scholarly journals Real-World Data of Off-Label Drug Use in Patients with Actionable Genomic Alterations on Next-Generation Sequencing

2021 ◽  
Author(s):  
Gabriel Roman Souza ◽  
Ahmed Abdalla ◽  
Sukeshi Patel Arora ◽  
Daruka Mahadevan
Keyword(s):  
Next Generation Sequencing ◽  
Stable Disease ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Study Endpoint ◽  
Primary Study ◽  
Next Generation ◽  
Off Label ◽  
Generation Sequencing

Abstract We analyzed the outcomes of patients in our institution treated with off-label drugs targeting actionable genomic alteration based on next-generation sequencing when clinical trials were not available. Our study endpoint was objective tumor response or stable disease at 16 weeks or later after treatment initiation. Sixteen patients were included in this study, 8 were treated with immune checkpoint inhibitors targeting PD-L1 or TP53 mutations and 8 with other drugs. Tumors were analyzed based on PD-L1 expression, TP53 mutation, MSI, TMB, MMR status, and other targetable alterations. Of the 16 patients in the intention-to-treat group, no patients had an objective response after 16 weeks. Eleven patients met the primary study endpoint with stable disease, 8 in the immune checkpoint inhibitors group and 3 in the non-immune checkpoint inhibitors group. Using the log-rank test, the p-value for the difference between groups was 0.008. In this study with off-label drugs, immune checkpoint inhibitors targeting TP53 mutations or PD-L1 expression were superior to the other drugs. This suggests the possibility of off-label use of anti-cancer drugs based on next-generation sequencing to be beneficial for advanced cancer patients without other therapeutic options.

scholarly journals Next generation sequencing of PD-L1 for predicting response to immune checkpoint inhibitors

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Jeffrey M. Conroy ◽  
Sarabjot Pabla ◽  
Mary K. Nesline ◽  
Sean T. Glenn ◽  
Antonios Papanicolau-Sengos ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Next Generation ◽  
Generation Sequencing

scholarly journals CD274 (PD-L1) Copy Number Changes (Gain) & Response to Immune Checkpoint Blockade Therapy in Carcinomas of the Urinary Tract

2021 ◽  
pp. 1-6
Author(s):  
Sounak Gupta ◽  
Chad M. Vanderbilt ◽  
Yanming Zhang ◽  
Satish K. Tickoo ◽  
Samson W. Fine ◽  
...  
Keyword(s):  
Urinary Tract ◽  
Next Generation Sequencing ◽  
Protein Expression ◽  
Urothelial Carcinoma ◽  
Immune Checkpoint ◽  
Copy Number ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
L1 Protein ◽  
Generation Sequencing

BACKGROUND: Immune checkpoint inhibitors are an important therapeutic option for urothelial carcinoma, but durable responses are achieved in a minority of patients. Identifying pre-treatment biomarkers that may predict response to these therapies or who exhibit intrinsic resistance, is of paramount importance. OBJECTIVE: To explore the prevalence of PD-L1 copy number alteration in urothelial carcinoma and correlate with response to immune checkpoint inhibitors. METHODS: We analyzed a cohort of 1050 carcinomas of the bladder and upper urinary tract that underwent targeted next generation sequencing, prospectively. We assessed PD-L1 protein expression, copy number status (next generation sequencing/FISH), and detailed treatment response. RESULTS: We identified 9 tumors with PD-L1 amplification and 9 tumors with PD-L1 deletion. PD-L1 protein expression was the highest in PD-L1 amplified tumors. Of the 9 patients whose tumors harbored PD-L1 amplification, 6 received immunotherapy with 4 deriving clinical benefit, and two achieving durable response. Of the 9 patients whose tumors had PD-L1 copy number losses, 4 received immunotherapy with 3 experiencing disease progression. CONCLUSIONS: PD-L1 copy number alterations may serve as potential biomarkers of response to immunotherapy in urothelial carcinoma patients, if validated in larger cohorts.

scholarly journals Complexities of Next-Generation Sequencing in Solid Tumors: Case Studies

2020 ◽  
Vol 18 (9) ◽  
pp. 1150-1155
Author(s):  
Alexandra O. Sokolova ◽  
Brian H. Shirts ◽  
Eric Q. Konnick ◽  
Ginger J. Tsai ◽  
Bernardo H.L. Goulart ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Case Studies ◽  
Checkpoint Inhibitors ◽  
Hereditary Cancer Syndrome ◽  
Next Generation ◽  
Cancer Syndrome ◽  
Expert Review ◽  
Tumor Boards ◽  
Tumor Sequencing ◽  
Generation Sequencing

With the promise and potential of clinical next-generation sequencing for tumor and germline testing to impact treatment and outcomes of patients with cancer, there are also risks of oversimplification, misinterpretation, and missed opportunities. These issues risk limiting clinical benefit and, at worst, perpetuating false conclusions that could lead to inappropriate treatment selection, avoidable toxicity, and harm to patients. This report presents 5 case studies illustrating challenges and opportunities in clinical next-generation sequencing interpretation and clinical application in solid tumor oncologic care. First is a case that dissects the origin of an ATM mutation as originating from a hematopoietic clone rather than the tumor. Second is a case illustrating the potential for tumor sequencing to suggest germline variants associated with a hereditary cancer syndrome. Third are 2 cases showing the potential for variant reclassification of a germline variant of uncertain significance when considered alongside family history and tumor sequencing results. Finally, we describe a case illustrating challenges with using microsatellite instability for predicting tumor response to immune checkpoint inhibitors. The common theme of the case studies is the importance of examining clinical context alongside expert review and interpretation, which together highlight an expanding role for contextual examination and multidisciplinary expert review through molecular tumor boards.

Immunotherapy in Gynecologic Cancers: What We Know Now and Where We Are Headed

2019 ◽  
pp. e126-e140 ◽  
Author(s):  
Kimberly Levinson ◽  
Oliver Dorigo ◽  
Krista Rubin ◽  
Kathleen Moore
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Gynecologic Cancer ◽  
Hematologic Malignancies ◽  
Next Generation ◽  
Gynecologic Cancers ◽  
Clinical Benefits

Immunotherapy, mainly in the form of immune checkpoint inhibitors (ICIs), has been transformative in both solid tumor and hematologic malignancies. Patients with previously terminal illnesses have experienced profound responses of great durability with these agents, fueling excitement among patients and providers regarding their use. Unfortunately, the gains seen in some solid tumors have not been replicated in a large percentage of patients with gynecologic cancer. This review focuses on the clinical benefits seen to date, toxicities and management when using ICIs, ways to improve prediction of who should receive immunotherapy, and a discussion of next-generation immunotherapy with cellular therapeutics and how these might relate to gynecologic cancers.

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