Highlights of FDA Oncology Approvals in 2023: Bispecific T-cell Engagers, Pediatric Indications, and Inclusive Drug Development.

SUMMARY: Cancer drug development remained robust in 2023. Highlights of U.S. drug approvals this year include new immunotherapies and targeted drug development in adult and pediatric patients as well as patients with rare diseases.

The Impact of Improved Treatments on Survival of Adult U.S. Leukemia Patients: 1990-2018.

INTRODUCTION: Molecularly targeted therapies such as tyrosine kinase inhibitors (TKI) are effective treatments for B-cell receptor (BCR)-ABL-bearing leukemias. We evaluated the impact of TKIs on historical chronic myeloid leukemia (CML) mortality trends compared with acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL). METHODS: Because mortality trends reflect combined effects of leukemia incidence and survival, we also evaluated the contribution of incidence and survival trends to mortality trends by subtypes. We used data from 13 U.S. (SEER) registries (1992-2017) among U.S. adults. We utilized histology codes to identify cases of CML, ALL, and CLL and death certificate data to calculate mortality. We used Joinpoint to characterize incidence (1992-2017) and mortality (1992-2018) trends by subtype and diagnosis year. RESULTS: For CML, mortality rates started declining in 1998 at an average rate of 12% annually. Imatinib was approved by the FDA for treating CML and ALL in 2001, leading to clear benefits for patients with CML. Five-year CML survival increased dramatically over time, especially between 1996 to 2011, 2.3% per year on average. ALL incidence increased 1.5% annually from 1992 to 2017. ALL mortality decreased 0.6% annually during 1992 to 2012 and then stopped declining. CLL incidence fluctuated during 1992 to 2017 while mortality decreased 1.1% annually during 1992 to 2011 and at a faster rate of 3.6% per year from 2011. Five-year survival increased 0.7% per year on average during 1992 to 2016. CONCLUSIONS: Survival benefit from TKIs and other novel therapies for treating leukemia subtypes has been demonstrated in clinical trials. IMPACT: Our study highlights the impact of molecularly targeted therapies at the population level.

Minimal Residual Disease Data in Hematologic Malignancy Drug Applications and Labeling: An FDA Perspective.

Minimal residual disease (MRD) is increasingly used as a prognostic biomarker, a measure of clinical efficacy, and a guide for treatment decisions in various hematologic malignancies. We sought to characterize MRD data in registrational trials in hematologic malignancies submitted to the U.S. Food and Drug Administration (FDA) with the ultimate goal of expanding the utility of MRD data in future drug applications. We descriptively analyzed MRD data collected in registrational trials, including the type of MRD endpoint, assay, disease compartment(s) assessed, and the acceptance of MRD data in the U.S. prescribing information (USPI). Of 196 drug applications submitted between January 2014 and February 2021, 55 (28%) included MRD data. Of the 55 applications, MRD data was proposed by the Applicant for inclusion in the USPI in 41 (75%) applications but was included in only 24 (59%). Despite an increasing number of applications that proposed to include MRD data in the USPI, the acceptance rate decreased over time. Although MRD data have the potential to expedite drug development, our analysis identified challenges and specific areas for improvement, including assay validation, standardization of collection methods to optimize performance, and considerations in trial design and statistical methodology.

Neuronal cilia in energy homeostasis.

A subset of genetic disorders termed ciliopathies are associated with obesity. The mechanisms behind cilia dysfunction and altered energy homeostasis in these syndromes are complex and likely involve deficits in both development and adult homeostasis. Interestingly, several cilia-associated gene mutations also lead to morbid obesity. While cilia have critical and diverse functions in energy homeostasis, including their roles in centrally mediated food intake and peripheral tissues, many questions remain. Here, we briefly discuss syndromic ciliopathies and monogenic cilia signaling mutations associated with obesity. We then focus on potential ways neuronal cilia regulate energy homeostasis. We discuss the literature around cilia and leptin-melanocortin signaling and changes in ciliary G protein-coupled receptor (GPCR) signaling. We also discuss the different brain regions where cilia are implicated in energy homeostasis and the potential for cilia dysfunction in neural development to contribute to obesity. We close with a short discussion on the challenges and opportunities associated with studies looking at neuronal cilia and energy homeostasis. This review highlights how neuronal cilia-mediated signaling is critical for proper energy homeostasis.

