AUDIENCE: Oncology, Nephrology
KEY FINDINGS: Cabozantinib plus nivolumab showed promising efficacy in most non–clear-cell RCC variants tested in this trial, particularly those with prominent papillary features, whereas treatment effects were limited in chromophobe RCC. Genomic findings in non–clear-cell RCC variants warrant further study as predictors of response.
BACKGROUND: Objective of this trial is to assess the efficacy and safety of cabozantinib plus nivolumab in a phase II trial in patients with non–clear-cell renal cell carcinoma (RCC).
DETAILS: Patients had advanced non–clear-cell renal carcinoma who underwent 0-1 prior systemic therapies excluding prior immune checkpoint inhibitors. Patients received cabozantinib 40 mg once daily plus nivolumab 240 mg once every 2 weeks or 480 mg once every 4 weeks. Cohort 1 enrolled patients with papillary, unclassified, or translocation-associated RCC; cohort 2 enrolled patients with chromophobe RCC. The primary end point was objective response rate (ORR) by RECIST 1.1; secondary end points included progression-free survival, overall survival, and safety. Next-generation sequencing results were correlated with response. A total of 47 patients were treated with a median follow-up of 13.1 months. Objective response rate for cohort 1 (n= 40) was 47.5% (95% CI, 31.5 to 63.9), with median progression-free survival of 12.5 months (95% CI, 6.3 to 16.4) and median overall survival of 28 months (95% CI, 16.3 to not evaluable). In cohort 2 (n= 7), no responses were observed; one patient had stable disease > 1 year. Grade 3/4 treatment-related adverse events were observed in 32% treated patients. Cabozantinib and nivolumab were discontinued because of toxicity in 13% and 17% of patients, respectively. Common mutations included NF2 and FH in cohort 1 and TP53 and PTEN in cohort 2. Objective responses were seen in 10/12 patients with either NF2 or FH mutations.
Copyright © American Society of Clinical Oncology. All rights reserved.
Source: Lee, C., Voss, M. H., Carlo, M. I., et al. (2022). Phase II Trial of Cabozantinib Plus Nivolumab in Patients With Non–Clear-Cell Renal Cell Carcinoma and Genomic Correlates. Journal of Clinical Oncology. 2021; 40(21): 2333-2341. Published: July 20, 2022. DOI: 0.1200/JCO.21.01944.
Actionable Tumor Alterations and Treatment Protocol Enrollment of Pediatric and Young Adult Patients With Refractory Cancers in the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial.
AUDIENCE: Oncology, Pediatric
KEY FINDINGS: The Pediatric MATCH trial has proven the feasibility of a nationwide screening Protocol for identification of actionable genetic alterations and assignment of pediatric and young adult patients with refractory cancers to trials of molecularly targeted therapies. These data support the early use of tumor molecular screening for childhood patients with cancer whose tumors have not responded to standard treatments.
BACKGROUND: The National Cancer Institute-Children's Oncology Group Pediatric MATCH trial aimed to facilitate evaluation of molecular-targeted therapies in biomarker-selected cohorts of childhood and young adult patients with cancer by screening tumors for actionable alterations.
DETAILS: Tumors from patients age 1-21 years with refractory solid tumors, lymphomas, or histiocytic disorders were subjected to cancer gene panel sequencing and limited immunohistochemistry to identify actionable alterations for assignment to phase II treatment arms. The rates of treatment arm assignment and enrollment were compared between clinical and demographic groups. Testing was completed for 94.7% of tumors submitted. Actionable alterations were detected in 31.5% of the first 1,000 tumors screened, with treatment arm assignment and enrollment occurring in 28.4% and 13.1% of patients, respectively. Assignment rates varied by tumor histology and were higher for patients with CNS tumors or enrolled at Pediatric Early Phase Clinical Trials Network sites. A reported history of prior clinical molecular testing was associated with higher assignment and enrollment rates. Actionable alterations in the mitogen-activated protein kinase signaling pathway were most frequent (11.2%). The most common reasons provided for not enrolling on treatment arms were patients receiving other treatment or poor clinical status.
Copyright © American Society of Clinical Oncology. All rights reserved.
