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Background Refractory cancers pose formidable management challenges. We hypothesized that such malignancies have unexplored vulnerabilities that can be identified using Encyclopedic Tumor Analysis (ETA) and effectively targeted using conventional agents in a label- and organ-agnostic manner to yield treatment benefit. The pan-cancer RESILIENT trial addressed patients with advanced refractory malignancies who were treated with ETA guided treatments regimens without any restrictive eligibility criteria. Methods Molecular Profiling (MP) of patients’ fresh tumor tissue interrogated gene alterations and differentially regulated metabolic pathways to identify molecular targets of approved anticancer agents in a label-agnostic manner. Immunohistochemistry (IHC) identified hormone receptors (HR) that could be targeted with endocrine agents. Chemoresistance and response (CRR) profiling of viable tumor derived cells (TDCs) identified functional vulnerabilities of the tumor against a panel of systemic anticancer agents. Synergistic integration of MP, IHC and CRR datasets (i.e., ETA) generated patient-specific drug priority lists with projected efficacy and safety. Patients who received such ETA-guided treatments were evaluated by PET-CT scans to determine treatment response as well as Objective Response Rate (ORR), Disease Control Rate (DCR) and Progression Free Survival (PFS). Results Among the 200 patients who were screened, 110 patients received ETA-guided treatments and were evaluable for response per protocol. PR was observed in 47 patients (ORR = 42.7%) and 99 patients continued to exhibit PR or SD at study termination (DCR = 90%). Median PFS was 125 days. Median PFS rate at 90 days was 94.0%. No significant therapy related adverse events (AEs) were noted – there were no grade IV AEs or treatment related deaths. Most patients reported stable to improved Quality of Life (QoL) in terms of disease-related symptoms and functional status. Conclusions ETA-guided treatments offer meaningful survival benefits and outperformed available alternatives including checkpoint inhibitors in this heavily pretreated pan-cancer population. Legal entity responsible for the study The authors. Funding Datar Cancer Genetics Limited. Disclosure D. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. D. Akolkar: Full / Part-time employment: Datar Cancer Genetics Limited. V. Datta: Full / Part-time employment: Datar Cancer Genetics Limited. A. Ghaisas: Full / Part-time employment: Datar Cancer Genetics Limited. R. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. H. Singh: Full / Part-time employment: Datar Cancer Genetics Limited. A. Srinivasan: Full / Part-time employment: Datar Cancer Genetics Limited. S. Apurwa: Full / Part-time employment: Datar Cancer Genetics Limited. R. Datar: Shareholder / Stockholder / Stock options, Licensing / Royalties, Officer / Board of Directors: Datar Cancer Genetics Limited. All other authors have declared no conflicts of interest.

Background Though mTOR inhibition is considered an attractive strategy for cancer management, anti-mTOR monotherapies have not shown meaningful benefits. We hypothesized that an Encyclopedic Tumor Analysis (ETA) can identify vulnerabilities in the tumor in addition to mTOR activation. We further hypothesized that tandem synergistic targeting of these vulnerabilities using combination of mTOR inhibitors and other systemic anticancer agents in a label- and organ-agnostic manner can improve outcomes in refractory solid organ cancers as compared to mTOR inhibition monotherapy alone. Methods Molecular Profiling (MP) of patients’ fresh tumor tissue interrogated gene alterations and differentially regulated metabolic pathways to identify druggable molecular targets in a label-agnostic manner. Immunohistochemistry (IHC) identified targetable hormone receptors (HR). Chemoresistance and response (CRR) profiling of viable tumor derived cells (TDCs) identified vulnerabilities of the tumor against a panel of systemic anticancer agents. Molecular indications linked to PIK3CA, mTOR, PTEN or TP53 genes were used for selection of mTOR inhibitors. Synergistic integration of MP, IHC and CRR datasets (i.e., ETA) generated patient-specific drug priority lists with projected efficacy and safety. Patients who received such ETA-guided treatments were evaluated by PET-CT scan to determine treatment response. Results Among 41 patients who received combination treatments, 23 patients showed PR (ORR = 56.1%), 16 showed SD (DCR = 95.1%) and progression was observed in 2 patients. One patient who received monotherapy progressed at 27 days. Median PFS was 110 days (range 27 to 592). In the SHIVA trial where patients with mTOR activation (n = 46) received monotherapy with mTOR inhibitor, median PFS of 72 days (range 57 to 100) was reported. No significant therapy–related adverse events were reported in any patient. Most patients reported stable to improved Quality of Life (QoL). Conclusions ETA-guided combination regimens with mTOR inhibitors offer a viable and efficient strategy in advanced refractory malignancies and outperform mTOR inhibitor monotherapy. Legal entity responsible for the study The authors. Funding Datar Cancer Genetics Limited. Disclosure D. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. D. Akolkar: Full / Part-time employment: Datar Cancer Genetics Limited. V. Datta: Full / Part-time employment: Datar Cancer Genetics Limited. A. Ghaisas: Full / Part-time employment: Datar Cancer Genetics Limited. R. Patil: Full / Part-time employment: Datar Cancer Genetics Limited. H. Singh: Full / Part-time employment: Datar Cancer Genetics Limited. A. Srinivasan: Full / Part-time employment: Datar Cancer Genetics Limited. S. Apurwa: Full / Part-time employment: Datar Cancer Genetics Limited. R. Datar: Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Datar Cancer Genetics Limited. All other authors have declared no conflicts of interest.