FDA Approval Summary: Selinexor for Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

In June 2020, the U.S. Food and Drug Administration granted accelerated approval to selinexor for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. Approval was based on SADAL, a multicenter trial of selinexor monotherapy in patients with DLBCL after two to five systemic regimens. Efficacy was based on independent review committee-assessed objective response rate (ORR) and duration of response using Lugano criteria. In 134 patients treated with the approved dosage (60 mg orally on days 1 and 3 of each week), the ORR was 29% (95% confidence interval, 22-38), with complete response in 13% and with 38% of responses lasting at least 6 months. Gastrointestinal toxicity developed in 80% of patients, hyponatremia in 61%, central neurological toxicity (such as dizziness and mental status changes) in 25%, and ocular toxicity in 18%. New or worsening grade 3 or 4 thrombocytopenia, lymphopenia, neutropenia, anemia, or hyponatremia developed in ≥15%. Adverse reactions led to selinexor dose interruption in 61% of patients, dose reduction in 49%, and permanent discontinuation in 17%, with thrombocytopenia being the leading cause of dose modifications. Postmarketing studies will evaluate reduced dosages of selinexor and further evaluate clinical benefit in patients with relapsed or refractory DLBCL. IMPLICATIONS FOR PRACTICE: Selinexor is a new potential option for adults with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, in the third-line setting or beyond. Toxicities are typically manageable but can be difficult to tolerate and necessitate close monitoring and supportive care.

FDA Approval Summary: Brentuximab Vedotin in First-Line Treatment of Peripheral T-Cell Lymphoma.

In November 2018, the U.S. Food and Drug Administration (FDA) approved brentuximab vedotin (BV) for the treatment of adult patients with 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 cyclophosphamide, doxorubicin, and prednisone (CHP). Approval was based on ECHELON-2, a randomized, double-blind, actively controlled trial that compared BV+CHP with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in 452 patients with newly diagnosed, CD30-expressing PTCL. Efficacy was based on independent review facility-assessed progression-free survival (PFS). The median PFS was 48.2 months with BV+CHP versus 20.8 months with CHOP, resulting in a hazard ratio (HR) of 0.71 (95% confidence interval [CI]: 0.54-0.93). The trial also demonstrated improvement in overall survival (HR 0.66; 95% CI: 0.46-0.95), complete response rate (68% vs. 56%), and overall response rate (83% vs. 72%) with BV+CHP. The most common adverse reactions (incidence ≥20%) observed ≥2% more with BV+CHP were nausea, diarrhea, fatigue or asthenia, mucositis, pyrexia, vomiting, and anemia. Peripheral neuropathy rates were similar (52% with BV+CHP, 55% with CHOP). Through the Real-Time Oncology Review pilot program, which allows FDA early access to key data, FDA granted this approval less than 2 weeks after official submission of the application. IMPLICATIONS FOR PRACTICE: This is the first U.S. Food and Drug Administration approval for treatment of patients with newly diagnosed peripheral T-cell lymphomas (PTCL). Improvement in progression-free and overall survival over cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, which has been the standard of care for decades, is unprecedented. The new regimen represents a major advance for the frontline treatment of patients with CD30-expressing PTCL.

Pediatric head trauma: abuse or not?

Your pager sounds at 3 am. You're called to admit a 4-month-old infant who sustained a temporal skull fracture. As the overnight pediatric hospitalist at a community hospital, you're asked to admit this child to observation. The fall was unwitnessed and the floor is hardwood. He vomited twice afterward. Head computed tomography scan reveals no additional intracranial injury apart from the skull fracture. A skeletal survey reveals no additional injuries. On examination, you see bruising of the area. The child is sleepy but neurologically intact. The emergency department has called local child protective services, and you wonder what you will tell them when they ask your opinion, especially when the family has no explanation for what happened.