Source: Parsons, D. W., Janeway, K. A., Patton, D. R., et al. (2022). Actionable Tumor Alterations and Treatment Protocol Enrollment of Pediatric and Young Adult Patients With Refractory Cancers in the National Cancer Institute-Children's Oncology Group Pediatric MATCH Trial. Journal of Clinical Oncology. 2022; 40(20): 2224-2234. Published: July 10, 2022. DOI: 10.1200/JCO.21.02838.
AUDIENCE: Hematology, Ob/Gyn, Family Medicine
KEY FINDINGS: Despite these limitations, this pilot study suggests that metformin is safe and well tolerated in FA and may afford clinical benefit in a subset of patients. Development of a subsequent multicenter efficacy study may provide greater clarity regarding metformin's role in the treatment of FA. Given the historical experience of treating FA-associated cytopenias with androgens, combination treatment of androgens with metformin could also be explored. Future efficacy end points should study the utility of metformin as both a prophylactic agent aimed at curtailing progression of bone marrow failure and as a chemo preventive agent aimed at reducing cancer risk in FA.
BACKGROUND: Fanconi anemia (FA), a genetic DNA repair disorder characterized by marrow failure and cancer susceptibility. In FA mice, metformin improves blood counts and delays tumor development.
DETAILS: A single institution study of metformin in nondiabetic patients with FA was conducted to determine feasibility and tolerability of metformin treatment and to assess for improvement in blood counts. Fourteen of 15 patients with at least 1 cytopenia (hemoglobin < 10 g/dL; platelet count < 100,000 cells/µL; or an absolute neutrophil count < 1000 cells/µL) were eligible to receive metformin for 6 months. Median patient age was 9.4 years (range 6.0-26.5 ). Thirteen of 14 subjects (93%) tolerated maximal dosing for age; 1 subject had dose reduction for grade 2 gastrointestinal symptoms. No subjects developed hypoglycemia or metabolic acidosis. No subjects had dose interruptions caused by toxicity, and no grade 3 or higher adverse events attributed to metformin were observed. Hematologic response based on modified Myelodysplastic Syndrome International Working Group criteria was observed in 4 of 13 evaluable patients (30.8%; 90% confidence interval, 11.3-57.3). Median time to response was 84.5 days (range 71-128 days). Responses were noted in neutrophils (n = 3), platelets (n = 1), and red blood cells (n = 1). No subjects met criteria for disease progression or relapse during treatment. Correlative studies explored potential mechanisms of metformin activity in FA. Plasma proteomics showed reduction in inflammatory pathways with metformin. Metformin is safe and tolerable in nondiabetic patients with FA and may provide therapeutic benefit.
Copyright © The American Society of Hematology. All rights reserved.
Source: Addo, O. W., Mei, Z., Hod, E. A., et al. (2022). Physiologically Based Serum Ferritin Thresholds for Iron Deficiency in Women of Reproductive Age Who Are Blood Donors. Blood Adv.. 2022; 6(12): 3803-3811. Published: June 28, 2022. DOI: 10.1182/bloodadvances.2021006490.
A Multicentre, Open-Label Phase 2 Trial
AUDIENCE: Family Medicine, Oncology
KEY FINDINGS: Patients aged at least 65 years, with advanced oesophageal squamous cell carcinoma might benefit from combined nivolumab and ipilimumab therapy in second-line treatment.
BACKGROUND: The overall survival of patients with advanced and refractory oesophageal squamous cell carcinoma, mostly aged 65 years and older, is poor. Treatment with PD-1 antibodies showed improved progression-free survival and overall survival. Assessed the safety and efficacy of combined nivolumab and ipilimumab therapy in this population.
