A Phase 0/I Pharmacokinetic and Pharmacodynamics and Safety and Tolerability Study of Letrozole in Combination with Standard Therapy in Recurrent High-Grade Gliomas.

PURPOSE: High-grade gliomas (HGG) carry a poor prognosis, with glioblastoma accounting for almost 50% of primary brain malignancies in the elderly. Unfortunately, despite the use of multiple treatment modalities, the prognosis remains poor in this population. Our preclinical studies suggest that the presence of aromatase expression, encoded by CYP19A1, is significantly upregulated in HGGs. Remarkably, we find that letrozole (LTZ), an FDA-approved aromatase inhibitor, has marked activity against HGGs. PATIENTS AND METHODS: We conducted a phase 0/I single-center clinical trial (NCT03122197) to assess the tumoral availability, pharmacokinetics (PK), safety, and tolerability of LTZ in recurrent patients with HGG. Planned dose cohorts included 2.5, 5, 10, 12.5, 15, 17.5, and 20 mg of LTZ administered daily pre- and postsurgery or biopsy. Tumor samples were assayed for LTZ content and relevant biomarkers. The recommended phase 2 dose (R2PD) was determined as the dose that resulted in predicted steady-state tumoral extracellular fluid (ECF; Css,ecf) >2 µmol/L and did not result in ≥33% dose-limiting adverse events (AE) assessed using CTCAE v5.0. RESULTS: Twenty-one patients were enrolled. Common LTZ-related AEs included fatigue, nausea, musculoskeletal, anxiety, and dysphoric mood. No DLTs were observed. The 15 mg dose achieved a Css,ecf of 3.6 ± 0.59 µmol/L. LTZ caused dose-dependent inhibition of estradiol synthesis and modulated DNA damage pathways in tumor tissues as evident using RNA-sequencing analysis. CONCLUSIONS: On the basis of safety, brain tumoral PK, and mechanistic data, 15 mg daily is identified as the RP2D for future trials.

The impact of cancer metastases on COVID-19 outcomes: A COVID-19 and Cancer Consortium registry-based retrospective cohort study.

BACKGROUND: COVID-19 can have a particularly detrimental effect on patients with cancer, but no studies to date have examined if the presence, or site, of metastatic cancer is related to COVID-19 outcomes. METHODS: Using the COVID-19 and Cancer Consortium (CCC19) registry, the authors identified 10,065 patients with COVID-19 and cancer (2325 with and 7740 without metastasis at the time of COVID-19 diagnosis). The primary ordinal outcome was COVID-19 severity: not hospitalized, hospitalized but did not receive supplemental O2, hospitalized and received supplemental O2, admitted to an intensive care unit, received mechanical ventilation, or died from any cause. The authors used ordinal logistic regression models to compare COVID-19 severity by presence and specific site of metastatic cancer. They used logistic regression models to assess 30-day all-cause mortality. RESULTS: Compared to patients without metastasis, patients with metastases have increased hospitalization rates (59% vs. 49%) and higher 30 day mortality (18% vs. 9%). Patients with metastasis to bone, lung, liver, lymph nodes, and brain have significantly higher COVID-19 severity (adjusted odds ratios [ORs], 1.38, 1.59, 1.38, 1.00, and 2.21) compared to patients without metastases at those sites. Patients with metastasis to the lung have significantly higher odds of 30-day mortality (adjusted OR, 1.53; 95% confidence interval, 1.17-2.00) when adjusting for COVID-19 severity. CONCLUSIONS: Patients with metastatic cancer, especially with metastasis to the brain, are more likely to have severe outcomes after COVID-19 whereas patients with metastasis to the lung, compared to patients with cancer metastasis to other sites, have the highest 30-day mortality after COVID-19.

Belzutifan, HIF-2α Inhibitor, and Clear Cell Renal Cell Carcinoma With Somatic Von-Hippel-Lindau Loss-of-Function Mutation.

