Recently, the U.S. Food and Drug Administration (FDA) granted Priority Reviews for a novel dosing regimen for durvalumab as well as for trilaciclib in small cell lung cancer; granted Fast Track designations to treatments for glioblastoma and B-cell acute lymphoblastic leukemia; and issued reports of breast implant illness and breast implant–associated lymphoma.
Priority Review for Less-Frequent, Fixed-Dose Use of Durvalumab
Durvalumab has received acceptance from the FDA for a supplemental biologics license application and has also been granted Priority Review for a new 4-week, fixed-dose regimen for treatment in the approved indications of non–small cell lung cancer (NSCLC) and bladder cancer. The Prescription Drug User Fee Act date for the regulatory decision is during the fourth quarter of 2020.
If approved, durvalumab could be administered intravenously every 4 weeks at a fixed dose of 1,500 mg in unresectable stage III NSCLC after chemoradiation therapy and previously treated advanced bladder cancer, consistent with the approved dosing in extensive-stage small cell lung cancer. The new dosing would be available as an alternative to the approved weight-based dosing of 10 mg/kg every 2 weeks.
The application was based on data from several clinical trials, including results from the phase III CASPIAN trial in extensive-stage small cell lung cancer which used the 4-week, fixed-dose regimen during maintenance.
Durvalumab is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80.
Priority Review for Trilaciclib in Small Cell Lung Cancer
The FDA accepted a new drug application for trilaciclib in patients with small cell lung cancer being treated with chemotherapy and granted the application Priority Review, with a Prescription Drug User Fee Act action date of February 15, 2021. Trilaciclib is a first-in-class investigational therapy designed to preserve bone marrow and immune system function during chemotherapy and improve patient outcomes.
The trilaciclib new drug application was supported by compelling myelopreservation data from three randomized, double-blind, placebo-controlled clinical trials in which trilaciclib was administered prior to chemotherapy treatment in patients with small cell lung cancer.
“While undergoing chemotherapy, many patients experience significant myelosuppression, become fatigued and susceptible to infection, and often require transfusions and growth factor administrations,” said Jared Weiss, MD, of the Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill. “Preventing bone marrow damage proactively is an opportunity to improve the quality of life of patients receiving chemotherapy for small cell lung cancer and reduce costly rescue interventions.”
In clinical trials, trilaciclib significantly reduced chemotherapy-induced myelosuppression, and patients receiving trilaciclib experienced fewer dose delays/reductions, infections, hospitalizations, and need for rescue therapies compared to patients receiving chemotherapy alone.
G1 is making trilaciclib available to patients with small cell lung cancer in the United States who are unable to enter clinical trials and for whom there are no appropriate alternative treatments while the trilaciclib new drug application is under regulatory review, pursuant to the FDA’s expanded access program. To facilitate needed access through the expanded access program, G1 is collaborating with Bionical Emas, a global specialist clinical research organization. For more information about expanded access to trilaciclib, e-mail patient.access.us@Bionical-emas.com.
Fast Track Designation for Paxalisib in Glioblastoma
The FDA granted Fast Track designation to paxalisib (formerly GDC-0084), a PI3K pathway inhibitor, for the treatment of glioblastoma, the most common and most aggressive form of primary brain cancer.
The specific indication for which the designation has been approved is “for the treatment of patients with newly diagnosed glioblastoma with unmethylated O6-methylguaninemethyltransferase (MGMT) promotor status who have completed initial radiation with concomitant temozolomide.”
Recruitment to a phase II clinical trial of paxalisib in newly diagnosed glioblastoma was completed in February 2020, and interim clinical data were presented at the American Association of Cancer Research Virtual Annual Meeting II in June 2020. Overall survival was calculated at 17.7 months, which compares favorably to a historical figure of 12.7 months for temozolomide, the existing FDA-approved standard of care.
Paxalisib has also been selected to join the international GBM AGILE pivotal study in glioblastoma.
Fast Track Designation for Investigational Allogeneic CAR T-Cell Therapy in B-Cell ALL
The FDA granted Fast Track designation to PBCAR0191, an investigational allogeneic chimeric antigen receptor (CAR) T-cell therapy, for the treatment of advanced B-cell precursor acute lymphoblastic leukemia (B-ALL).
PBCAR0191 is being evaluated in a phase I/IIa multicenter, nonrandomized, open-label, parallel assignment, dose-escalation, dose-expansion study to evaluate the safety and tolerability of PBCAR0191 in adult patients with relapsed or refractory B-ALL and relapsed or refractory non-Hodgkin lymphoma. The non-Hodgkin lymphoma cohort includes patients with mantle cell lymphoma.
Updated Analysis of Medical Device Reports of Breast Implant Illness and Breast Implant–Associated Lymphoma
The FDA provided an update on adverse events reported to the agency related to breast implants, including breast implant–associated anaplastic large cell lymphoma (BIA-ALCL), and systemic signs and symptoms referred to by patients as breast implant illness, which some patients report after receiving breast implants.
