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Patient-Derived Tumor Explants As a "Live" Preclinical Platform for Predicting Drug Resistance in Patients
Published on: February 7, 2021
Pan-cancer molecular tumor board experience with biomarker-driven precision immunotherapy
Bryan H Louie1, Shumei Kato2, Ki Hwan Kim3
1Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, UC San Diego Moores Cancer Center, La Jolla, CA, USA. b1louie@health.ucsd.edu.
Abstract:
Despite remarkable responses to immune checkpoint blockade (ICB) in some advanced cancers, most patients do not benefit, perhaps due to the complexity of tumor/immune/genome interactions. We implemented a multidisciplinary Molecular Tumor Board (MTB) that reviewed multi-omic cancer characteristics to develop N-of-One therapies for patients in the pan-cancer, advanced, refractory setting. This study evaluates the experience of 80 patients who were presented to the MTB and received a treatment regimen that included ICB. Overall, 60/80 patients (75%) who received ICB following MTB discussion had a high degree of matching between tumor molecular characteristics, including ICB biomarkers (reflected by a high Matching Score (≥50%)) and therapy administered. Patients with high versus low Matching Score experienced significantly longer median progression-free survival (6.4 vs. 3.0 months; p = 0.011) and median overall survival (15.3 vs. 4.7 months; p = 0.014) and higher clinical benefit rates (stable disease ≥6 months/partial response/complete response) (53% vs. 21%, p = 0.019). Although most patients (52/80 (65%)) received a personalized combination therapy (e.g., targeted, hormonal, chemotherapy, or a second immunotherapy agent), administering >1 drug was not associated with outcome. Only degree of matching and age, but no other variables, including individual biomarkers (e.g., microsatellite status, tumor mutational burden, or PD-L1 status), were independently correlated with outcome. In the pan-cancer setting, the MTB facilitated a precision medicine strategy to match therapeutic regimens that included ICB alone or combined with matched targeted drugs to patients with advanced malignancy, which was associated with improved clinical outcomes.
Insights
A Molecular Tumor Board (MTB) improved outcomes for advanced cancer patients receiving immune checkpoint blockade (ICB) by matching therapies to tumor molecular profiles. Higher matching scores correlated with significantly longer progression-free and overall survival, demonstrating precision medicine
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- Most advanced cancer patients do not benefit from immune checkpoint blockade (ICB).
- Tumor/immune/genome interactions are complex and may limit ICB efficacy.
- N-of-One therapies aim to personalize treatment for refractory cancers.
Purpose of the Study:
- To evaluate the impact of a multidisciplinary Molecular Tumor Board (MTB) on N-of-One therapy selection and patient outcomes.
- To assess the correlation between molecular profile matching and clinical benefit in advanced cancer patients receiving ICB.
- To identify factors associated with improved survival in patients treated with precision medicine strategies.
Main Methods:
- Implementation of a multidisciplinary MTB to review multi-omic cancer data.
- Selection of 80 advanced, refractory cancer patients who received ICB based on MTB recommendations.
- Analysis of the degree of matching between tumor molecular characteristics and administered therapy (Matching Score).
- Comparison of progression-free survival (PFS), overall survival (OS), and clinical benefit rates (CBR) between high and low Matching Score groups.
Main Results:
- 75% of patients had a high degree of matching (≥50%) between tumor molecular profiles and therapy.
- Patients with high Matching Scores had significantly longer median PFS (6.4 vs. 3.0 months) and OS (15.3 vs. 4.7 months).
- Higher clinical benefit rates were observed in the high Matching Score group (53% vs. 21%).
- Only the degree of matching and patient age independently correlated with outcomes; individual biomarkers did not.
Conclusions:
- A precision medicine strategy using an MTB to match therapies, including ICB, to molecular profiles in advanced cancers is associated with improved clinical outcomes.
- The degree of molecular matching, not the number of drugs or specific biomarkers, is a key predictor of treatment success.
- MTBs can facilitate personalized treatment approaches for refractory cancers, enhancing efficacy of therapies like ICB.
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