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Real-world application of tumor mutational burden-high (TMB-high) and microsatellite instability (MSI) confirms their utility as immunotherapy biomarkers
Palmeri, M; Mehnert, J; Silk, A W; Jabbour, S K; Ganesan, S; Popli, P; Riedlinger, G; Stephenson, R; de Meritens, A B; Leiser, A; Mayer, T; Chan, N; Spencer, K; Girda, E; Malhotra, J; Chan, T; Subbiah, V; Groisberg, R
INTRODUCTION/BACKGROUND:Microsatellite instability (MSI) testing and tumor mutational burden (TMB) are genomic biomarkers used to identify patients who are likely to benefit from immune checkpoint inhibitors. Pembrolizumab was recently approved by the Food and Drug Administration for use in TMB-high (TMB-H) tumors, regardless of histology, based on KEYNOTE-158. The primary objective of this retrospective study was real-world applicability and use of immunotherapy in TMB/MSI-high patients to lend credence to and refine this biomarker. METHODS:Charts of patients with advanced solid tumors who had MSI/TMB status determined by next generation sequencing (NGS) (FoundationOne CDx) were reviewed. Demographics, diagnosis, treatment history, and overall response rate (ORR) were abstracted. Progression-free survival (PFS) was determined from Kaplan-Meier curves. PFS1 (chemotherapy PFS) and PFS2 (immunotherapy PFS) were determined for patients who received immunotherapy after progressing on chemotherapy. The median PFS2/PFS1 ratio was recorded. RESULTS:MSI-high or TMB-H [≥20 mutations per megabase (mut/MB)] was detected in 157 adults with a total of 27 distinct tumor histologies. Median turnaround time for NGS was 73 days. ORR for most recent chemotherapy was 34.4%. ORR for immunotherapy was 55.9%. Median PFS for patients who received chemotherapy versus immunotherapy was 6.75 months (95% confidence interval, 3.9-10.9 months) and 24.2 months (95% confidence interval, 9.6 months to not reached), respectively (P = 0.042). Median PFS2/PFS1 ratio was 4.7 in favor of immunotherapy. CONCLUSION/CONCLUSIONS:This real-world study reinforces the use of TMB as a predictive biomarker. Barriers exist to the timely implementation of NGS-based biomarkers and more data are needed to raise awareness about the clinical utility of TMB. Clinicians should consider treating TMB-H patients with immunotherapy regardless of their histology.
PMCID:8717431
PMID: 34953399
ISSN: 2059-7029
CID: 5109232
Prescreening to Increase Therapeutic Oncology Trial Enrollment at the Largest Public Hospital in the United States
Wu, Jennifer; Yakubov, Amin; Abdul-Hay, Maher; Love, Erica; Kroening, Gianna; Cohen, Deirdre; Spalink, Christy; Joshi, Ankeeta; Balar, Arjun; Joseph, Kathie-Ann; Ravenell, Joseph; Mehnert, Janice
PURPOSE/UNASSIGNED:The recruitment of underserved patients into therapeutic oncology trials is imperative. The National Institutes of Health mandates the inclusion of minorities in clinical research, although their participation remains under-represented. Institutions have used data mining to match patients to clinical trials. In a public health care system, such expensive tools are unavailable. METHODS/UNASSIGNED:The NYU Clinical Trials Office implemented a quality improvement program at Bellevue Hospital Cancer Center to increase therapeutic trial enrollment. Patients are screened through the electronic medical record, tumor board conferences, and the cancer registry. Our analysis evaluated two variables: number of patients identified and those enrolled into clinical trials. RESULTS/UNASSIGNED:Two years before the program, there were 31 patients enrolled. For a period of 24 months (July 2017 to July 2019), we identified 255 patients, of whom 143 (56.1%) were enrolled. Of those enrolled, 121 (84.6%) received treatment, and 22 (15%) were screen failures. Fifty-five (38.5%) were referred to NYU Perlmutter Cancer Center for therapy. Of the total enrollees, 64% were female, 56% were non-White, and overall median age was 55 years (range: 33-88 years). Our participants spoke 16 different languages, and 57% were non-English-speaking. We enrolled patients into eight different disease categories, with 38% recruited to breast cancer trials. Eighty-three percent of our patients reside in low-income areas, with 62% in both low-income and Health Professional Shortage Areas. CONCLUSION/UNASSIGNED:Prescreening at Bellevue has led to a 4.6-fold increase in patient enrollment to clinical trials. Future research into using prescreening programs at public institutions may improve access to clinical trials for underserved populations.
