Clinical Actionability Of Molecular Targets Research Articles

97P - Reanalysis of the efficacy of molecular targeted agents (MTAs) given in the randomized trial SHIVA01 according to the ESMO ESCAT scale of actionability

BackgroundSIVHA01 was the first randomized precision medicine trial in patients (pts) with metastatic solid tumors comparing the efficacy of matched MTA outside their indications and conventional chemotherapy in pts with any kind of cancer who had failed standard of care therapy (Le Tourneau et al., Lancet Oncol 2015). No statistical difference was reported between the 2 groups in terms of progression-free survival (PFS), challenging the treatment algorithm used. Several scales of actionability have been developed to address this point, the latest one being the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) that defines clinical evidence-based criteria to prioritize genomic alterations to select MTAs for pts (Mateo et al., Ann Oncol 2018). We aimed to retrospectively evaluate the efficacy of MTAs given in SHIVA01 according to ESCAT. MethodsAll SHIVA01 molecular alterations targeted were ranked according to ESCAT by assessing the level of evidence reported in the literature, taking into account the tumor type and the administered MTA among 11. PFS and overall survival (OS) according to the ESCAT rank were compared using a log-rank test.All SHIVA01 molecular alterations targeted were ranked according to ESCAT by assessing the level of evidence reported in the literature, taking into account the tumor type and the administered MTA among 11. PFS and overall survival (OS) according to the ESCAT rank were compared using a log-rank test. ResultsThe 153 pts treated with a MTA in SHIVA01 were included. Molecular alterations were ranked as II, IIIA, IIIB, and IVA according to ESCAT in 38 (25%), 98 (64%), 7 (5%), and 10 pts (7%), respectively. Median PFS was 2.0 months (mo) in tier II, 3.1mo in IIIA; 1.7mo in IIIB, and 3.2mo in IVA (p=0.13). Median OS was 11.7mo in tier II, 11.2mo in IIIA, 6.3mo in IIIB, and 12.1mo in IVA (p=0.002). ConclusionsThe majority of molecular alterations taken into account in SHIVA01 were tier IIIA hypothetical targets according to ESCAT. Pts with a tier IIIB molecular alteration had the worst survival, highlighting the crucial impact of the types of molecular alterations beyond the gene and the signaling pathway. Legal entity responsible for the studyInstitut Curie. FundingANR-10-EQPX-03 from the Agence Nationale de le Recherche (Investissements d’avenir) and SiRIC (Site de Recherche Intégré contre le Cancer). DisclosureAll authors have declared no conflicts of interest.

Clinical actionability of molecular targets in endometrial cancer.

Endometrial cancer accounts for ~76,000 deaths among women each year worldwide. Disease mortality and the increasing number of new diagnoses make endometrial cancer an important consideration in women's health, particularly in industrialized countries, where the incidence of this tumour type is highest. Most endometrial cancers are carcinomas, with the remainder being sarcomas. Endometrial carcinomas can be classified into several histological subtypes, including endometrioid, serous and clear cell carcinomas. Histological subtyping is currently used routinely to guide prognosis and treatment decisions for endometrial cancer patients, while ongoing studies are evaluating the potential clinical utility of molecular subtyping. In this Review, we summarize the overarching molecular features of endometrial cancers and highlight recent studies assessing the potential clinical utility of specific molecular features for early detection, disease risk stratification and directing targeted therapies.

Comprehensive genomic profiling (CGP) of upper-tract (UTUC) and bladder (BUC) urothelial carcinoma reveals opportunities for therapeutic and biomarker development.

4581 Background: To understand the genomic landscape and inform the therapeutic development of UC, 2463 cases were analyzed by CGP for genomic alterations (GAs) and for genome wide signatures. Methods: 479 UTUC and 1984 BUC FFPE tissues (77%/70% primary [PT] and 23%/30% metastatic tumors [MT] from unmatched patients [pts]) underwent hybrid-capture based CGP to evaluate all classes of GA. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 114 loci. Targetable GA and signatures were assessed according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Results: 48% of UC pts overall harbored ≥1 tier 1-2 GA suggesting benefit from approved or investigational targeted therapies (TT). Additionally, 17% had a tier 3 GA that provides a strong rationale for clinical trial consideration. Non- FGFR3 kinase fusions were observed in 1% of pts (0.6% UTUC v 1.1% BUC), including BRAF/RAF1 fusions in 0.5%. BRAF mut/fusions were observed in 2% (49/2463) of cases and were mutually exclusive with FGFR3 GA (p = 0.002). In comparing UC from anatomic sites, there were no differences of TMB-H (≥20 mut/mb)/MSI-H for PT and MT but UTUC was enriched for MSI-H (3.4%) relative to BUC (0.77%, p < 0.001, all TMB-H). Excluding MSI-H pts, UTUC has lower median TMB (4.35 mut/mb) than BUC (6.96 mut/mb). FGFR3 GA (26% v 19%, p < 0.05) and specifically short variants (SV) (20% v 13%) were enriched in UTUC vs BUC. HRAS SV were also enriched in UTUC vs BC (7.3% v 3.0%), attributed to an enrichment in renal pelvis UC (10.1%) v ureteral UC (1.8%, p < 0.05). RB1 GA were more frequent in BUC vs UTUC (21% v 7.8% p < 0.001). Conclusions: Against a background of 50% actionability in UC with opportunities for immunotherapy, TT, or combinations thereof, the UTUC cohort is enriched for FGFR3 and HRAS SV relative to BUC, with the observation of HRAS mutations predominantly in UC of the renal pelvis, that warrants further investigation into the distinct modes of oncogenesis for UC as stratified by anatomic origin. These results argue strongly for the routine incorporation of CGP prior to systemic therapy initiation in metastatic UC.

