FDA Pipeline: New Priority Reviews, Designations, and Clearances, Plus Statements on Genetic Testing and Class Labeling


The U.S. Food and Drug Administration (FDA) recently issued the following new approvals and designations:

Priority Review for Atezolizumab in Combination With Chemotherapy for the Initial Treatment of Extensive-Stage SCLC

The FDA accepted a supplemental biologics license application (sBLA) and granted Priority Review for atezolizumab (Tecentriq) in combination with carboplatin and etoposide for the first-line treatment of patients with extensive-stage small cell lung cancer (SCLC). The FDA is expected to make a decision on approval by March 18, 2019.

This sBLA is based on results from the phase III IMpower133 study, a multicenter, double-blinded, randomized placebo-controlled study evaluating the efficacy and safety of atezolizumab in combination with carboplatin and etoposide vs carboplatin and etoposide alone in chemotherapy-naive patients with extensive-stage SCLC.

IMpower133 met its co-primary endpoints of overall survival and progression-free survival in the initial treatment of people with extensive-stage SCLC. The safety profile of the combination was consistent with the safety profiles of the individual medicines, and no new safety signals were identified.

Priority Review for Quizartinib in Relapsed or Refractory FLT3-ITD–Positive AML

The FDA accepted a new drug application (NDA) and granted Priority Review for quizartinib for the treatment of adult patients with relapsed or refractory FLT3-ITD–positive acute myeloid leukemia (AML). The FDA is expected to make a decision on approval by May 25, 2019.

The NDA is based on results of the phase III QuANTUM-R study, which was the first randomized phase III study to show that a FLT3 inhibitor prolonged overall survival as an oral, single agent compared to chemotherapy in patients with relapsed/refractory FLT3-ITD–positive AML. Topline results of QuANTUM-R were presented during the plenary program at the 23rd Congress of the European Hematology Association (Abstract LB2600), and new analyses were presented during an oral presentation at the 2018 American Society of Hematology (ASH) Annual Meeting & Exposition (Abstract 563, Abstract 1392).

QuANTUM-R is a pivotal, global, phase III, open-label randomized study that enrolled 367 patients with FLT3-ITD–positive AML who were refractory to or in relapse with duration of remission of 6 months or less following standard first-line AML therapy with or without hematopoietic stem cell transplantation. Patients were randomly assigned 2:1 to receive either single agent oral quizartinib or salvage chemotherapy. The primary objective of the study was to determine whether single agent quizartinib prolonged overall survival compared to salvage chemotherapy. The study met its primary endpoint of improving overall survival.

Breakthrough Therapy Designation for Brentuximab Vedotin for Frontline Peripheral T-Cell Lymphomas

The FDA granted Breakthrough Therapy designation to brentuximab vedotin (Adcetris) for previously untreated systemic anaplastic large cell lymphoma or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with CHP (cyclophosphamide, doxorubicin, and prednisone). The positive topline results of the phase III ECHELON-2 clinical trial were announced in October 2018, followed by the submission of a sBLA to the FDA in November 2018. Additional data was presented at the ASH Annual Meeting & Exposition (Abstract 997). 

Brentuximab vedotin is an antibody-drug conjugate (ADC) directed to CD30, which is expressed on the surface of several types of PTCL. This Breakthrough Therapy designation was based on data from the phase III ECHELON-2 clinical trial evaluating the combination of brentuximab vedotin plus CHP vs the control arm, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), in previously untreated CD30-expressing PTCL. The ECHELON-2 study met its primary endpoint, demonstrating a statistically significant improvement in progression-free survival (PFS) of brentuximab vedotin in combination with CHP vs CHOP as assessed by an Independent Review Facility (IRF; hazard ratio [HR] = 0.71; P = .0110). The brentuximab vedotin plus CHP arm also demonstrated superior overall survival compared to CHOP (HR = 0.66; P = .0244). All other key secondary endpoints, including PFS in patients with systemic anaplastic large cell lymphoma (sALCL), complete remission rate, and objective response rate were statistically significant in favor of the brentuximab vedotin plus CHP arm. The safety profile of brentuximab vedotin plus CHP in the ECHELON-2 trial was comparable to CHOP and consistent with the established safety profile of brentuximab vedotin in combination with chemotherapy.

Clearance of ProFound AI for Digital Breast Tomosynthesis

iCAD, Inc, announced clearance by the FDA for their latest deep-learning cancer detection software solution for digital breast tomosynthesis (DBT), ProFound AI, clearing the technology for commercial sales and clinical use in the United States. The solution built on artificial intelligence (AI) is now available to health-care facilities in the United States.

The FDA clearance is based on positive clinical results from a large reader study. The research was performed with 24 radiologists who read 260 tomosynthesis cases both with and without iCAD’s ProFound AI solution. The findings showed results including increased cancer detection rates, reduced false positive rates and patient recalls, and a significant decrease in interpretation times. 

