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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Real-world data of off-label drug use in patients with actionable genomic alterations on next-generation sequencing
Gabriel Roman Souza1, Ahmed Abdalla2, Sukeshi Arora2
1Division of Hematology and Medical Oncology, Mays Cancer Center, University of Texas Health San Antonio MD Anderson Cancer Center, Texas, USA. romansouza@uthscsa.edu.
Abstract:
Introduction We analyzed the outcomes of patients with advanced cancers in our institution treated with off-label drugs targeting actionable genomic alteration based on next-generation sequencing who did not qualify for clinical trials. Purposes Our study endpoint was objective tumor response or stable disease at 16 weeks or later after treatment initiation. Methods Sixteen patients were included, 8 treated with immune checkpoint inhibitors targeting PD-L1 expression 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. Results 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. Conclusions 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.
Insights
Off-label immune checkpoint inhibitors targeting TP53 mutations or PD-L1 expression showed superior efficacy in advanced cancer patients lacking clinical trial options. This approach offers potential benefits for patients with limited therapeutic choices.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Advanced cancer patients often lack treatment options, especially those ineligible for clinical trials.
- Next-generation sequencing (NGS) identifies actionable genomic alterations for targeted therapies.
- Off-label drug use is considered when standard treatments are exhausted.
Purpose of the Study:
- To evaluate the efficacy of off-label targeted drugs in advanced cancer patients.
- To compare immune checkpoint inhibitors (ICIs) with other targeted agents.
- To assess tumor response or stable disease at 16 weeks as the primary endpoint.
Main Methods:
- Retrospective analysis of 16 advanced cancer patients treated with off-label drugs.
- Tumor profiling included PD-L1 expression, TP53 mutations, MSI, TMB, and MMR status.
- Patients received either ICIs targeting PD-L1 or TP53, or other targeted drugs.
Main Results:
- No objective tumor response was observed in the intention-to-treat group after 16 weeks.
- Eleven patients (68.75%) achieved stable disease, meeting the primary endpoint.
- Stable disease was more frequent in the ICI group (8/8) compared to the non-ICI group (3/8), with a p-value of 0.008.
Conclusions:
- Off-label ICIs targeting TP53 mutations or PD-L1 expression demonstrated superior outcomes compared to other off-label drugs.
- NGS-guided off-label targeted therapy may benefit advanced cancer patients without other options.
- This strategy warrants further investigation for broader clinical application.
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