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.

FDA approval summary: Crizotinib for pediatric and young adult patients with relapsed or refractory systemic anaplastic large cell lymphoma.

In January 2021, the U.S. Food and Drug Administration (FDA) approved crizotinib for pediatric patients 1 year and older and young adults with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). This is the first approval for pediatric sALCL. Approval was based on a single-arm trial of crizotinib monotherapy that included 26 patients, aged 1-20 years, with previously treated sALCL. Efficacy was based on centrally assessed objective response rate (88%) and duration of response. Herein, we highlight unique aspects of the regulatory review, including extension of the indication to young adults, postmarketing safety, and dose optimization strategies.

The Hallux Metatarsophalangeal Capsule: An Anatomic Study With Respect to Percutaneous Hallux Valgus Correction.

BACKGROUND: Minimally invasive surgery for the treatment of hallux valgus deformities has become increasingly popular. Knowledge of the location of the hallux metatarsophalangeal (MTP) proximal capsular origin on the metatarsal neck is essential for surgeons in planning and executing extracapsular corrective osteotomies. A cadaveric study was undertaken to further study this anatomic relationship. METHODS: Ten nonpaired fresh-frozen frozen cadaveric specimens were used for this study. Careful dissection was performed, and the capsular origin of the hallux MTP joint was measured from the central portion of the metatarsal head in the medial, lateral, dorsal, plantarmedial, and plantarlateral dimensions. RESULTS: The ten specimens had a mean age of 77 years, with 5 female and 5 male. The mean distances from the central hallux metatarsal head to the MTP capsular origin were 15.2 mm dorsally, 8.4 mm medially, 9.6 mm laterally, 19.3 mm plantarmedially, and 21.0 mm plantarlaterally. CONCLUSION: The MTP capsular origin at the hallux metatarsal varies at different anatomic positions. Knowledge of this capsular anatomy is critical for orthopaedic surgeons when planning and performing minimally invasive distal metatarsal osteotomies for the correction of hallux valgus. TYPE OF STUDY: Cadaveric Study.

Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies: ACCELERATE in collaboration with the European Medicines Agency with the participation of the Food and Drug Administration.

The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children.

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.

Comparison study of patient demographics and risk factors for surgical site infections following open reduction and internal fixation for lateral malleolar ankle fractures within the medicare population.

BACKGROUND: The purpose of this study was to analyze a comprehensive database to 1) compare patient demographic profiles; and 2) identify patient-related risk factors for surgical site infections (SSIs) following open reduction and internal fixation (ORIF) for lateral malleolar ankle fractures. METHODS: Patients treated with ORIF for lateral malleolar ankle fractures that developed SSIs within 1-year following the procedure were identified. Study group demographics were compared to a control cohort and risks for developing SSI were calculated using multivariate logistic regression analysis. RESULTS: There were statistically significant differences between the control group and patients with SSIs. The study showed that morbidly obese patients, peripheral vascular disease, and electrolyte/fluid imbalance were the greatest risk factors for developing SSIs following ORIF for lateral malleolar fractures. CONCLUSION: The study is useful as it can allow orthopaedists to optimize these high-risk patients to potentially mitigate this adverse event.

FDA approval summary: Dalteparin for the treatment of symptomatic venous thromboembolism in pediatric patients.

On May 16, 2019, the U.S. Food and Drug Administration (FDA) approved dalteparin sodium for the treatment of symptomatic venous thromboembolism (VTE) to reduce the risk of recurrence in pediatric patients 1 month of age and older. Approval was primarily based on FDA review of a single-arm trial evaluating dalteparin administered subcutaneous twice daily in 38 pediatric patients with symptomatic VTE. Efficacy was based on the achievement of therapeutic plasma anti-Xa levels. The FDA concluded that dalteparin has efficacy and acceptable safety for pediatric patients.

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.

Intracompartmental Versus Extracompartmental Transposition of the Extensor Pollicis Longus for Treating Thumb-in-Palm Deformity: A Biomechanical Comparison.

PURPOSE: Transecting the extensor pollicis longus (EPL) tendon and rerouting it through the first extensor compartment is an established technique for treating thumb-in-palm deformity (TIPD). An alternative technique that approximates the trajectory of the first extensor compartment without violating the compartment or transecting the EPL tendon can be accomplished by creating an artificial sheath from the extensor retinaculum to radialize the tendon glide path. This study compares this extracompartmental (EC) EPL transposition to the established, intracompartmental (IC) transposition by evaluating, in a cadaver model, the extent of thumb extension in both techniques. METHODS: Eighteen fresh-frozen cadaveric hands were each tested under 3 different conditions: EPL in situ (baseline); EPL rerouted above the first extensor compartment (EC); and EPL rerouted through the first extensor compartment (IC). A controlled traction of 10 N was applied to the EPL under each condition. The range of thumb extension with respect to the fixed index finger was recorded utilizing infrared reflective markers and digital video capture. RESULTS: The mean extension of the thumb with the EPL tendon in situ was 16.7°. The mean extension of the thumb was 22.0° with the EC transposition versus 25.0° with the IC technique. The measured thumb extension in both the EC and the IC techniques were found to be similar because both EPL transpositions yielded a significant difference in thumb extension when compared with baseline. CONCLUSIONS: This biomechanical model demonstrates that radial transposition of the EPL tendon enhances extension of the thumb regardless of whether the tendon is routed through, or superficial to, the first extensor compartment. CLINICAL RELEVANCE: A novel technique, the EC EPL transposition, offers a similar enhancement in measured thumb extension as the already-described IC EPL transposition.

