Purpose Combination PD-1/CTLA-4 blockade and dual BRAF/MEK inhibition have each shown significant clinical benefit in patients with BRAFV600 mutant metastatic melanoma, leading to broad regulatory approval. Little prospective data exist to guide the choice of either initial therapy or treatment sequence in this population. This study was conducted to determine which initial treatment or treatment sequence produced the best efficacy. Methods In a phase III trial, patients with treatment-naïve BRAFV600-mutant metastatic melanoma were randomized to receive either combination nivolumab/ipilimumab (Arm A) or dabrafenib/trametinib (Arm B) in Step 1, and at disease progression were enrolled in Step 2 receiving the alternate therapy, dabrafenib/trametinib (Arm C) or nivolumab/ipilimumab (Arm D). The primary endpoint was 2-year overall survival. Secondary endpoints were 3-year overall survival, objective response rate, response duration, progression-free survival, crossover feasibility and safety. Results 265 patients were enrolled with 73 going onto Step 2 (27 Arm C, 46 Arm D). The study was stopped early by the independent DSMC due to a clinically significant endpoint being achieved. The 2-year overall survival for those starting on Arm A was 71.8% (62.5, 79.1%) and Arm B 51.5% (41.7, 60.4%) (log-rank p=0.010). Step 1 progression-free survival favored Arm A (p=0.054). Objective response rates were: Arm A:46.0%; Arm B:43.0%; Arm C:47.8%; Arm D:29.6%. Median duration of response was not reached for Arm A and 12.7 months for Arm B (p<0.001). Crossover occurred in 52% of patients with documented disease progression. Grade >3 toxicities occurred with similar frequency between arms and regimen toxicity profiles were as anticipated. Conclusion Combination nivolumab/ipilimumab followed by BRAF and MEK inhibitor therapy, if necessary, should be the preferred treatment sequence for a large majority of patients.
SummaryB-cell lymphoma, unclassifiable (B-UCL), with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma, is a poorly characterized entity. Therefore, we investigated cases of B-UCL treated by the Nebraska Lymphoma Study Group (NLSG). We searched the NLSG registry for years 1985-2010 for cases of B-UCL. Immunohistochemical stains and fluorescence in situ hybridization studies for MYC, BCL2 and BCL6 gene rearrangements were performed. Among the 39 cases studied, 54% were male and 46% were female, with a median age of 69 years. The majority of patients presented with advanced-stage disease (62%) and had high (3-5) International Prognostic Index (IPI) scores (54%). The median overall survival (OS) was only 9 months and the 5-year OS was 30%. Patients with low IPI scores (0-2) had a better survival than those with high scores (3-5). The cases were genetically heterogeneous and included 11 'double-hit' lymphomas with rearrangements of both MYC and BCL2 or BCL6. None of the immunohistochemical or genetic features was predictive of survival. This B-cell lymphoma is a morphologically-recognizable entity with a spectrum of genetic abnormalities. New and better treatments are needed for this aggressive lymphoma.
Upper urinary tract tumors develop at a younger age and are more likely to be in the ureter with an almost equal gender ratio in patients with Lynch syndrome. It has high grade potential similar to that in the general population.
Dermatofibrosarcoma Protuberans (DFSP) is a rare skin tumor, characterized by frequent local recurrence but is seldom metastatic. It is histologically characterized by storiform arrangement of spindle cells. Cytogenetically, most tumors are characterized by translocation 17:22 leading to overexpression of tyrosine kinase PDGFB which can be targeted with tyrosine kinase inhibitor, Imatinib. We describe the first case of unresectable pancreatic metastases from DFSP treated with neoadjuvant Imatinib and subsequently R0 metastectomy. Additionally, a comprehensive systematic review of DFSP pancreatic metastases and the current published data on the use of Imatinib in DFSP is summarized.
TPS597 Background: Albumin-bound ( nab)-sirolimus, a novel mTOR inhibitor (mTORi) that utilizes nanoparticle technology to preferentially target tumors, is approved in the US for the treatment of adults with malignant PEComa. In an exploratory analysis of the AMPECT registrational trial of nab-sirolimus in advanced malignant PEComa (NCT02494570), 8/9 (89%) and 1/5 (20%) patients with TSC1 and TSC2 inactivating alterations, respectively, had confirmed response (Wagner, J Clin Oncol. 2021). Importantly, both TSC1 and TSC2 alterations have been observed in patients with various gastrointestinal cancers (Table). Overall, most treatment-related adverse events (TRAEs) in AMPECT were grade 1/2 and manageable for long-term treatment; no grade ≥4 TRAEs occurred. Methods: PRECISION I (NCT05103358) is a phase 2, open-label, multi-institutional basket trial evaluating efficacy and safety of nab-sirolimus in patients with alterations in TSC1 (Arm A) and TSC2 (Arm B). Patients ≥12 years old with malignant solid tumors harboring pathogenic inactivating alterations in TSC1 or TSC2 (confirmed by central review of next-generation sequencing reports) who have progressed on standard therapies and are mTORi-naïve are eligible. nab-Sirolimus 100 mg/m2 will be administered weekly as an intravenous infusion over 30 minutes on Days 1 and 8 of each 21-day cycle. The primary endpoint is overall response rate determined by independent review using RECIST v1.1; other endpoints include duration of response, disease control rate, time to response progression-free survival by independent radiographic review, overall survival, patient-reported quality of life, and safety. Enrollment is ongoing. The most frequent tumor types expected in this tissue-agnostic trial are bladder, hepatobiliary, endometrial, soft tissue sarcoma, ovarian, and esophagogastric based on the prevalence of TSC1 or TSC2 alterations (Table). Clinical trial information: NCT05103358 . [Table: see text]
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