Independent action models and prediction of combination treatment effects for response rate, duration of response and tumor size change in oncology drug development

Sun, Linda; Wu, Cai; Li, Xiaoyun; Chen, Cong; Schmidt, Emmett V.

doi:10.1016/j.cct.2021.106434

Cited by 9 publications

(7 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although we cannot differentiate patients among the three groups in practice, the independent action model allows us to account for the difference in the prediction of the DoR for the combination therapy. Notice that, consistent with clinical trial data, the predicted DoR of a combination therapy generally fall between the two individual components 13 .…”

Section: Resultssupporting

confidence: 68%

“…A positive correlation implies the possibility of cross-resistance, while a negative correlation, albeit less common, implies the possibility of a collateral sensitivity 6-9 . However, consistent with findings from preclinical models 10 , the benefits in early efficacy endpoints (ORR, PFS, DoR) for many combination therapies have been successfully predicted under the assumption of zero correlation or a small positive correlation 6-9,11-13 . We will provide a simple AAA index of MRD under the assumption of zero correlation for practical purpose.…”

Section: Introductionsupporting

confidence: 54%

See 1 more Smart Citation

Assessment of Added Activity of An Antitumor Agent

Chen

Sun

Ren

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

An unprecedented number of novel oncology drugs are under preclinical and clinical development, and nearly all are developed in combinations. With an over-reliance on biological hypotheses, there is less effort to establish single agent activity before initiating late clinical development. This may be contributing to a decreased success rate going from phase 1 to approval in the immunotherapy era. Growing evidence in clinical trial data shows that the treatment benefit from most approved combination therapies can be explained by the independent drug action model. Using this working model, we develop a simple index to measure the added antitumor activity of a new drug based on mean response duration, an endpoint that naturally combines both response status and duration information for all patients, which is shown to be highly predictive of clinical benefit of FDA-approved anti-PD-(L)1 immunotherapies. This index sheds light on challenges and opportunities in contemporary oncology drug development and provides a practical tool to assist with decision-making.

show abstract

Section: Resultssupporting

confidence: 68%

Section: Introductionsupporting

confidence: 54%

Assessment of Added Activity of An Antitumor Agent

Chen

Sun

Ren

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Finally, descriptive statistics shown for observed combination DORs match the statistics of DORs predicted by independent action but not above independent action (additive) (Figure 1f ). More formal modeling of DOR mathematics has been presented elsewhere (Chen et al 2022, Sun et al 2021.…”

Section: Independent Action and Time To Event Endpointsmentioning

confidence: 99%

Rationales for Combining Therapies to Treat Cancer: Independent Action, Response Correlation, and Collateral Sensitivity Versus Synergy

Schmidt

Sun

Palmer

et al. 2023

Annu. Rev. Cancer Biol.

Self Cite

View full text Add to dashboard Cite

The principle of independent drug action proposes that responses to drug combinations result from responses to one or the other of two combining agents, but not both. Explorations of biological pathway interactions in signal transduction and immunobiology as synergy have not been connected to mathematical demonstrations of above–independent action activity, which would define pharmacologic synergy. We review independent action as the explanation for cancer drug combinations and find no evidence for pharmacologic synergy. Rather, a measure of correlation of response ( ρ) when positive can explain below–independent action results, and negative correlation can explain above–independent action results. Anticorrelated responses may be a mathematical demonstration of collateral sensitivity, which can achieve above–independent action activity. Inappropriate use of biological concepts of synergy may be contributing to high failure rates for immuno-oncology clinical trials, indicating a need for more rigorous applications of independent action to the development of cancer drug combination therapy. Expected final online publication date for the Annual Review of Cancer Biology, Volume 7 is April 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

show abstract

“…Conversely, curative combination therapies generally involve many active therapies where all principles apply. Recent experimental, computational, and statistical innovations have expanded our ability to measure and predict the consequence of independent drug action to inform the design of combination therapies [6,13,14,22,[39][40][41][42]. There are exciting opportunities to apply these principles to develop clinically superior combination therapies (see Outstanding questions), including via newly discovered vulnerabilities in cancer cells (e.g., metabolism) or previously undruggable targets (e.g., RAS), which may render previously incurable cancers curable.…”

Section: Outstanding Questionsmentioning

confidence: 99%