The Von-Hippel-Lindau (VHL) gene, acting as a tumor suppressor, plays a crucial role in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). Approximately 90% of individuals with advanced ccRCC exhibit somatic mutations in the VHL gene. Belzutifan, orally administered small-molecule inhibitor of hypoxia-induced factor-2α, has demonstrated promising efficacy in solid tumors associated with germline loss-of-function mutations in VHL, including ccRCC. However, its impact on cases with somatic or sporadic VHL mutations remains unclear. Here, we present 2 cases where belzutifan monotherapy was employed in patients with advanced ccRCC and somatic loss-of-function mutations in VHL. Both patients exhibited a swift and sustained response, underscoring the potential role of belzutifan as a viable option in second or subsequent lines of therapy for individuals with somatic VHL mutations. Despite both patients experiencing a pulmonary crisis with respiratory compromise, their rapid response to belzutifan further emphasizes its potential utility in cases involving pulmonary or visceral crises. This report contributes valuable insights into the treatment landscape for advanced ccRCC with somatic VHL mutations.

Current state of the art: immunotherapy in esophageal cancer and gastroesophageal junction cancer.

Esophageal cancers have a high mortality rate and limited treatment options especially in the advanced/metastatic setting. Squamous cell carcinoma (SCC) and adenocarcinoma are two distinct types of esophageal cancer. Esophageal SCC is more common in nonindustrialized countries with risk factors including smoking, alcohol use, and achalasia. Adenocarcinoma is the predominant esophageal cancer in developed nations, and risk factors include chronic gastroesophageal reflux disease, obesity, and smoking. Chemotherapy has been the mainstay of therapy for decades until immunotherapy made its debut in the past few years. Immune checkpoint inhibitors have been tested in many studies now and are becoming an essential component of esophageal cancer treatment. Monoclonal antibodies that selectively inhibit programmed cell death-1 (PD-1) activity such as pembrolizumab and nivolumab, have become standard of care in the treatment of esophageal cancer. Several other anti-PD-1 antibodies like camrelizumab, toripalimab, sintilimab, trislelizumab are under investigation in different stages of clinical trials. Here we provide a comprehensive review of extant literature as well as ongoing trials with various combinations of chemotherapy or other targeted therapy with a focus on different histological subgroups of esophageal cancer and in different clinical settings.

Somatic BRCA2 Mutation-Positive Concurrent Accessory Male Breast Cancer (BC) and Non-Small Cell Lung Cancer (NSCLC): Excellent Efficacy of Palbociclib, Fulvestrant and Leuprolide in Platinum-Exposed and Endocrine-Refractory BC Associated with Cyclin D1 and FGFR1 Amplification and of Carboplatin, Paclitaxel and Radiation in NSCLC.

Accessory male breast cancer (BC) is a rare entity and is associated with poor outcome. We report a 76-year-old patient who was diagnosed with concurrent accessory breast and primary lung cancer, both were positive for somatic BRCA-2 (E1593D) mutation. He received concurrent radiation and platinum-based chemotherapy for lung cancer with good response, but breast cancer progressed in about 8 months, and further progressed after single agent anastrozole in 10 months. Next Generation Sequencing (NGS) of breast cancer was also positive for CCND1 (Cyclin D1) and FGFR1 amplifications. Despite a poor molecular profile of breast cancer, and progression following platinum-based chemotherapy and anastrozole, he was successfully treated with the Cyclin-dependent kinase (CKD) 4/6 inhibitor palbociclib, estrogen-receptor down-regulator fulvestrant and luteinizing hormone-releasing hormone (LHRH) agonist leuprolide with the duration of response of 21 months which has exceeded duration of response to prior treatments. This case is of interest given FDA expanded the approval of palbociclib in combination with AI or fulvestrant for male patients with HR-positive, HER2-negative metastatic breast cancer in Apr. 2019 based on real-world data from electronic health records.