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 patient2,3,4,5,6. To date, precision oncology trials have been based on molecular matching with predetermined monotherapies7,8,9,10,11,12,13,14. 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.
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We thank J. Wrolstad, M. Scur, and J. Porter for their critical roles in clinical trial and data management, L. Marquez for medication acquisition, D. Sandler, C. M. Tang, H. Yoon, M. Yerba and S. Silverman for assistance with manuscript preparation, T. Reya for her critical review of the manuscript, and most importantly, the patients and their families. This work was supported in part by Foundation Medicine, Inc. (J.K.S., R.O., B.L.-J., R.K.), as well as the Joan and Irwin Jacobs Philanthropic Fund (R.K.), the Jon Schneider Memorial Cancer Research Fund (J.K.S., P.T.F.), and National Institutes of Health (NIH) grant nos. P30CA023100 (J.K.S., S.M.L., R.K.) and P30CA016672 (J.J.L.). The authors also acknowledge the support of NIH grant nos. K08CA168999 and R21CA192072, as well as Pedal the Cause, The David Foundation, and Kristen Ann Carr Fund (J.K.S.).
Extended Data Fig. 1 Consolidated Standards of Reporting Trials (CONSORT) diagram, which includes the 149 patients that consented to I-PREDICT.
*Treated evaluable patients includes patients who received >10 d of treatment for drugs given on a daily basis (generally drugs given by mouth) or at least two doses of a drug normally given every two weeks or more frequently (the latter generally being intravenous drugs). Only patients whose treatment was reviewed and validated by data analysis lockdown are included. **One patient had inadequate tissue for NGS and declined biopsy; he was later reenrolled after he agreed to undergo biopsy. One treated patient who initially was believed to have prior therapy was found, after data lockdown analysis, to have not received the prior regimen.
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Nature Medicine (2019)
Nature Reviews Clinical Oncology (2019)