ProFound AI showed an improvement of cancer detection rates by an average of 8% and decreasing unnecessary patient recall rates by an average of 7%. The new technology is trained to detect malignant soft-tissue densities and calcifications. It also provides radiologists with scoring information representing the likelihood that a detection or case is malignant based on the large dataset of clinical images used to train the algorithm.

In addition to improving clinical performance related to breast cancer detection and false positive rates, study results showed that ProFound AI can reduce radiologists’ reading time by more than 50% on average. An increase in reading time has been a significant challenge for radiologists when moving from 2D to 3D mammography.

The solution is currently available for use with leading DBT systems in the United States, Canada and Europe.

IND for FT500, an Off-the-Shelf NK Cell Cancer Immunotherapy

The FDA accepted an investigational new drug (IND) application for FT500, an off-the-shelf natural killer (NK) cell product candidate derived from a clonal master induced pluripotent stem cell (iPSC) line. The clinical trial of FT500 is expected to be the first-ever clinical investigation in the U.S. of an iPSC-derived cell product.

The manufacturer plans to initiate first-in-human clinical testing of FT500 in combination with checkpoint inhibitor therapy for the treatment of advanced solid tumors. This study is expected to evaluate the safety and tolerability of multiple doses of FT500, in multiple dosing cycles with nivolumab (Opdivo), pembrolizumab (Keytruda), or atezolizumab (Tecentriq), in subjects that have progressed or failed on checkpoint inhibitor therapy.

IND for a Bispecific GD2 Antibody in Solid Tumors

The FDA has cleared an IND application for a humanized bispecific GD2 antibody manufactured by Y-mAbs Therapeutics, Inc. It is anticipated that a phase I/II clinical trial will soon be initiated to begin screening patients with relapsed or refractory neuroblastoma, high grade osteosarcoma, and other GD2(+) solid tumors, where patients have relapsed or refractory disease that is resistant to standard therapy.

This bispecific product candidate is a fully humanized IgG-scFv format antibody, licensed by Memorial Sloan Kettering to Y-mAbs, in which the anti-CD3 scFv is linked to naxitamab IgG1 and the Fc region is mutated to help prevent cytokine release as well as complement-mediated pain side effects. This bispecific GD2 antibody may have potential advantages over other bispecific antibodies, such as improved potency due to bivalency, binding to neonatal Fc receptor, and longer serum half-life, which obviates continuous infusion and enables more convenient administration to the patient.

RMAT Designation for P-BCMA-101 in Multiple Myeloma

The FDA granted a Regenerative Medicine Advanced Therapy (RMAT) designation to P-BCMA-101, a chimeric antigen receptor (CAR)-T therapeutic candidate currently in a phase I clinical trial for the treatment of patients with relapsed or refractory multiple myeloma.

The RMAT designation is a program under the 21st Century Cures Act that is intended to expedite the development and review of regenerative medicines for the treatment of serious or life-threatening diseases and conditions. A regenerative medicine therapy is eligible for the designation if it is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition, and preliminary clinical evidence indicates that the product has the potential to address unmet medical needs for such a disease or condition.

P-BCMA-101 is an autologous CAR-T therapeutic candidate being developed to treat patients with relapsed/refractory multiple myeloma. P-BCMA-101 targets cells that express B-cell maturation antigen, or BCMA, which is expressed on essentially all multiple myeloma cells. Preliminary results from an ongoing phase I clinical trial suggest that P-BCMA-101 may have improved response rates with a favorable safety profile compared to published results from clinical trials of other CAR-T therapies at similar doses. Low to no levels of cytokine release syndrome or neurotoxicity have been seen.

The FDA also recently issued the following statements:

FDA Takes Action to Advance Development of Reliable and Beneficial Genetic Tests

The FDA took a significant step forward in driving the efficient development of novel diagnostic technologies that scan a person’s DNA to diagnose genetic diseases and guide medical treatments. For the first time, the agency has formally recognized a public database that contains information about genes, genetic variants and their relationship to disease. The FDA is recognizing the genetic variant information in the Clinical Genome Resource (ClinGen) consortium’s ClinGen Expert Curated Human Genetic Data, which is funded by the National Institutes of Health (NIH), as a source of valid scientific evidence that can be used to support clinical validity in premarket submissions. The information contained in this open database has been collected and studied by researchers across the world. This recognition by the FDA will facilitate test developers, including those that use next-generation sequencing, to rely on the information available in the database to support the validity of their tests, instead of having to generate the information on their own.

“Technological and clinical advances in genetic tests mean that patients and providers have a better understanding of the causes of disease and potential treatment options. The availability of genetic tests is opening up new opportunities to segment illnesses into more treatable subsets and enabling the development of targeted therapeutics aimed at these previously unknown categories of disease. These new medicines increasingly show outsized benefits in small populations of patients with rare, hard-to-treat and sometimes fatal conditions. The ability to use diagnostics to identify these rare subsets is a key element in driving this transformation in medical care and drug development,” said FDA Commissioner Scott Gottlieb, MD.

