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Investigation of Profile-Related Evidence Determining Individualized Cancer Therapy (I-PREDICT) N-of-1 Precision
Jason K Sicklick1,2,3, Daisuke Nishizaki3,4, Hirotaka Miyashita5
1Division of Surgical Oncology, Department of Surgery, UC San Diego, San Diego, CA.
Purpose:
Malignancies have complex and distinct molecular profiles that may not segregate by tumor type. However, most precision oncology treatments are matched to a single biomarker. We aimed to optimize therapy for advanced cancers using individually dosed drug regimens customized to cotarget multiple molecular alterations.
Methods:
Investigation of Profile-Related Evidence Determining Individualized Cancer Therapy (I-PREDICT; NCT02534675) is a prospective, investigator-initiated, multidepartment/pan-cancer trial for aggressive advanced/metastatic malignancies. Patients had tissue and/or blood next-generation sequencing (NGS; Foundation Medicine). A molecular tumor board made suggestions. Degree of biomarker matching to drugs given was calculated by a matching score (MS; broadly, number of pathogenic alterations targeted divided by total pathogenic alterations).
Results:
Overall, 210 evaluable patients (n = 456 consented) received ≥1 US Food and Drug Administration-approved drug (mostly off label) after NGS. Median number of pathogenic alterations/tumor was five (range, 0-20); approximately 95% of patients had unique molecular landscapes. Consistent with I-PREDICT's objective to optimize/tailor treatment for each patient, we administered 157 different regimens (including 103 personalized combinations without established safety/dosing data). For previously unstudied combinations, starting doses were reduced and titrated to tolerance (intrapatient dose-finding); only 6.5% experienced Grade 3/4 drug-related toxicities (v 15.5% of those receiving established regimens). Higher disease control rate (stable disease ≥6 months/objective response), and longer progression-free survival and overall survival correlated significantly/independently/linearly with greater degrees of drug matching to alterations (higher MS), but did not vary by drug number or dosages.
Conclusion:
The I-PREDICT strategy of maximizing personalized biomarker matching with individually dosed customized drug combinations enabled safe and active N-of-1 matched treatment, including regimens previously unstudied in Phase I trials. I-PREDICT represents a blueprint for a new personalized precision oncology paradigm, which merits validation via additional prospective trials.
Insights
Precision oncology can be optimized by tailoring drug regimens to target multiple molecular alterations in advanced cancers. This approach, using customized combinations, demonstrated safety and improved outcomes in the I-PREDICT trial.
Area of Science:
- Oncology
- Genomics
- Pharmacology
Background:
- Malignancies exhibit complex molecular profiles not always aligned with tumor type.
- Current precision oncology often relies on single biomarker matching for treatment.
- Advanced cancers require innovative therapeutic strategies beyond standard approaches.
Purpose of the Study:
- To optimize therapy for advanced cancers by customizing drug regimens to cotarget multiple molecular alterations.
- To investigate the efficacy and safety of individually dosed, combination therapies based on comprehensive genomic profiling.
- To establish a novel precision oncology paradigm through personalized biomarker matching.
Main Methods:
- Prospective, pan-cancer trial (I-PREDICT) for aggressive advanced/metastatic malignancies.
- Next-generation sequencing (NGS) of tissue and/or blood for molecular profiling.
- Calculation of a matching score (MS) based on targeted versus total pathogenic alterations.
Main Results:
- 210 evaluable patients received NGS-guided therapy with 157 unique regimens.
- Novel combinations were safely administered with reduced starting doses, showing low Grade 3/4 toxicity (6.5%).
- Higher matching scores (MS) correlated significantly with improved disease control, progression-free survival, and overall survival.
Conclusions:
- The I-PREDICT strategy enables safe and active N-of-1 matched treatments by maximizing personalized biomarker matching.
- Individually dosed, customized drug combinations represent a viable new paradigm in precision oncology.
- Further prospective trials are warranted to validate this personalized treatment approach.
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