Faculty Collaboration Database

Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat Med 2019 May;25(5):744-750

Date

04/24/2019

Pubmed ID

31011206

Pubmed Central ID

PMC6553618

DOI

10.1038/s41591-019-0407-5

Scopus ID

2-s2.0-85064759962 (requires institutional sign-in at Scopus site)   427 Citations

Abstract

Cancer treatments have evolved from indiscriminate cytotoxic agents to selective genome- and immune-targeted drugs that have transformed the outcomes of some malignancies¹. Tumor complexity and heterogeneity suggest that the 'precision medicine' paradigm of cancer therapy requires treatment to be personalized to the individual patient^2-6. To date, precision oncology trials have been based on molecular matching with predetermined monotherapies^7-14. Several of these trials have been hindered by very low matching rates, often in the 5-10% range¹⁵, and low response rates. Low matching rates may be due to the use of limited gene panels, restrictive molecular matching algorithms, lack of drug availability, or the deterioration and death of end-stage patients before therapy can be implemented. We hypothesized that personalized treatment with combination therapies would improve outcomes in patients with refractory malignancies. As a first test of this concept, we implemented a cross-institutional prospective study (I-PREDICT, NCT02534675 ) that used tumor DNA sequencing and timely recommendations for individualized treatment with combination therapies. We found that administration of customized multidrug regimens was feasible, with 49% of consented patients receiving personalized treatment. Targeting of a larger fraction of identified molecular alterations, yielding a higher 'matching score', was correlated with significantly improved disease control rates, as well as longer progression-free and overall survival rates, compared to targeting of fewer somatic alterations. Our findings suggest that the current clinical trial paradigm for precision oncology, which pairs one driver mutation with one drug, may be optimized by treating molecularly complex and heterogeneous cancers with combinations of customized agents.

Author List

Sicklick JK, Kato S, Okamura R, Schwaederle M, Hahn ME, Williams CB, De P, Krie A, Piccioni DE, Miller VA, Ross JS, Benson A, Webster J, Stephens PJ, Lee JJ, Fanta PT, Lippman SM, Leyland-Jones B, Kurzrock R

Author

Razelle Kurzrock MD Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Combined Modality Therapy
Female
Gene Expression Profiling
High-Throughput Nucleotide Sequencing
Humans
Male
Middle Aged
Molecular Targeted Therapy
Neoplasms
Precision Medicine
Prospective Studies
Young Adult