Readability of the Most Commonly Accessed Arthroscopy-Related Online Patient Education Materials.

PURPOSE: To assess the readability and comprehension of written text by the most commonly visited websites containing patient education materials on common conditions that can be treated arthroscopically. METHODS: We examined 50 websites, assessed independently by 2 orthopaedic surgery residents (S.A. and G.G.), with educational materials on 5 common conditions treated by arthroscopic surgeons: anterior cruciate ligament (ACL) tear, meniscus tear, hip labral tear, shoulder labral tear, and rotator cuff tear. Following a Google search for each condition, we analyzed the 10 most visited websites for each disorder using a widely used and validated tool for assessing the reading levels of written materials (Flesch-Kincaid formula). RESULTS: The average grade reading level of the 50 websites studied was 9.90 with a reading ease of 52.14 ("fairly difficult, high school"). Only 26% of the websites were at or below the national average of an eighth-grade reading level. Of the 5 conditions treated by arthroscopic surgery, ACL tear had the highest average grade reading level at 10.73 ± 1.54, whereas meniscus tear had the lowest at 9.31 ± 1.81. Every condition in this study had an average readability at or above the ninth-grade reading level. CONCLUSIONS: The most frequently accessed materials for patients with injuries requiring arthroscopic surgery exceeds the readability recommendations of the American Medical Association and National Institutes of Health, as well as the average reading ability of US adults. Given the fact that these are the most commonly visited websites by the lay public, there needs to be a greater emphasis on tailoring written information to the literacy levels of the patient population. CLINICAL RELEVANCE: This study emphasizes the discrepancy between the recommended versus the measured reading levels of online patient education materials related to conditions treated by arthroscopic surgeons. The subject matter of these conditions is inherently complex; thus, relying solely on text to inform patients increases the likelihood that the reading level of the material exceeds that of the majority of the lay public.

Computer Assisted Cobb Angle Measurements: A novel algorithm.

BACKGROUND: The standard for evaluating scoliosis is PA radiographs using Cobb angle to measure curve magnitude. Newer PACS systems allow easier Cobb angle calculations, but have not improved inter/intra observer precision of measurement. Cobb angle and its progression are important to determine treatment; therefore, angle variability is not optimal. This study seeks to demonstrate that a performance equivalent to that achieved in the manual method is possible using a novel computer algorithm with limited user input. The authors compared Cobb angles from predetermined spinal levels in the average attending score versus the computer assisted approach. METHODS: Retrospective analysis of PA radiographs from 58 patients previously evaluated for scoliosis was collected. Predesignated spinal levels (e.g., T2-T10) were assigned for different curves and calculated by Cobb method. Four spine surgeons evaluated these Cobb angles. Their average scores were measured and compared to formulated values using the novel computer-based algorithm. Literature reports inter-observer reliability is 6.3-7.2degrees. Limits of accuracy were set at 5 degrees of average orthopedic surgeons' score. RESULTS: The computer-based algorithm calculated Cobb angles within 5 degrees of orthopedic surgeons' average with a standard deviation of 3.2 degrees. This result was based on a 95% confidence interval with p values <0.001. The computer algorithm was plotted against average angle determined by the surgeons, with individual determinations and linear regression (r2 =0.90). The average difference between surgeons' measures and computer algorithm was 0.4 degrees(SD= 3.2degrees, n=79). There was a tendency for the computer algorithm program to overestimate the angle at larger angles, but difference was small with r2 = 0.09. CONCLUSIONS: Our study showed the novel computer based algorithm was an efficient and reliable method to assess scoliotic curvature in the coronal plane with the possibility of expediting clinic visits, ensuring reliability of calculation and decreasing patient exposure to radiation. Level of Evidence: III.

Division Tenorrhaphy: A Novel Technique for Chronic or Failed Nonoperatively Treated Achilles Tendon Rupture.

