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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\u2010term efficacy of these treatments. Our analysis aim was to develop a semi\u2010mechanistic longitudinal exposure\u2010tumor 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\u2010estimated on\u2010treatment tumor growth rate constant was 1.7\u2010fold higher for apitolisib compared to everolimus. Estimated half\u2010life 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\u2010growth for apitolisib patients likely due to the emergence of resistance. Goodness\u2010of\u2010fit plots including visual predictive check indicated a good model fit and the model was able to capture individual tumor size\u2013time 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\u2010informed drug development for targeted cancer therapy.<\/jats:p>","DOI":"10.1002\/jcph.2444","type":"journal-article","created":{"date-parts":[[2024,4,19]],"date-time":"2024-04-19T09:04:30Z","timestamp":1713517470000},"page":"1101-1111","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Quantitative Assessment of Drug Efficacy and Emergence of Resistance in Patients with Metastatic Renal Cell Carcinoma Using a Longitudinal Exposure\u2010Tumor Growth Inhibition Model: Apitolisib (Dual PI3K\/mTORC1\/2 Inhibitor) Versus Everolimus (mTORC1 Inhibitor)"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-1320-7384","authenticated-orcid":false,"given":"Anita","family":"Moein","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences University of British Columbia Vancouver British Columbia Canada"},{"name":"Genentech, Inc., a member of the Roche Group South San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin Y.","family":"Jin","sequence":"additional","affiliation":[{"name":"Genentech, Inc., a member of the Roche Group South San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R.","family":"Wright","sequence":"additional","affiliation":[{"name":"Genentech, Inc., a member of the Roche Group South San Francisco CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harvey","family":"Wong","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences University of British Columbia Vancouver British Columbia Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,4,19]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.25219"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-1314"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2017-0144"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-2123"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.14.5482"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2013.02.016"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1009290"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-015-0218-6"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mds011"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-2403"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2015.64.8808"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11523-017-0482-9"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-11-0446"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2008.10.026"},{"key":"e_1_2_10_16_1","unstructured":"FDA. 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