PMID: 34748371
ISSN: 2688-1535
CID: 5050262
Use of tumor cell lysate to develop peptide vaccine targeting cancer-testis antigens [Comment]
Malhotra, Jyoti; Mehnert, Janice M
PMID: 35004237
ISSN: 2218-6751
CID: 5116052
Preexisting immune-mediated inflammatory disease is associated with improved survival and increased toxicity in melanoma patients who receive immune checkpoint inhibitors
Gulati, Nicholas; Celen, Arda; Johannet, Paul; Mehnert, Janice M; Weber, Jeffrey; Krogsgaard, Michelle; Osman, Iman; Zhong, Judy
BACKGROUND:Immune-related adverse events (irAEs) are common, clinically significant autoinflammatory toxicities observed with immune checkpoint inhibitors (ICI). Preexisting immune-mediated inflammatory disease (pre-IMID) is considered a relative contraindication to ICI due to the risk of inciting flares. Improved understanding of the risks and benefits of treating pre-IMID patients with ICI is needed. METHODS:We studied melanoma patients treated with ICI and enrolled in a prospective clinicopathological database. We compiled a list of 23 immune-mediated inflammatory diseases and evaluated their presence prior to ICI. We tested the associations between pre-IMID and progression-free survival (PFS), overall survival (OS), and irAEs. RESULTS:In total, 483 melanoma patients were included in the study; 74 had pre-IMID and 409 did not. In patients receiving ICI as a standard of care (SoC), pre-IMID was significantly associated with irAEs (p = 0.04) as well as improved PFS (p = 0.024) and OS (p = 0.007). There was no significant association between pre-IMID and irAEs (p = 0.54), PFS (p = 0.197), or OS (p = 0.746) in patients treated through a clinical trial. Pre-IMID was significantly associated with improved OS in females (p = 0.012), but not in males (p = 0.35). CONCLUSIONS:The dichotomy of the impact of pre-IMID on survival and irAEs in SoC versus clinical trial patients may reflect the inherit selection bias in patients accrued in clinical trials. Future mechanistic work is required to better understand the differences in outcomes between female and male pre-IMID patients. Our data challenge the notion that clinicians should avoid ICI in pre-IMID patients, although close monitoring and prospective clinical trials evaluating ICI in this population are warranted.
PMCID:8559502
PMID: 34647433
ISSN: 2045-7634
CID: 5062002
Anuric Kidney Failure in a Patient With Metastatic Melanoma
Kolla, Avani M; Jour, George; Mehnert, Janice M
PMID: 34410310
ISSN: 2374-2445
CID: 5066882
Publisher Correction: Autophagy promotes growth of tumors with high mutational burden by inhibiting a T-cell immune response
Poillet-Perez, Laura; Sharp, Daniel W; Yang, Yang; Laddha, Saurabh V; Ibrahim, Maria; Bommareddy, Praveen K; Hu, Zhixian Sherrie; Vieth, Joshua; Haas, Michael; Bosenberg, Marcus W; Rabinowitz, Joshua D; Cao, Jian; Guan, Jun-Lin; Ganesan, Shridar; Chan, Chang S; Mehnert, Janice M; Lattime, Edmund C; White, Eileen
PMID: 35121870
ISSN: 2662-1347
CID: 5709952
The Association of Radiation Therapy and Chemotherapy on Overall Survival in Merkel Cell Carcinoma: A Population-Based Analysis
Vayntraub, Aleksander; Tayeb, Nadine; Squires, Bryan; Mehnert, Janice M; Hassan Ii, Quais; Sebastian, Nikhil T; Deryaniyagala, Rohan; Quinn, Thomas J
Purpose/objective(s) Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous neoplasm traditionally managed with surgical resection followed by radiotherapy (RT). With the recent approval of checkpoint inhibitors, chemotherapy is less commonly utilized. We analyzed the impact of RT and chemotherapy on overall survival (OS) in patients with MCC using Surveillance, Epidemiology, and End Results (SEER), a population-level database. Materials and methods We performed retrospective analyses on SEER 18 Custom Data registries for MCC (ICD-0-3 8247). Data from 1980 to 2016 was queried for analysis, and an initial list of 9,792 patients was populated (ICD: C00, C07.9, C44, C80.9). Selection for cases with chemotherapy and RT status, single primary tumor, primary tumor location and surgery treatment type yielded 5,002 cases for analysis. Baseline characteristics were compared with Chi-square or Mann-Whitney U test. Univariate and multivariable analysis using Kaplan-Meier and Cox proportional hazards regression modeling were performed. Propensity-score matched analysis with inverse probability of treatment weighting (IPTW) was used to account for indication bias. Results Median follow-up time was 178 months (68 to 217 months). Independent prognostic factors positively correlated with increased OS, for both unadjusted Multivariate analysis and IPTW adjusted MVA were age, male sex, year of diagnosis, stage, RT status, and chemotherapy status. On adjusted MVA, use of chemotherapy was associated with worse OS (hazard ratio: 1.22 [95% CI 1.1-1.35], p<0.001), whereas RT was associated with improved OS (HR:0.9 [95% CI, 0.83-0.97], p=0.008). Conclusions The current study demonstrates that RT is associated with improved survival for patients with MCC. Chemotherapy was associated with worse OS. This supports the recent clinical shift towards immune checkpoints inhibitors as standard of care in the metastatic setting, and promising trials in the adjuvant and advanced settings.