This action—which recognizes the ClinGen consortium’s ClinGen Expert Curated Human Genetic Data as a source of valid scientific evidence that can support clinical validity—means that developers of genetic tests have assurance of the reliability of the freely available data that they can use in support of their applications for marketing authorizations with the agency, rather than generating the same data on their own. The new recognition means developers will not need to demonstrate to the FDA the reliability of the database, the data and information within which can be used to support the relationship between a gene variation and a specific disease that are within the scope of the recognition.

“A major current challenge for precision medicine is the need to translate new discoveries and data from the Human Genome Project so that this information can be used by physicians and other health-care providers to improve health,” said NIH Director Francis S. Collins, MD, PhD. “ClinGen provides a standard curated data reference of genetic variants to facilitate the development and implementation of genetic tests for use by health-care professionals, which is critically important for moving science into practice.”

The FDA reviewed ClinGen’s standard operating procedures and policies, including processes and validation studies for variant evaluation, data integrity, and security, as well as transparency of all evidence. The FDA also reviewed the policies for how the consortia qualifies and approves researchers and clinicians to evaluate variants, including conflict of interest and disclosure policies.

ClinGen brings together more than 700 clinical and research experts to develop standard processes for reviewing data and genetic variants and their connections to health and disease. The experts who are part of the consortium determine how each variant is associated with a specific hereditary disease or condition and make that information available for unrestricted use in the community.

In its recognition of ClinGen, the FDA reviewed variant classifications and the processes that support them for gene changes in reproductive cells (germline variant) in hereditary disease where there is a high likelihood that the disease or condition will materialize if the gene is altered. Genetic tests may use germline variant information to detect for cardiomyopathy, hearing loss, inborn errors of metabolism, and other hereditary conditions.

The FDA’s recognition anticipates that ClinGen may add new or modify existing genetic variant information on an ongoing basis, provided they are within the scope of recognition.

Statement From FDA Commissioner on Developing and Class Labeling of In Vitro Companion Diagnostics for Classes of Oncology Therapeutic Products

FDA Commissioner Scott Gottlieb, MD, recently issued the following statement:

“With a new draft guidance document that the FDA issued … our aim is to make it easier to get class labeling on diagnostic tests for oncology therapeutic products, where scientifically appropriate. [The] draft guidance notes that in some cases, if evidence is sufficient to conclude that the companion diagnostic is appropriate for use with a specific group or class of therapeutic products, the companion diagnostic’s intended use should name the specific group or class of therapeutic products, rather than specific products.”

“The policy reflected in this guidance, when finalized, will make it easier for providers to use the same test in helping guide the use of a class of oncology therapeutic products, rather than one specific oncology therapeutic product within that class. The guidance will help guide test developers who could use the data generated from the study of an approved or cleared diagnostic test that’s evaluated in relation to just one oncology therapeutic product in a class of molecularly-targeted oncology therapeutic products to then extrapolate the use of that same approved or cleared diagnostic test to the entire oncology therapeutic product class.”

“We’re advancing this guidance to promote better patient care. We also recognize that there are commercial challenges for companion diagnostics. And so we’re trying to help sponsors more efficiently meet the requirements to support broader labeling. To advance these goals, the proposed guidance will describe considerations for the development and labeling of in vitro companion diagnostic devices to support the indicated uses of multiple oncology therapeutic products.”

“As noted, that specificity in labeling can limit a potentially broader use of a companion diagnostic that may be scientifically appropriate. In some cases, there are multiple companion diagnostics approved or cleared by the FDA to detect the same mutations in the same specimen type. Similarly, in some cases, there are multiple FDA-approved therapeutics within a specific group or class of oncology therapeutic products … The result is that, in some cases, not all of the oncology therapeutic products in a specific group or class are being included on all of the labels of approved or cleared companion diagnostics to detect mutations that define the specific group or class.”

“We’re concerned that the current situation is not optimal for patient care because a clinician may need to order a different companion diagnostic (i.e., one that includes other therapeutic products on the label), obtain an additional biopsy from a patient, or both, to have additional therapy treatment options. This is among the reasons why we’re looking to work with sponsors to pursue labeling a companion diagnostic to reference a specific group or class of oncology therapeutic products, when the evidence would support expanding the indication, for instance to “include a specific group or class of therapeutic products, rather than specific products.”

In oncology, precision medicine aims to match therapeutic products to those patients (and only those patients) who will positively respond to that therapeutic product, to maximize benefits and minimize risks from the therapeutic product received. Companion diagnostics inform both the development and the approved use of therapeutic products.”

“These products could enable greater flexibility for clinicians in choosing the most appropriate therapeutic product based on a patient’s biomarker status. It could also help advance better patient care.”

View the full statement from Dr. Gottlieb.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.