The FDA is also qualifying the BREAST-Q Reconstruction Module as a medical device development tool (MDDT) to aid in the assessment of certain medical devices such as breast implants. Qualification of the BREAST-Q Reconstruction Module MDDT included the Physical Well-Being (Chest), Psychosocial Well-Being, Sexual Well-Being, and Satisfaction With Breasts scales. An MDDT is scientifically validated and can be qualified for use in device evaluation and to support regulatory decision-making. Examples of MDDTs are clinical outcome assessments, assessments of biomarkers, and nonclinical assessment methods or models. The use of a qualified MDDT by a product sponsor is voluntary.
“The FDA has been diligently monitoring adverse events associated with breast implants for decades and has been working to better understand the quality of life and satisfaction a [patient who has undergone] breast reconstruction may experience in order to refine our evaluation of breast implant benefits and risks. Our qualification of the BREAST-Q Reconstruction Module as a validated tool to assess outcomes of breast reconstruction surgery in terms of quality of life and satisfaction helps accomplish this,” said Binita Ashar, MD, Director of the Office of Surgical and Infection Control Devices in the Center for Devices and Radiological Health. “In addition, we continue to increase our scientific knowledge regarding BIA-ALCL and systemic symptoms referred to as breast implant illness, and remain committed to keeping the public informed.”
The FDA analysis of global medical device reports for BIA-ALCL covers reports received through January 5, 2020. It updates the FDA’s last public report with new information from July 7, 2019, to January 5, 2020. The FDA updated the table on the agency’s BIA-ALCL webpage to include a total of 733 unique cases and 36 patient deaths globally, which reflect an increase of 160 new cases and 3 deaths since the July 2019 update.
Specifically, of the 733 total unique cases of BIA-ALCL reported to FDA, 620 cases were reported for Allergan implants, and 47 cases involved implants with an unknown manufacturer. With respect to implant surface for the 733 total unique cases of BIA-ALCL, 496 cases were reported to have textured implants, and 209 cases did not specify the implant surface. Of the 36 total patient deaths reported to FDA, 15 of the 16 patients for which the manufacturer of the implant is known are reported to have had an Allergan breast implant at the time of their BIA-ALCL diagnosis. In terms of implant surface, of the 36 cases of patient deaths reported, 16 cases involved textured implants, and 19 cases did not contain information on the implant surface.
In addition to the update on BIA-ALCL, the FDA is provided data on medical device reports received concerning systemic signs and symptoms referred to by patients as breast implant illness. A new table on FDA’s website summarizes unique breast implant illness medical device reports from the U.S. and worldwide that the FDA has received from January 1, 2008, to October 31, 2019. The data show that the FDA received 2,497 medical device reports containing symptoms consistent with breast implant illness from November 2018 to October 2019. The FDA’s data from January 2008 to October 2018 showed 1,080 reports that contained such symptoms.
While there is limited use of the term “breast implant illness” in medical literature, symptoms such as fatigue, memory loss, rash, “brain fog,” and joint pain may be associated with breast implants, and some patients and clinicians may use the term “breast implant illness” to describe these symptoms or use these terms when reporting them to the FDA. The top 10 most common symptoms reported to the FDA’s medical device report database for patients with breast implants include fatigue (49%), brain fog (25%), joint pain (25%), anxiety (24%), hair loss (21%), depression (19%), rash (18%), autoimmune diseases (18%), inflammation (18%), and/or weight problems (18%).
Researchers are investigating these symptoms to better understand their origins and connection to breast implants. Although the FDA doesn’t have definitive evidence demonstrating breast implants cause these symptoms, the current evidence supports that some patients experience systemic symptoms that may resolve when their breast implants are removed.
The FDA also announced the qualification of a validated, self-administered questionnaire—the BREAST-Q Reconstruction Module—through the agency’s MDDT program.
The paper and electronic self-administered versions of the BREAST-Q Reconstruction Module’s Psychosocial Well-Being, Sexual Well-Being, Physical Well-Being (Chest), and Satisfaction With Breasts scales are used to quantify different aspects of a woman’s quality of life and satisfaction with breast reconstruction surgery. These scales may be used by medical device sponsors and sponsor-investigators in feasibility, pivotal, and post-approval studies to support the effectiveness of breast reconstruction-related medical devices, such as an implant or mesh, befitting the clinical meaningfulness of the scale to support the proposed indication.
Lastly, today the FDA released a video on seven things patients should know about breast implants, including risks, complications, and information about BIA-ALCL and systemic symptoms.
The FDA will continue to analyze all available information regarding risks associated with breast implants, routinely update the BIA-ALCL and breast implant illness analysis published on its website, and take additional action when and where necessary.
