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Impact of molecular testing in advanced melanoma on outcomes in a tertiary cancer center and as reported in a publicly available database

Dimitrova, Maya; Kim, Min Jae; Osman, Iman; Jour, George
BACKGROUND:In patients with advanced melanoma (MM), genomic profiling may guide treatment decisions in the frontline setting and beyond as specific tumor mutations can be treated with targeted therapy (TT). The range of panel sizes used to identify targetable mutations (TM) can range from a few dozen to whole exome sequencing (WES). AIM/OBJECTIVE:We investigated the impact of panel size and mutation status on first-line treatment selection and outcomes in MM. METHODS AND RESULTS/RESULTS:We analyzed data for 1109 MM patients from three cohorts: 169 patients at NYULH and profiled with the 50 gene Ion Torrent panel (IT), 195 patients at MSKCC, profiled with the 400-gene MSK-IMPACT panel (MSK-I) and 745 patients at seven different sites profiled with WES. Data for cohorts 2 and 3 were extrapolated from the publicly available cBioPortal. Treatment information was available for 100%, 25%, and 0% of patients in cohort 1, 2, and 3, respectively. BRAF and NRAS were among the top five most commonly mutated genes in the IT and MSK-I, whereas for WES only BRAF was a top five mutation. There was no significant difference in OS for BRAF MUT patients treated with immune checkpoint inhibitors (ICI) vs TT in cohort 1 (P = .19), nor for BRAF MUT patients from cohort 1 treated with ICI vs those from cohort 2 treated with TT (P = .762). CONCLUSION/CONCLUSIONS:Public datasets provide population-level data; however, the heterogeneity of reported clinical information limits their value and calls for data standardization. Without evidence of clear clinical benefit of a larger panel size, there is a rationale for adopting smaller, more cost effective panels in MM.
PMID: 34109763
ISSN: 2573-8348
CID: 4900152

Chronic Immune-Related Adverse Events Following Adjuvant Anti-PD-1 Therapy for High-risk Resected Melanoma

Patrinely, J Randall; Johnson, Rebecca; Lawless, Aleigha R; Bhave, Prachi; Sawyers, Amelia; Dimitrova, Maya; Yeoh, Hui Ling; Palmeri, Marisa; Ye, Fei; Fan, Run; Davis, Elizabeth J; Rapisuwon, Suthee; Long, Georgina V; Haydon, Andrew; Osman, Iman; Mehnert, Janice M; Carlino, Matteo S; Sullivan, Ryan J; Menzies, Alexander M; Johnson, Douglas B
Importance/UNASSIGNED:Agents targeting programmed cell death 1 (PD-1)/PD ligand 1 (PD-L1) improve long-term survival across many advanced cancers and are now used as adjuvant therapy for resected stage III and IV melanomas. The incidence and spectrum of chronic immune-related adverse events (irAEs) have not been well defined. Objective/UNASSIGNED:To determine the incidence, time course, spectrum, and associations of chronic irAEs arising from adjuvant anti-PD-1 therapy. Design, Setting, and Participants/UNASSIGNED:This retrospective multicenter cohort study was conducted between 2015 and 2020 across 8 academic medical centers in the United States and Australia. Patients with stage III to IV melanomas treated with anti-PD-1 in the adjuvant setting were included. Main Outcomes and Measures/UNASSIGNED:Incidence, types, and time course of chronic irAEs (defined as irAEs persisting at least 12 weeks after therapy cessation). Results/UNASSIGNED:Among 387 patients, the median (range) age was 63 (17-88) years, and 235 (60.7%) were male. Of these patients, 267 (69.0%) had any acute irAE, defined as those arising during treatment with anti-PD-1, including 52 (19.5%) with grades 3 through 5 events; 1 patient each had fatal myocarditis and neurotoxicity. Chronic irAEs, defined as those that persisted beyond 12 weeks of anti-PD-1 discontinuation, developed in 167 (43.2%) patients, of which most (n = 161; 96.4%) were mild (grade 1 or 2) and most persisted until last available follow-up (n = 143; 85.6%). Endocrinopathies (73 of 88; 83.0%), arthritis (22 of 45; 48.9%), xerostomia (9 of 17; 52.9%), neurotoxicities (11 of 15; 73.3%), and ocular events (5 of 8; 62.5%) were particularly likely to become chronic. In contrast, irAEs affecting visceral organs (liver, colon, lungs, kidneys) had much lower rates of becoming chronic irAEs; for example, colitis became chronic in 6 of 44 (13.6%) cases, of which 4 of 6 (66.7%) resolved with prolonged follow-up. Age, gender, time of onset, and need for steroids were not associated with the likelihood of chronicity of irAEs. Conclusion and Relevance/UNASSIGNED:In this multicenter cohort study, chronic irAEs associated with anti-PD-1 therapy appear to be more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low grade. The risks of chronic irAEs should be integrated into treatment decision-making.
PMID: 33764387
ISSN: 2374-2445
CID: 4822812

A multicenter characterization of chronic toxicities following adjuvant anti-PD-1 therapy for high risk resected melanoma [Meeting Abstract]

