Recently, the U.S. Food and Drug Administration (FDA) issued regulatory decisions related to treatments for urothelial cancer, cervical cancer, cholangiocarcinoma, solid tumors, and colorectal cancer.
Acceptance of Two Supplemental Biologics License Applications for Enfortumab Vedotin-ejfv in Locally Advanced or Metastatic Urothelial Cancer
The FDA has accepted two supplemental biologics license application submissions for enfortumab vedotin-ejfv for review as part of the Real-Time Oncology Review (RTOR) pilot program. The applications were granted Priority Review, with a target action date of August 17, 2021. The review of both applications will also be conducted under Project Orbis, an initiative of the FDA Oncology Center of Excellence.
The FDA’s RTOR program aims to explore a more efficient review process to ensure that safe and effective treatments are available to patients as early as possible. Project Orbis provides a framework for concurrent submission and review of oncology drugs among participating international partners.
The first application is based on the phase III EV-301 trial and seeks to convert enfortumab vedotin’s accelerated approval to regular approval. The second application, based on the pivotal trial EV-201’s cohort 2, requests an expansion of the current indication to include patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1 or PD-L1 inhibitor and are ineligible for cisplatin. Results from EV-301 were published in The New England Journal of Medicine; results from EV-301 and EV-201 cohort 2 were presented at the 2021 Genitourinary Cancers Symposium (Abstract 393 and Abstract 394, respectively).
Health authorities in Australia and Canada will evaluate data from EV-301 and EV-201 for initial registrations under Project Orbis. In March, the companies announced regulatory submissions in Japan and the European Union.
In 2019, enfortumab vedotin received accelerated approval in the United States for the treatment of adult patients with locally advanced or metastatic urothelial cancer who have previously received a PD-1/PD-L1 inhibitor and a platinum-containing chemotherapy before or after surgery or in a locally advanced or metastatic urothelial cancer setting. Enfortumab vedotin is currently only approved for use in the United States.
The EV-301 trial (ClinicalTrials.gov identifier NCT03474107) is a global, multicenter, open-label, randomized phase III trial designed to evaluate enfortumab vedotin vs physician's choice of chemotherapy (docetaxel, paclitaxel, or vinflunine) in approximately 600 patients with locally advanced or metastatic urothelial cancer who were previously treated with a PD-1/PD-L1 inhibitor and a platinum-based therapy. The primary endpoint is overall survival; secondary endpoints include progression-free survival, overall response rate, duration of response, and disease control rate, as well as assessment of safety/tolerability and quality-of-life parameters.
The EV-201 trial (NCT03219333) is a single-arm, dual-cohort, pivotal phase II clinical trial of enfortumab vedotin for patients with locally advanced or metastatic urothelial cancer who have been previously treated with a PD-1 or PD-L1 inhibitor, including those who have also been treated with a platinum-containing chemotherapy (cohort 1) and those who have not received a platinum-containing chemotherapy in this setting and who are ineligible for cisplatin (cohort 2). The trial enrolled 128 patients in cohort 1 and 91 patients in cohort 2 at multiple centers internationally. The primary endpoint is confirmed objective response rate per blinded independent central review; secondary endpoints include assessments of duration of response, disease control rate, progression-free survival, overall survival, safety, and tolerability.
Priority Review for Tisotumab Vedotin in Recurrent or Metastatic Cervical Cancer
The FDA accepted for Priority Review a biologics license application seeking accelerated approval for tisotumab vedotin. The application requests FDA approval of tisotumab vedotin for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Under the Prescription Drug User Fee Act, the FDA has set a target action date of October 10, 2021. Tisotumab vedotin is an investigational antibody-drug conjugate directed to tissue factor—a cell-surface protein expressed on multiple solid tumors, including cervical cancer—and is associated with tumor growth, angiogenesis, metastasis, and poor prognosis.
The submission is based on the results of the innovaTV 204 pivotal phase II single-arm clinical trial (NCT03438396) evaluating tisotumab vedotin as monotherapy in patients with previously treated recurrent or metastatic cervical cancer. These data were presented at the European Society for Medical Oncology Virtual Congress 2020 (Abstract LBA32).
innovaTV 204 (also known as GCT1015-04 or innovaTV 204/GOG-3023/ENGOT-cx6) is an ongoing single-arm, global, multicenter study of tisotumab vedotin for patients with recurrent or metastatic cervical cancer who were previously treated with doublet chemotherapy with or without bevacizumab. Additionally, patients were eligible if they had received up to two prior lines of therapy in the recurrent or metastatic setting.
In the study, 101 patients were treated with tisotumab vedotin at multiple centers in the United States and Europe. The primary endpoint of the trial was confirmed objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 as assessed by independent central review. Key secondary endpoints included duration of response, progression-free survival, overall survival, safety, and tolerability.
Breakthrough Therapy Designation for Futibatinib in Advanced FGFR2-Mutated Cholangiocarcinoma
The FDA has granted Breakthrough Therapy designation to futibatinib (also known as TAS-120), a covalently binding FGFR inhibitor, for the treatment of patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring FGFR2 gene rearrangements, including gene fusions.
