Combination Cancer Therapy Can Confer Benefit via Patient-to-Patient Variability without Drug Additivity or Synergy
Open accessAbstract
Combination cancer therapies aim to improve the probability and magnitude of therapeutic responses and reduce the likelihood of acquired resistance in an individual patient. However, drugs are tested in clinical trials on genetically diverse patient populations. We show here that patient-to-patient variability and independent drug action are sufficient to explain the superiority of many FDA-approved drug combinations in the absence of drug synergy or additivity. This is also true for combinations tested in patient-derived tumor xenografts. In a combination exhibiting independent drug action, each patient benefits solely from the drug to which his or her tumor is most sensitive, with no added benefit from other drugs. Even when drug combinations exhibit additivity or synergy in pre-clinical models, patient-to-patient variability and low cross-resistance make independent action the dominant mechanism in clinical populations. This insight represents a different way to interpret trial data and a different way to design combination therapies.
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No relevant clinical activity has been observed in trials encompassing a variety of solid tumour types, including immunotherapy-sensitive tumours such as renal cell carcinoma and melanoma.
“Notably, no relevant clinical activity has been observed in trials encompassing a variety of solid tumour types, including immunotherapy-sensitive tumours such as renal cell carcinoma63 and melanoma64.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [63]
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- Authors
- Palmer, A. C., & Sorger, P. K.
- Affiliations
- Harvard University (US)
- Corresponding author
- Sorger, Peter K.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-12
- Volume
- 171
- Issue
- 7
- Pages
- 1678-1691.e13
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5741091
- OpenAlex
- W2774112395
- Cited by
- 642
- References
- 54
- Citations by year
- 2026: 51 · 2025: 82 · 2024: 74 · 2023: 77 · 2022: 82 · 2021: 102 · 2020: 86 · 2019: 51 · 2018: 34 · 2017: 1 · 2012: 1
- FWCI
- 20.73
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NHMRC (1072965)
- NIH (GM107618)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Physical Sciences › Mathematics › Modeling and Simulation › Mathematical Biology Tumor Growth
- Physical Sciences › Mathematics › Statistics and Probability › Statistical Methods in Clinical Trials
- Keywords
- combination cancer therapy, patient-to-patient variability, drug synergy, drug additivity, cross-resistance, acquired drug resistance, patient-derived xenografts, drug combination design, tumor sensitivity
- MeSH terms
- Biological Variation, Individual, Animals, Antineoplastic Combined Chemotherapy Protocols, Clinical Trials as Topic, Drug Interactions, Humans, Immunotherapy, Neoplasm Transplantation, Neoplasms, Drug Delivery Systems, Drug Resistance, Neoplasm, Heterografts
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