Here we describe a modified open technique for the repair of a ruptured Achilles tendon using multiple looped sutures with the creation of interdigitating tendon stumps maximizing surface area for suture application as well as allowing for significant tissue overlay. This technique produces a high strength repair that is useful in cases of extensive degeneration or poor-quality tissue. Degenerative tissue may be encountered with chronic ruptures or failed nonoperative treatment, as well as those ruptures that occur at the proximal myotendinous junction. We present 2 cases in which the technique was utilized: one of a failed nonoperatively treated rupture and another of a chronic rupture. The technique was found to be successful for both patients with improvement in visual analogue scale, Achilles tendon total rupture score, American Orthopaedic Foot and Ankle Score, and Foot and Ankle Disability Index. LEVELS OF EVIDENCE: Level IV.

Biomechanical Evaluation of Custom Foot Orthoses for Hallux Valgus Deformity.

The purpose of the present study was to compare the hallux valgus deformity pressure parameters seen in standard footwear (no orthosis) versus the pressure observed in the same footwear with the addition of 3 different length orthoses. The forefoot pressure at a hallux valgus deformity was recorded with pressure sensors placed on the plantar, medial, and dorsal surface of the first metatarsal head. The participants performed walking trials without an orthosis and with orthoses of 3 different lengths. The average pressure and maximum pressure of each area was recorded for each orthosis, and comparisons were made across the groups. The plantar pressures were decreased in the full length and 3/4 length orthoses, and the dorsal pressures were increased with the use of the full-length and sulcus-length orthoses. Significant changes in medial pressure were not seen with the addition of any orthosis compared with standard footwear alone. However, a trend toward increased medial pressures was seen with the full- and sulcus-length orthoses, and the 3/4-length orthoses exhibited a trend toward decreased medial pressures. We were unable to demonstrate that the use of a custom foot orthosis significantly decreases the medial pressures on the first metatarsal head in patients with hallux valgus deformity. The 3/4-length orthosis was less likely to negatively affect the dorsal or medial pressures, which were noted to increase with the sulcus- and full-length orthoses. Our data suggest that if a clinician uses this treatment option, a 3/4-length orthosis might be a better choice than a sulcus- or full-length orthosis.

Impact of Total Shoulder Arthroplasty on Golfing Activity.

OBJECTIVE: Golf is a widely popular sport in the United States with 29 million Americans participating in the game. With an aging population and increased incidence of glenohumeral degenerative arthritis, the number of active golfers requiring total shoulder replacement is on the rise. This study aims to evaluate the effect of total shoulder replacement on golfing activity. DESIGN: Retrospective; questionnaire. SETTING: Survey. PARTICIPANTS: Three hundred sixty-seven patients were identified based on Current Procedural Terminology codes who underwent total shoulder arthroplasty (TSA) between January 2004 and January 2013. INTERVENTIONS: A voluntary anonymous questionnaire was sent to patients by mail including both objective and subjective questions about their level of golf activity and ability both before and after the surgery. MAIN OUTCOME MEASURES: Two hundred sixty-eight (73%) patients responded with 35 (34 right-handed and 1 left-handed patients) golfers completing the questionnaire. Results including visual analog pain scores, handicap change, and driving distance were evaluated statistically using the Student t test. RESULTS: Thirty-five golfers at an average time of 3.2 years after TSA completed the questionnaire with 31/35 being able to return to the sport at an average time of 8.4 months postoperatively. Thirty of 31 patients reported improvement in their pain level during and after golfing activity by an average of 4.3 (P < 0.05) on a visual analog scale (VAS) for pain. On average, driving distances increased by 12.5 yd (P = 0.0012) and handicap improved by 1.4 strokes (P = 0.03). CONCLUSIONS: Patients who undergo TSA for primary glenohumeral arthritis can safely return to golfing activity with a significant decrease in their perceived pain level as per VAS scores. Statistically significant findings included an increase in driving distance by 12.5 yd and an improvement in handicap by 1.4. CLINICAL RELEVANCE: In counseling patients, it is the authors' opinion that based on our experience with golfers undergoing TSA, patients can safely return to sport at an average of 8.4 months. The likelihood of return to play was quite high, but not 100%, and as such no guarantee should be provided to patients. Outcomes of patients with TSA desiring a return to golf are positive, and possible benefits include improvement of pain and possible improvements in driving distance and handicap. LEVEL OF EVIDENCE: IV.

Synthesis of two 3,5-disubstituted sulfonamide catechol ligands and evaluation of their iron(III) complexes for use as MRI contrast agents.

Two 3,5-disubstituted sulfonamide catechol ligands were synthesized. Tris(ligand) iron(III) complexes were prepared and investigated as MRI contrast agents. Longitudinal relaxivity (r1) values were determined for the complexes. The r1 values in water were substantially higher than those of typical six-coordinate iron(III) complexes. The r1 values in plasma under the same conditions increased. The iron(III) complexes were administered to rats, and the kidney and liver signal intensities were measured by T1-weighted MR imaging experiments.