Futibatinib is an investigational, oral, potent, selective, and irreversible small-molecule inhibitor of FGFR1, FGFR2, FGFR3, and FGFR4 being studied as a potential treatment for patients with advanced solid tumors with FGFR1–4 genetic aberrations, including cholangiocarcinoma, who were previously treated with chemotherapy or other therapies. Futibatinib selectively and irreversibly binds to the ATP binding pocket of FGFR1–4, resulting in the inhibition of FGFR-mediated signal transduction pathways, reduced tumor cell proliferation, and increased tumor cell death in tumors with FGFR1–4 genetic aberrations.
The decision by the FDA to grant this designation is based on efficacy and safety results from the phase II FOENIX-CCA2 study, which were presented at the American Association for Cancer Research (AACR) Annual Meeting 2021 (Abstract CT010). In May 2018, the FDA Office of Orphan Drug Development granted futibatinib orphan drug status for the treatment of cholangiocarcinoma.
Investigational New Drug Application Accepted for XB002 in Patients With Advanced Solid Tumors
The FDA accepted an investigational new drug application to evaluate the safety, tolerability, pharmacokinetics, and preliminary antitumor activity of XB002 in patients with advanced solid tumors. As a next-generation tissue factor–targeting antibody-drug conjugate, XB002 has the potential for an improved therapeutic index and may provide a favorable safety profile compared with earlier-generation tissue factor-targeting antibody-drug conjugates.
XB002 is an antibody-drug conjugate composed of a human monoclonal antibody against tissue factor that is conjugated to a cytotoxic agent. After binding to tissue factor on tumor cells, XB002 is internalized, and the cytotoxic agent is released, resulting in targeted tumor cell death. XB002 is a rationally designed next-generation antibody-drug conjugate that leverages proprietary linker-payload technology.
Preclinical data demonstrated that XB002 binds to tissue factor without affecting the coagulation cascade, in contrast with prior therapies in this class. The data also demonstrated encouraging activity of XB002 in multiple solid tumor cancer models, as well as improved tolerability compared with other tissue factor–targeting antibody-drug conjugates.
XB002 has shown significant tumor growth inhibition and, in some cases, complete regression. The rational design and preclinical profile of this novel tissue factor–targeting antibody-drug conjugate suggest that, if borne out in clinical evaluation, XB002 could have an improved therapeutic index and favorable safety profile compared with earlier tissue factor–targeting antibody-drug conjugates.
FDA Authorizes Marketing of First Device that Uses AI to Help Detect Potential Signs of Colon Cancer
The FDA has authorized marketing of the GI Genius, the first device that uses artificial intelligence (AI) based on machine learning to assist clinicians in detecting lesions, such as polyps or suspected tumors, in the colon in real time during a colonoscopy.
“AI has the potential to transform health care to better assist providers and improve patient care. When AI is combined with traditional screenings or surveillance methods, it could help find problems early on, when they may be easier to treat,” said Courtney H. Lias, PhD, Acting Director of the GastroRenal, ObGyn, General Hospital, and Urology Devices Office in the FDA’s Center for Devices and Radiological Health. “Studies show that during colorectal cancer screenings, missed lesions can be a problem even for well-trained clinicians. With the FDA’s authorization of this device, clinicians now have a tool that could help improve their ability to detect gastrointestinal lesions they may have missed otherwise.”
The GI Genius is composed of hardware and software designed to highlight portions of the colon where the device detects a potential lesion. The software uses AI algorithm techniques to identify regions of interest. During a colonoscopy, the GI Genius system generates markers, which look like green squares and are accompanied by a short, low-volume sound, and superimposes them on the video from the endoscope camera when it identifies a potential lesion. These signs signal to the clinician that further assessment may be needed, such as a closer visual inspection; tissue sampling, testing, or removal; or ablation of the lesion. The GI Genius is designed to be compatible with many FDA-cleared standard video endoscopy systems.
The FDA assessed the safety and effectiveness of the GI Genius through a multicenter, prospective, randomized, controlled study in Italy with 700 patients aged 40 to 80 who were undergoing a colonoscopy. The primary analyses from the study were based on a subpopulation of 263 patients who were being screened or surveilled every 3 years or more. Study subjects underwent either white-light standard colonoscopy with the GI Genius (n = 136) or standard white-light colonoscopy alone (n = 127).
The primary endpoint of the study compared how often colonoscopy plus GI Genius identified a patient with at least one lab-confirmed adenoma or carcinoma to how often standard colonoscopy made the same identifications. In the study, colonoscopy plus GI Genius was able to identify lab-confirmed adenomas or carcinomas in 55.1% of patients compared to identifying them in 42.0% of patients with standard colonoscopy—an observed difference of 13%.
While use of this device led to more biopsies being performed, there were no adverse events reported with the additional biopsies, such as perforations, infections, or bleeding. However, there was a slight increase in the number of lesions biopsied that were not adenomas.
The GI Genius is not intended to characterize or classify a lesion, nor to replace lab sampling as a means of diagnosis. The device does not provide any diagnostic assessments of colorectal polyp pathology, nor does it suggest to the clinician how to manage suspicious polyps. GI Genius only identifies regions of the colon within the endoscope’s field of view where a colorectal polyp might be located, allowing for a more extended examination in real time during colonoscopy. It is up to the clinician to decide whether the identified region actually contains a suspected lesion, and how the lesion should be managed and processed per standard clinical practice and guidelines.
The FDA reviewed the GI Genius through the De Novo premarket review pathway, a regulatory pathway for some low- to moderate-risk devices that are novel and for which there is no legally marketed predicate device to which the device can claim substantial equivalence.
