 patients with relapsed, recurrent and/or metastatic cervical cancer with a median age of 43 years. Of these patients, 91% had received prior treatment with a platinum and/or taxane-based chemotherapy regimen and 71% had received prior bevacizumab (Avastin®; Genentech/Roche).

Key findings include:

  • Of the 34 patients evaluable for response, 11 patients (32%) achieved a response. Fifty percent of patients achieved clinical benefit after 12 weeks.
  • Median duration of confirmed responses was 8.3 months. Three responders remained on study.
  • The most common adverse events of any grade were conjunctivitis (50%), epistaxis, fatigue and alopecia (47% each) and nausea (44%).
  • The most common grade 3 or higher adverse events were vomiting (15%) and fatigue, nausea and abdominal pain (9% each).
  • Ocular events of any grade occurred in 53% of patients, including three percent with grade 3 or higher. The most common ocular event was conjunctivitis, which was substantially reduced through the introduction of a mitigation plan that involved a prophylactic steroid, lubricating eye drops and cooling eye masks worn during treatment infusion, as well as stricter dose adjustment guidance.

The part 2 portion of the clinical trial is ongoing in multiple solid tumors, including ovarian, prostate, bladder, esophageal and endometrial.


Last Editorial Review: September 8, 2017

Featured Image: Research at Seattle Genetics Courtesy: © 2017. Seattle Genetics. 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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