Everolimus monotherapy use for metastatic clear cell-RCC (mRCC) has diminished due to recent approvals of immune checkpoint and VEGF inhibitors. We hypothesized that gene expression associated with everolimus benefit may provide rationale to select appropriate patients.
To address this hypothesis, tumors from a phase I/II trial that compared everolimus alone or with BNC105P, a vascular disrupting agent (VDA), were profiled using Nanostring as a discovery cohort. A phase III trial (CheckMate 025) was used for validation. Clinical benefit (CB) was defined as response, or stable disease for {greater than or equal to}6 months. A propensity score covariate adjustment was used, and model discrimination performance was assessed using the area under the ROC curve (AUC). In a discovery cohort of 82 patients, 35 (43%) were treated with everolimus alone and 47 (57%) received everolimus+BNC105P. Median PFS (mPFS) was 4.9 (95%CI=2.8-6.2) months. A 4-gene signature (ASXL1, DUSP6, ERCC2, and HSPA6) correlated with CB with everolimus+/-BNC105P (AUC 86.9% [95%CI=79.2-94.7]). This was validated in 130 patients from CheckMate 025 treated with everolimus (AUC 60.2% [95%CI=49.7-70.7]). Among 43 patients (52.4%) with low expression of an 18-gene signature, everolimus+BNC105P was associated with significantly longer mPFS compared to everolimus alone (10.4 vs 6.9 months, HR 0.49, 95%CI=0.24-1.002, p=0.047). These signatures warrant further validation to select patients who may benefit from everolimus alone or with a VDA.
Molecular cancer therapeutics. 2021 Jun 09 [Epub ahead of print]
Eddy S Yang, Amin H Nassar, Elio Adib, Opeyemi A Jegede, Sarah Abou Alaiwi, Deborah L Della Manna, David A Braun, Mahsa Zarei, Heng Du, Sumanta K Pal, Gurudatta Naik, Guru P Sonpavde
Department of Radiation Oncology, University of Alabama at Birmingham ., Division of Pulmonary Medicine, Brigham and Women's Hospital., Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital., Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute., Medical Oncology, Dana-Farber Cancer Institute., Radiation Oncology, University of Alabama at Birmingham., Department of Medicine, Harvard Medical University., Pulmonary and Critical Care Medicine, Brigham and Women's Hospital., Medical Oncology and Therapeutics Research, City Of Hope National Medical Center., Division of Hematology and Oncology, University of Alabama at Birmingham., Department of Medical Oncology, Dana-Farber/Harvard Cancer Center.
PubMed http://www.ncbi.nlm.nih.gov/pubmed/34108261