PMCID:8545516
PMID: 34722054
ISSN: 2168-8184
CID: 5037782
Complete response of brainstem metastasis in BRAF-mutated melanoma without stereotactic radiosurgery after initiation of encorafenib and binimetinib
Khullar, Karishma; Hanft, Simon; Mehnert, Janice M; Weiner, Joseph P
Metastatic melanoma is often accompanied by the development of brain metastases, at presentation or during the course of therapy. Local therapies such as surgery and radiation have been considered standard treatments for intracranial disease. However, the emergence of systemic therapies has been changing the treatment paradigm for the management of brain metastases. In patients with BRAF-mutated melanoma, combined BRAF and MEK inhibition has been found to elicit significant clinical responses. Patients who develop resistance to MAP kinase (MAPK) targeted therapy can achieve significant responses upon rechallenge. In this case, a 68-year-old woman with metastatic melanoma who had received multiple treatment courses including combination immunotherapy and combination MAPK-targeted therapy presented with a brainstem metastasis and demonstrated a complete response upon initiation of encorafenib and binimetinib, thereby obviating the need for stereotactic radiosurgery.
PMID: 34054058
ISSN: 1473-5636
CID: 4890802
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
Montelukast in hospitalized patients diagnosed with COVID-19
Khan, Ahsan R; Misdary, Christian; Yegya-Raman, Nikhil; Kim, Sinae; Narayanan, Navaneeth; Siddiqui, Sheraz; Salgame, Padmini; Radbel, Jared; Groote, Frank De; Michel, Carl; Mehnert, Janice; Hernandez, Caleb; Braciale, Thomas; Malhotra, Jyoti; Gentile, Michael A; Jabbour, Salma K
OBJECTIVE/UNASSIGNED:Several therapeutic agents have been assessed for the treatment of COVID-19, but few approaches have been proven efficacious. Because leukotriene receptor antagonists, such as montelukast have been shown to reduce both cytokine release and lung inflammation in preclinical models of viral influenza and acute respiratory distress syndrome, we hypothesized that therapy with montelukast could be used to treat COVID-19. The objective of this study was to determine if montelukast treatment would reduce the rate of clinical deterioration as measured by the COVID-19 Ordinal Scale. METHODS/UNASSIGNED:We performed a retrospective analysis of COVID-19 confirmed hospitalized patients treated with or without montelukast. We used "clinical deterioration" as the primary endpoint, a binary outcome defined as any increase in the Ordinal Scale value from Day 1 to Day 3 of the hospital stay, as these data were uniformly available for all admitted patients before hospital discharge. Rates of clinical deterioration between the montelukast and non-montelukast groups were compared using the Fisher's exact test. Univariate logistic regression was also used to assess the association between montelukast use and clinical deterioration. A total of 92 patients were analyzed, 30 who received montelukast at the discretion of the treating physician and 62 patients who did not receive montelukast. RESULTS/UNASSIGNED: = 0.022). Our findings suggest that montelukast associates with a reduction in clinical deterioration for COVID-19 confirmed patients as measured on the COVID-19 Ordinal Scale. CONCLUSIONS/UNASSIGNED:Hospitalized COVID-19 patients treated with montelukast had fewer events of clinical deterioration, indicating that this treatment may have clinical activity. While this retrospective study highlights a potential pathway for COVID-19 treatment, this hypothesis requires further study by prospective studies.
PMCID:7938648
PMID: 33577360
ISSN: 1532-4303
CID: 4829642