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.

Trends in the approval of cancer therapies by the FDA in the twenty-first century.

The cancer treatment landscape has changed dramatically since the turn of the century, resulting in substantial improvements in outcomes for patients. This Review summarizes trends in the approval of oncology therapeutic products by the United States Food and Drug Administration (FDA) from January 2000 to October 2022, based on a categorization of these products by their mechanism of action and primary target. Notably, the rate of oncology indication approvals has increased in this time, driven by approvals for targeted therapies, as has the rate of introduction of new therapeutic approaches. Kinase inhibitors are the dominant product class by number of approved products and indications, yet immune checkpoint inhibitors have the second most approvals despite not entering the market until 2011. Other trends include a slight increase in the share of approvals for biomarker-defined populations and the emergence of tumour-site-agnostic approvals. Finally, we consider the implications of the trends for the future of oncology therapeutic product development, including the impact of novel therapeutic approaches and technologies.

Project Confirm: Accelerated Drug Approvals for Chronic Myeloid Leukemia.

The FDA has an accelerated approval program for drugs that have been identified as promising treatments for serious conditions when the available data suggest that the benefits outweigh the foreseeable risks. All of the currently available treatment options for chronic myeloid leukemia (CML) initially went through the accelerated approval program. Here, a group of academic CML experts, patient panelists, and members from the FDA convened to discuss the utility of the accelerated approval program as it pertains to CML, and the utility of this program in future drug development in this disease. The results of that discussion are summarized here.

Highlights of FDA Oncology Approvals in 2022: Tissue-Agnostic Indications, Dosage Optimization, and Diversity in Drug Development.

In 2022, cancer drug development continued to progress rapidly despite the lingering COVID-19 pandemic. Highlights of U.S. drug approvals for oncology indications this year include ongoing development in rare diseases and molecular subgroups, improved dosage optimization, and updated data for drugs granted accelerated approval, with confirmatory studies demonstrating verification of clinical benefit in some instances, as well as indication withdrawal when clinical benefit was not verified.

The impact of new generic formulations of imatinib mesylate on general quality of life in chronic phase chronic myeloid leukaemia patients.

Treatment with tyrosine kinase inhibitors (TKIs) has dramatically changed the life expectancy of chronic myeloid leukaemia (CML) patients. Although the impact of first-generation TKIs on quality of life (QoL) was shown in CML, the effects of new generic formulations of imatinib mesylate (IM) are unclear. We evaluated differences in QoL under treatment with first- or second-generation TKIs. Fifty-two patients diagnosed with CP-CML completed the European Organization for Research and Treatment of Cancer Quality of Life Questionaire-C30, Hospital Anxiety and Depression Scale, and General Health Questionnaire. General QoL scores were similar between groups. There was a significant difference in the frequency of diarrhoea between IM group and the group using new generic formulations of IM (P = 0.012). General QoL score tended to be higher in patients with disease duration longer than 3 years (P = 0.052). GHQ, anxiety and depression scores correlated positively with symptom scales and negatively with functional subscales.CML patients using new generic formulations of IM reported a higher frequency of diarrhoea than patients using original IM and second-generation TKIs that could result in more drug discontinuation.

17p Deletion is associated with resistance of B-cell chronic lymphocytic leukemia cells to in vitro fludarabine-induced apoptosis.

We explored the relationship between the cytogenetic/biologic characteristics of B-chronic lymphocytic leukemia (B-CLL) cells and their tendency to undergo spontaneous or fludarabine-induced apoptosis in vitro. B cells from 36 B-CLL patients were incubated with or without fludarabine for 48 h. Apoptosis was determined by two assays: annexin V staining and DNA staining. Fluorescence in situ hybridization was used for detection of trisomy 12, 11q deletion, and 17p deletion. Bcl-2 and CD38 expressions were determined by flow cytometry. Five patients had 17p deletion, 6 had trisomy 12, and another 6 had 11q deletion. B-CLL cells with 17p deletion had significant resistance to apoptosis induced by fludarabine and a slight spontaneous resistance to apoptosis. Bcl-2 and CD38 were not associated with in vitro spontaneous and fludarabine-induced apoptosis. In conclusion, 17p deletion, which causes loss of p53 gene, is associated with resistance to fludarabine-induced apoptosis in vitro. New treatment modalities should be tried in B-CLL patients with 17p deletion.

Increased circulating platelet-neutrophil, platelet-monocyte complexes, and platelet activation in patients with ulcerative colitis: a comparative study.

It is reported that the incidence of thromboembolism is increased in ulcerative colitis (UC), and hypercoagulability persists even when patients are in remission. We evaluated the association of inflammatory response parameters with UC activity, and activation parameters of the platelets, endothelium, and the coagulation system in UC. Eighteen UC patients and 19 healthy subjects were included in the study. The patients' clinical features were recorded down; whole blood counts and acute phase parameters were evaluated. UC patients were divided into two as active (9 patients) and inactive (9 patients) according to combined clinical activity index (CAI) and endoscopic activity index (EAI) scores. In all subjects, platelet CD62P expression, platelet-monocyte complexes (PMC), platelet-neutrophil complexes (PNC), and platelet microparticles (PMP) were determined by flow cytometry. E-selectin, thrombin-antithrombin complex (TAT) levels in plasma, and sCD40L levels in serum were determined by ELISA. In both active and inactive UC patients, platelet CD62P expression, the percentages of PMC, and PNC were significantly higher than those in the control group (P< 0.01). PMP level was higher in the control group than in inactive UC patients (P = 0.001). sCD40L level was significantly higher in active UC group than in the control group (P < 0.01). EAI score correlated significantly with PMP (r = 0.5, P = 0.04) and sCD40L (r = 0.48, P = 0.044); CAI score had a negative correlation (r = -0.68, P = 0.002) with sE-selectin level. In addition to increased CD62P expression and sCD40L, increased formation of PMC and PNC suggests a role for platelet-leukocyte complex formation together with platelet activation in thromboembolic events observed in UC.

Dorsal sural nerve conduction study in vitamin B(12) deficiency with megaloblastic anemia.

Peripheral neuropathy is frequently observed in B(12) deficiency. In spite of this, there is little knowledge about peripheral neuropathy in B(12) deficiency because the severity of clinical involvement of the central nervous system clearly outweighs signs and symptoms due to peripheral nervous system involvement. We primarily investigated peripheral neuropathy with dorsal sural conduction study, which is a new method for detection of early peripheral neuropathy, in B(12) deficiency with megaloblastic anemia. Conventional nerve conduction studies and tibial sensory-evoked potential (SEP) recording were also performed. Twenty-eight B(12)-deficient patients (15 male, 13 female, mean age 65.8 years) with megaloblastic anemia and 18 age- and sex-matched controls were included in the study. Although dorsal sural sensory nerve action potentials (SNAPs) were not recorded in 15 (54%) of 28 patients, only 9 (32%) of them were found to have polyneuropathy by conventional conduction studies. Furthermore, patients with dorsal sural SNAP had mean lower amplitude, mean longer latency, and slower velocity response when compared with controls. Twenty patients (71%) were diagnosed as having myelopathy by the combination of tibial SEP and neurological findings. Two patients whose dorsal sural SNAPs were not recorded had normal tibial SEP responses; therefore, these patients were considered to have isolated peripheral neuropathy. As a result, we conclude that dorsal sural nerve conduction study is a reliable method for detection of early peripheral neuropathy in B(12) deficiency.