In an interview with PharmaShots, Jan van de Winkel, co-founder, President, and CEO at Genmab shared his views on the US FDA's Accelerated Approval of Tivdak (tisotumab vedotin-tftv) for the Treatment of Recurrent or Metastatic Cervical Cancer

Shots:

• Genmab and Seagen have reported the US FDA's accelerated approval which is based on the P-II innovaTV 204 clinical trials evaluating tisotumab vedotin in 101 patients with r/mCC who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including one prior Pt-based CT regimen
• The results showed an ORR (24%) as assessed by IRC, m-DoR (8.3mos.)
• Tivdak is the 1st approved ADC which is directed to TF & Seagen's ADC technology utilizes a protease-cleavable linker & covalently attaches the microtubule-disrupting agent MMAE to Ab. The P-III innovaTV 301clinical trial of Tivdak is underway that is intended to support global registrations

Tuba: Can we first talk about Tivdak, MoA, ROA, frequency, dosing, and its target?  

Jan van de Winkel: The approval of Tivdak is a milestone moment for women with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. It is a first-of-its-kind treatment that has demonstrated positive efficacy in clinical trials with durable responses and a well-tolerated safety profile in patients with recurrent or metastatic cervical cancer. 

Tivdak is an antibody-drug conjugate, often referred to as an ADC, that is directed to tissue factors. In cancer biology, tissue factor is a cell-surface protein that is associated with tumor growth, the formation of new blood vessels, metastasis, and poor prognosis. Tissue factor is prevalent in several solid tumors, including cervical cancer. Based on its elevated expression in multiple solid tumors, its rapid internalization, and compelling preclinical models, we selected tissue factor as a target for an ADC approach. Tivdak is Seagen's third FDA-approved antibody-drug conjugate, and at Genmab it is our first U.S. FDA-approved medicine. 

In the pivotal Phase 2 innovaTV, 204 study with 101 patients treated with TIVDAK, the median duration of treatment was 4.2 months. The median number of cycles patients received was 6. The recommended dose of Tivdak is 2 mg/kg (up to a maximum of 200 mg for patients >100 kg) administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. Results from the trial showed a 24 percent confirmed objective response rate (ORR) (95% CI; 15.9-33.3), as assessed by an independent review committee (IRC) using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. The median duration of response (DOR) was 8.3 months (95% CI; 4.2 to not reached).

Tivdak is approved for intravenous infusion only and should not be administered as an intravenous push or bolus. Tivdak should not be mixed with, or administered as an infusion with, other medicinal products.

Tuba: Please tell us about the innovaTV 204 trial and its eligibility criteria. 

Jan van de Winkel: The accelerated approval of Tivdak was based on the innovaTV 204 clinical trial in which it was evaluated in patients who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior platinum-based chemotherapy regimen. Patients were excluded if they had an active ocular surface disease, any prior episode of cicatricial conjunctivitis, or Stevens-Johnson syndrome, Grade =2 peripheral neuropathy, or known coagulation defect leading to an increased risk of bleeding.

As reported at ESMO 2020, key secondary endpoints from the innovaTV 204 trial included duration of response, time to response, progression-free survival, overall survival, safety, complete response, and tolerability. In the Phase 2 innovaTV 204 trial, Tivdak was well-tolerated and manageable with most adverse reactions being mild to moderate, including peripheral neuropathy, ocular, and bleeding events.

Tuba: Could you tell us briefly about the core opinions of the data presented at ESMO? 

Jan van de Winkel: We were very pleased with our data presence at ESMO. The data presented this year at the conference was from innovaTV 205, a different study than the innovaTV 204 study that supported Tivdak's approval. In innovaTV 205, tisotumab vedotin in combination with carboplatin showed encouraging and durable anti-tumor activity as potential first-line treatment regimen with 55% objective response rate (ORR), and tisotumab vedotin in combination with pembrolizumab showed encouraging, durable anti-tumor activity in previously treated patients with 38% ORR. Interim results from the innovaTV 205 study demonstrate the potential for tisotumab vedotin in combination with currently used anti-cancer agents as treatment options for patients with advanced cervical cancer.  

Tuba: How was the journey of gaining the US FDA's approvals for Tivdak? Were there any roadblocks? 

Jan van de Winkel: The approval of Tivdak signifies our first step towards achieving our 2025 vision of transforming cancer treatment through our own innovative products. Tivdak represents the maturity of Genmab's pipeline development and the growth of our organization as we work to make a difference in the treatment of people with cancer. Tivdak is being co-developed by Genmab and Seagen, under an agreement in which the companies share costs and profits for the product on a 50:50 basis.

