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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
Personalized matched targeted therapy in advanced pancreatic cancer: a pilot cohort analysis
Justin Shaya1,2, Shumei Kato3,4, Jacob J Adashek5
1Division of Hematology and Oncology, Department of Medicine, University of California San Diego Moores Cancer Center, La Jolla, CA, USA.
Abstract:
Despite progress, 2-year pancreatic cancer survival remains dismal. We evaluated a biomarker-driven, combination/N-of-one strategy in 18 patients (advanced/metastatic pancreatic cancer) (from Molecular Tumor Board). Targeted agents administered/patient = 2.5 (median) (range, 1-4); first-line therapy (N = 5); second line, (N = 13). Comparing patients (high versus low degrees of matching) (matching score ≥50% versus <50%; reflecting number of alterations matched to targeted agents divided by number of pathogenic alterations), survival was significantly longer (hazard ratio [HR] 0.24 (95% confidence interval [CI], 0.078-0.76, P = 0.016); clinical benefit rates (CBR) (stable disease ≥6 months/partial/complete response) trended higher (45.5 vs 0.0%, P = 0.10); progression-free survival, HR, 95% CI, 0.36 (0.12-1.10) (p = 0.075). First versus ≥2nd-line therapy had higher CBRs (80.0 vs 7.7%, P = 0.008). No grade 3-4 toxicities occurred. The longest responder achieved partial remission (17.5 months) by co-targeting MEK and CDK4/6 alterations (chemotherapy-free). Therefore, genomically matched targeted agent combinations were active in these advanced pancreatic cancers. Larger prospective trials are warranted.
Insights
Biomarker-driven targeted therapy improved survival for advanced pancreatic cancer patients. Genomically matched combinations showed significant survival benefits and low toxicity, warranting further trials.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Pancreatic cancer survival rates remain low despite advancements.
- Targeted therapies offer potential but require precise patient selection.
Purpose of the Study:
- To evaluate a biomarker-driven, combination/N-of-one targeted therapy strategy for advanced pancreatic cancer.
- To assess the efficacy and safety of matching targeted agents to genomic alterations.
Main Methods:
- Retrospective analysis of 18 advanced/metastatic pancreatic cancer patients treated via Molecular Tumor Board.
- Patients received a median of 2.5 targeted agents based on genomic profiling.
- Comparison of outcomes based on the degree of genomic matching (≥50% vs <50%).
Main Results:
- Higher genomic matching scores correlated with significantly longer survival (HR 0.24, P=0.016).
- Clinical benefit rates trended higher in the high-matching group (45.5% vs 0.0%, P=0.10).
- First-line therapy demonstrated superior clinical benefit rates (80.0% vs 7.7%, P=0.008) with no grade 3-4 toxicities.
Conclusions:
- Genomically matched targeted agent combinations are active and well-tolerated in advanced pancreatic cancer.
- This precision medicine approach, including chemotherapy-free options, shows promise.
- Larger prospective trials are necessary to confirm these findings.
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