Patrinely, J; Johnson, R; Lawless, A; Bhave, P; Sawyers, A; Dimitrova, M; Yeohc, H; Palmeri, M; Davis, E; Rapisuwon, S; Long, G; Haydon, A; Osman, I; Mehnert, J; Carlino, M; Sullivan, R; Menzies, A; Johnson, D
Background Anti-programmed death-1 (anti-PD-1) therapies have improved long-term survival across many advanced cancers. However, chronic immune-related adverse events (irAEs) are not well-defined. We sought to determine the incidence, time-course, spectrum, and predictors of chronic irAEs arising from adjuvant anti-PD-1. Methods In this retrospective cohort, we analyzed patients from 8 academic medical centers with stage III-IV melanoma treated with anti-PD-1 in the adjuvant setting. Acute and chronic (persisting at least 3 months after therapy cessation) irAEs were characterized by type, time-course, management, and incidence. Results Among 387 patients, most were male (60.7%) with a median age of 63 years, had cutaneous primaries (85.8%), BRAF/NRAS WT (51.2%), and resected stage IIIb (33.1%) or IIIc (39.5%) melanomas. Median overall survival and relapsefree survival (RFS) were not reached. 359 patients (93.0%) were alive at median follow-up of 529 days. Patients with acute (p<0.009) or chronic (p<0.001) irAEs had superior RFS compared with patients lacking irAEs. Treatment was discontinued for therapy completion (50.0%), irAEs (25.3%), and disease progression (20.9%). 267 patients (69.0%) had any acute irAE, including 19.5% (n=52) with grade 3-5 events. Acute irAEs were most commonly dermatitis/pruritis (25.8%), thyroiditis/hypothyroid (16.3%), arthralgias (10.6%), colitis/ diarrhea (9.8%) and required glucocorticoids in 109 patients (28.2%). Of these, 167 patients (43.2%) developed chronic irAEs; 82 (49.1%) were symptomatic, 55 (32.9%) required glucocorticoids, and most were grade 1-2 (96.4%). Endocrinopathies (73/88, 83.0%) arthritis (22/45, 48.9%), xerostomia (9/17, 52.9%), neurotoxicities (8/8, 100.0%), and ocular events (5/8, 63.0%) were likely to become chronic events. In contrast, colitis (6/44, 13.6%), hepatitis (4/25, 16.0%), pneumonitis (6/18, 33.3%) were less likely to become chronic. Overall, the most common chronic irAEs were hypothyroidism (14.0%), dermatitis/pruritis (6.6%) arthralgias (5.7%), adrenal insufficiency (3.1%), and xerostomia (2.3%). Age (p=0.67), gender (p=0.31), time of onset of acute irAEs (p=0.95), and initial need for glucocorticoids (p=0.15) were not associated with chronicity. Only 24 (14.4%) of chronic irAEs ultimately resolved during the median 529-day follow-up. In particular, endocrinopathies (100%) arthralgias (100%) ocular events (100%), xerostomia (88.9%), and cutaneous events (89.5%) had high rates of persistence at last follow-up. Conclusions Chronic irAEs to anti-PD-1 were more common than previously recognized and frequently persisted even with prolonged follow-up, although most were low-grade. The risks of chronic toxic effects should be integrated into treatment decision making
ISSN: 2051-1426
CID: 4885132

Colonic salvage with antiperistaltic cecorectal anastomosis [Case Report]

Jones, Douglas W; Dimitrova, Maya; Nandakumar, Govind
BACKGROUND:Following colon resection, the construction of a well-perfused, tension-free isoperistaltic anastomosis can be made difficult by multiple factors including prior abdominal surgery or compromised vascular supply. Here, we describe the technique of antiperistaltic cecorectal anastomosis as a method for preserving viable colon without compromising functional outcome. TECHNIQUE/METHODS:Following extensive colorectal resection, different techniques for isoperistaltic reconstruction using the cecum and ascending colon have been described, including the Deloyers procedure and limited isoperistaltic cecorectal anastomosis. However, these isoperistaltic reconstructions often require ligation of the middle colic and right colic arteries and/or sacrifice of viable distal colon to aid reconstruction. In complex situations that require preservation of normal vascular anatomy, an antiperistaltic cecorectal anastomosis can be constructed that maintains the orientation of the vascular pedicle. In addition to the preservation of the colonic arterial supply, a distinguishing feature of this technique is the substantial portion of antiperistaltic colon that is preserved and interposed to reestablish continuity. RESULTS:In a case where it was used, construction of an antiperistaltic cecorectal anastomosis was technically successful and led to a good functional outcome. CONCLUSION/CONCLUSIONS:Antiperistaltic cecorectal anastomosis should be considered as an option in colonic reconstruction for patients with extensive prior abdominal surgery or when complex anatomic issues require preservation of native vascular anatomy. In these situations, this technique offers several advantages over isoperistaltic reconstruction and may be the only option for reconstruction that uses the remaining cecum and colon.
PMID: 25585090
ISSN: 1530-0358
CID: 4995632