Prior to the approval of Tivdak, women with recurrent or metastatic cervical cancer faced limited treatment options available to them once the disease has progressed beyond chemotherapy and no standard of care. Tivdak is helping to address an unmet need for more treatment options in this disease area. 

Tuba: What was the major supporting element in receiving the US FDA's accelerated approval? 

Jan van de Winkel: The strength of the data, along with the drive of a large unmet need both went into supporting Tivdak's approval by the FDA. The results of the Phase 2 innovaTV 204 clinical trial demonstrate clinically meaningful, durable responses with a well-tolerated safety profile for patients with a disease that has limited treatment options. In clinical studies, Tivdak has demonstrated clinically meaningful and durable antitumor activity, rapid time to response, and a well-tolerated safety profile in patients with recurrent or metastatic cervical cancer.

Tuba: What are the recommended doses for Tivdak?

Jan van de Winkel: The recommended dose of Tivdak is 2 mg/kg (up to a maximum of 200 mg for patients >100 kg) administered as an intravenous infusion over 30 minutes every 3 weeks until disease progression or unacceptable toxicity. Tivdak is approved for intravenous infusion only and should not be administered as an intravenous push or bolus. It should not be mixed with, or administered as an infusion with, other medicinal products. 

Tuba: What will be the Company's commercialization strategies for Tivdak? 

Jan van de Winkel: Our 1st priority is to continue our work with our partner Seagen towards the successful launch of TV, now that we received FDA approval. We have a fully trained field team in place (across OAMs & MSLs) to launch TV in m/r CC with Seagen. We also have a robust launch plan in place to ensure broad awareness and adoption of TV upon approval. As we build our capabilities in commercialization, I continue to be impressed with the caliber, experience, and top-tier talent we continue to attract from top oncology companies to join our team.

Tuba: Please comment about the expected progress of Tivdak's ongoing trials for various other indications. 

Jan van de Winkel: We are deeply committed to helping patients with cancer, and in addition to recurrent or metastatic cervical cancer, we believe that there may be other opportunities for Tivdak. Tissue factor is expressed in a variety of tumors including (in addition to cervical and ovarian cancers) lung, head & neck, esophageal, colorectal, and pancreatic cancers, many of which are difficult to treat.

In January 2021, we announced the initiation of the innovaTV 301 trial, a phase 3 study to evaluate the efficacy of Tivdak compared to chemotherapy in patients with previously treated recurrent or metastatic cervical cancer. This trial is intended to serve as a confirmatory trial for the US and is intended to support global regulatory applications.

More on all our ongoing clinical trials, including enrolling sites, is available at www.clinicaltrials.gov. Here, find more information on: innovaTV 205, innovaTV 206, innovaTV 207, and innovaTV 208. We look forward to reporting new and promising data in 2022 and the future. 

Tuba: What are the possible side effects of Tivdak?

Jan van de Winkel: In the innovaTV 204 clinical trial evaluating the efficacy and safety of treatment with Tivdak, ocular adverse reactions occurred in 60% of patients with cervical cancer. Grade 3 ocular adverse reactions occurred in 3.8% of patients, including severe ulcerative keratitis in 3.2% of patients. The most common were conjunctival adverse reactions, dry eye, corneal adverse reactions, and blepharitis. In some cases, Tivdak caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration.

I recommend carefully reading the prescribing information for more background on dosing and the boxed warning which states Tivdak caused changes in the corneal epithelium and conjunctiva resulting in changes in vision, including severe vision loss, and corneal ulceration. Conduct an ophthalmic exam at baseline, prior to each dose, and as clinically indicated. Adhere to premedication and required eye care before, during, and after infusion. Withhold Tivdak until improvement and resume, reduce the dose, or permanently discontinue, based on severity.

Tuba: How are you planning to overcome the risk of ocular adverse reactions related to its administration? 

Jan van de Winkel: Genmab, along with our Seagen partner, are committed to developing therapies that offer meaningful treatment outcomes with patient safety in mind. During clinical trials, we found that ocular adverse reactions associated with Tivdak were manageable with consistent implementation of the required eye care, working closely with oncology care teams and eye care professionals.

We have taken careful consideration of the patient experience to better understand how we can support healthcare practitioners and patients at numerous touchpoints throughout the treatment journey and help minimize any barriers to adherence. 

To support required eye care and reduce barriers to treatment, patients, caregivers, and healthcare professionals will be provided with educational resources and services. Financial assistance programs and referral support for an eye care provider can be accessed through Seagen Secure® (SGS), a patient services hub.

Source: Trial Site News

About Author: Jan van de Winkel is a co-founder, CEO & President of Genmab. He has over 20 years of experience in the therapeutic antibody field. He holds M.S. and Ph.D. degrees from the University of Nijmegen. Dr. van de Winkel holds a professorship of immunotherapy at Utrecht University

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