Reanalysis of the efficacy of molecular targeted agents (MTAs) given in the randomized trial SHIVA01 according to the ESMO ESCAT scale of actionability.

e14750 Background: SIVHA01 was the first randomized precision medicine trial in patients (pts) with metastatic solid tumors comparing the efficacy of matched MTA outside their indications and conventional chemotherapy in pts with any kind of cancer who had failed standard of care therapy (Le Tourneau et al., Lancet Oncol 2015). No statistical difference was reported between the 2 groups in terms of progression-free survival (PFS), challenging the treatment algorithm used. Several scales of actionability have been developed to address this point, the latest one being the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) that defines clinical evidence-based criteria to prioritize genomic alterations to select MTAs for pts (Mateo et al., Ann Oncol 2018). We aimed to retrospectively evaluate the efficacy of MTAs given in SHIVA01 according to ESCAT. Methods: All SHIVA01 molecular alterations targeted were ranked according to ESCAT by assessing the level of evidence reported in the literature, taking into account the tumor type and the administered MTA among 11. PFS and overall survival (OS) according to the ESCAT rank were compared using a log-rank test. Results: The 153 pts treated with a MTA in SHIVA01 were included. Molecular alterations were ranked as II, IIIA, IIIB, and IVA according to ESCAT in 38 (25%), 98 (64%), 7 (5%), and 10 pts (7%), respectively. Median PFS was 2.0 months (mo) in tier II, 3.1 mo in IIIA; 1.7 mo in IIIB, and 3.2 mo in IVA (p = 0.13). Median OS was 11.7 mo in tier II, 11.2 mo in IIIA, 6.3 mo in IIIB, and 12.1 mo in IVA (p = 0.002). Conclusions: The majority of molecular alterations taken into account in SHIVA01 were tier IIIA hypothetical targets according to ESCAT. Pts with a tier IIIB molecular alteration had the worst survival, highlighting the crucial impact of the types of molecular alterations beyond the gene and the signaling pathway.

Prospective Longitudinal ctDNA Workflow Reveals Clinically Actionable Alterations in Ovarian Cancer.

PURPOSECirculating tumor DNA (ctDNA) detection is a minimally invasive technique that offers dynamic molecular snapshots of genomic alterations in cancer. Although ctDNA markers can be used for early detection of cancers or for monitoring treatment efficacy, the value of ctDNA in guiding treatment decisions in solid cancers is controversial. Here, we monitored ctDNA to detect clinically actionable alterations during treatment of high-grade serous ovarian cancer, the most common and aggressive form of epithelial ovarian cancer with a 5-year survival rate of 43%.PATIENTS AND METHODSWe implemented a clinical ctDNA workflow to detect clinically actionable alterations in more than 500 cancer-related genes. We applied the workflow to a prospective cohort consisting of 78 ctDNA samples from 12 patients with high-grade serous ovarian cancer before, during, and after treatment. These longitudinal data sets were analyzed using our open-access ctDNA-tailored bioinformatics analysis pipeline and in-house Translational Oncology Knowledgebase to detect clinically actionable genomic alterations. The alterations were ranked according to the European Society for Medical Oncology scale for clinical actionability of molecular targets.RESULTSOur results show good concordance of mutations and copy number alterations in ctDNA and tumor samples, and alterations associated with clinically available drugs were detected in seven patients (58%). Treatment of one chemoresistant patient was changed on the basis of detection of ERBB2 amplification, and this ctDNA-guided decision was followed by significant tumor shrinkage and complete normalization of the cancer antigen 125 tumor marker.CONCLUSIONOur results demonstrate a proof of concept for using ctDNA to guide clinical decisions. Furthermore, our results show that longitudinal ctDNA samples can be used to identify poor-responding patients after first cycles of chemotherapy. We provide what we believe to be the first comprehensive, open-source ctDNA workflow for detecting clinically actionable alterations in solid cancers.

The promise of ESCAT: a new system for evaluating cancer drug-target pairs.

The ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) will be useful as a common language to harmonize discussions in precision oncology and could also guide policy and reimbursement decisions, but it is far from perfect. Herein, we highlight how ESCAT can be further improved to increase its utility in clinical and policy decisions.

A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)

BackgroundIn order to facilitate implementation of precision medicine in clinical management of cancer, there is a need to harmonise and standardise the reporting and interpretation of clinically relevant genomics data. MethodsThe European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to propose a classification system for molecular aberrations based on the evidence available supporting their value as clinical targets. A group of experts from several institutions was assembled to review available evidence, reach a consensus on grading criteria and present a classification system. This was then reviewed, amended and finally approved by the ESMO TR and PM WG and the ESMO leadership. ResultsThis first version of the ESMO Scale of Clinical Actionability for molecular Targets (ESCAT) defines six levels of clinical evidence for molecular targets according to the implications for patient management: tier I, targets ready for implementation in routine clinical decisions; tier II, investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed; tier III, clinical benefit previously demonstrated in other tumour types or for similar molecular targets; tier IV, preclinical evidence of actionability; tier V, evidence supporting co-targeting approaches; and tier X, lack of evidence for actionability. ConclusionsThe ESCAT defines clinical evidence-based criteria to prioritise genomic alterations as markers to select patients for targeted therapies. This classification system aims to offer a common language for all the relevant stakeholders in cancer medicine and drug development.