Cancer remains a significant global health challenge, and despite remarkable advancements in therapeutic strategies, poor tolerability of drugs (causing dose reduction/interruptions) and/or the emergence of drug resistance are major obstacles to successful treatment outcomes. Metastatic renal cell carcinoma (mRCC) accounts for 2% of global cancer diagnoses and deaths. Despite the initial success of targeted therapies in mRCC, challenges remain to overcome drug resistance that limits the long-term efficacy of these treatments. Our analysis aim was to develop a semi-mechanistic longitudinal exposure-tumor growth inhibition model for patients with mRCC to characterize and compare everolimus (mTORC1) and apitolisib's (dual PI3K/mTORC1/2) ability to inhibit tumor growth, and quantitate each drug's efficacy decay caused by emergence of tumor resistance over time. Model-estimated on-treatment tumor growth rate constant was 1.7-fold higher for apitolisib compared to everolimus. Estimated half-life for loss of treatment effect over time for everolimus was 16.1 weeks compared to 7.72 weeks for apitolisib, suggesting a faster rate of tumor re-growth for apitolisib patients likely due to the emergence of resistance. Goodness-of-fit plots including visual predictive check indicated a good model fit and the model was able to capture individual tumor size-time profiles. Based on our knowledge, this is the first clinical report to quantitatively assess everolimus (mTORC1) and apitolisib (PI3K/mTORC1/2) efficacy decay in patients with mRCC. These results highlight the difference in overall efficacy of 2 drugs due to the quantified efficacy decay caused by emergence of resistance, and emphasize the importance of model-informed drug development for targeted cancer therapy.
Journal of clinical pharmacology. 2024 Apr 19 [Epub ahead of print]
Anita Moein, Jin Y Jin, Matthew R Wright, Harvey Wong
Department of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada., Genentech, Inc., a member of the Roche Group, South San Francisco, CA, USA.