DETAILS: This multicentre, open-label, phase 2 trial done in 32 sites in Germany included patients aged 65 years and older with oesophageal squamous cell carcinoma and disease progression or recurrence following first-line therapy. Patients were treated with nivolumab (240 mg fixed dose once every 2 weeks, intravenously) in the safety run-in phase and continued with nivolumab and ipilimumab (nivolumab 240 mg fixed dose once every 2 weeks and ipilimumab 1 mg/kg once every 6 weeks, intravenously). The primary endpoint was overall survival, which was compared with a historical cohort receiving standard chemotherapy in the intention-to-treat population. Between March 2, 2018, and Aug 20, 2020, we screened 75 patients with advanced oesophageal squamous cell carcinoma. We enrolled 66 patients (50 [76%] men and 16 [24%] women; median age 70.5 years [IQR 67.0-76.0]), 44 (67%) of whom received combined nivolumab and ipilimumab therapy and 22 (33%) received nivolumab alone. Median overall survival time at the prespecified data cutoff was 7.2 months (95% CI 5.7-12.4) and significantly higher than in a historical cohort receiving standard chemotherapy (p=0.0063). The most common treatment-related adverse events were fatigue (12 [29%] of 42), nausea (11 [26%]), and diarrhoea (ten [24%]). Grade 3-5 treatment-related adverse events occurred in 13 (20%) of 66 patients. Treatment-related death occurred in one patient with bronchiolitis obliterans while on nivolumab and ipilimumab treatment.
Copyright © Elsevier Ltd. All rights reserved.
Source: Ebert, M. P., Meindl-Beinker, N. M., Gutting, T., et al. (2022). Second-line Therapy With Nivolumab Plus Ipilimumab For Older Patients With Oesophageal Squamous Cell Cancer (RAMONA): A Multicentre, Open-Label Phase 2 Trial. The Lancet. 2022; 3(6): 417-427. Published: June 1, 2022. DOI: 10.1016/S2666-7568(22)00116-7.
Ukoniq (umbralisib): Drug Safety Communication - FDA Approval of Lymphoma Medicine is Withdrawn Due to Safety Concerns
BACKGROUND Ukoniq was approved to treat two specific types of lymphoma: marginal zone lymphoma and follicular lymphoma.
Health care professionals should stop prescribing Ukoniq and switch patients to alternative treatments. Inform patients currently taking Ukoniq of the increased risk of death seen in the clinical trial and advise them to stop taking the medicine. In limited circumstances in which a patient may be receiving benefit from Ukoniq, TG Therapeutics plans to make it available under expanded access.
Patients should talk to your health care professionals about alternative treatments and stop taking Ukoniq. It is best to dispose of unused Ukoniq using a drug take-back location such as in a pharmacy, but if one is not available, you can dispose of Ukoniq in your household trash by doing the following:
Health care professionals and patients are encouraged to report adverse events or side effects related to the use of these products to the FDA's MedWatch Safety Information and Adverse Event Reporting Program:
Source: FDA Published: June 1, 2021
AUDIENCE: Ob/Gyn, Oncology, Family Medicine
KEY FINDINGS: In EC patients with coexistent adenomyosis, the risk of death is halved compared with EC patients without adenomyosis. However, the independence of this association needs to be verified in future studies.
BACKGROUND: Despite the high prevalence of adenomyosis in hysterectomy specimens of endometrial carcinoma (EC) patients, the relationship between adenomyosis and EC prognosis appears unclear. Aim of the study was to assess the prognostic value of coexistent adenomyosis in patients with EC.
DETAILS: A systematic review and meta-analysis was performed by searching six electronic databases for studies reporting data on prognosis of EC patients with and without coexistent adenomyosis. Studies with patient selection based on prognostic factors were excluded. Pooled univariate hazard ratio (HR) analyses for overall survival (OS) and disease-free survival (DRF) were performed, using EC patients without adenomyosis as a control group. For DFS, pooled multivariate HR analysis was also evaluable. Three studies of 2505 EC patients (553 with and 1952 without adenomyosis) were included. Compared with EC patients without adenomyosis, EC patients with coexistent adenomyosis showed a pooled HR of 0.533 (CI 95%, 0.329-0.864) for OS at univariate analysis; 0.536 (CI 95%, 0.334-0.859) for DFS at univariate analysis; and 0.875 (CI 95%, 0.331-2.315) for DFS at multivariate analysis.
Copyright © John Wiley & Sons, Inc. All rights reserved
Source: Raimondo, D., Raffone, A., Travaglino, A., et al. (2022). Impact of Adenomyosis On The Prognosis Of Patients With Endometrial Cancer. Intl J Gynecol Obstet.. 2022; 157(2): 265-270. Published: May, 2022. DOI: 10.1002/ijgo.13818.