Clinical Actionability Of Molecular Targets Research Articles

Clinical utility of comprehensive liquid molecular profiling in patients with advanced endometrial cancer.

Molecular characterization has significantly improved the management of advanced endometrial cancer (EC). It distinguishes four molecular subclasses associated with prognosis and personalized therapeutic strategies. This study assesses the clinical utility of cell-free DNA (cfDNA) profiling in EC to identify targetable alterations. Women with metastatic or recurrent EC were prospectively recruited within the framework of the STING trial (NCT04932525), during which cfDNA was analyzed. Genomic alterations were identified with the FoundationOne CDx assay. Each molecular report underwent review by a molecular tumor board. Alterations were categorized via the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT). A total of 61 patients were enrolled. The median age was 66.9 years, with 43% presenting frontline metastatic disease. All histologic subgroups were represented. Notably, 89% of patients yielded informative cfDNA analysis. Six tumors were classified with deficient mismatch repair/microsatellite instability (11%) and 37 as TP53 gene mutant (67%), and 12 had nonspecific molecular profiles (22%). Molecular classification based on liquid biopsy showed 87.5% accuracy in correlating with tissue results. Moreover, 65% of cases exhibited ≥1 actionable alteration, including 25% ESCAT I alterations and 13% ESCAT II alterations. Consequently, 16% of patients received a molecularly matched therapy, and presented with a 56% response rate and median progression-free survival of 7.7 months. cfDNA sequencing in EC is a feasible approach that produces informative results in 89% of cases and accurately categorizes patients into the main molecular subclasses. It also reveals multiple actionable alterations, which offers the potential for personalized therapeutic strategies.

Clinical applicability of guideline-recommended molecular targets and genome-targeted cancer therapies.

11049 Background: Genomic testing has expanded the possibilities of precision medicine, particularly for advanced, treatment-resistant cancer cases. However, the clinical relevance of most genetic alterations remains uncertain, which can lead physicians to overestimate the benefits of tailored therapies. The National Comprehensive Cancer Network (NCCN) guidelines are cancer-specific treatment recommendations that often determine insurance coverage. We assessed the evidence for clinical benefit and actionability of molecular targets for genome-targeted cancer drugs recommended by NCCN. Methods: We identified genome-targeted therapies for solid cancers from the most recent NCCN guidelines. Trial design characteristics were obtained from publications supporting the NCCN recommendations. Genome target actionability was assessed with the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT). This ranges from genome alternation-therapy combinations that lead to improved outcomes (Tier I) to treatments with potential clinical relevance (Tiers II or III) to those with undetermined relevance (Tiers IV to X). Clinical benefit was evaluated using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Molecular targets at ESCAT Tier I in combination with a given treatment associated with studies demonstrating substantial clinical benefit by ESMO-MCBS (Grades 4-5) were designated as high-benefit, while those linked to studies achieving an ESMO-MCBS Grade of 3 were categorized as promising but unproven. Results: We extracted411 recommendations from NCCN supporting 74 genome-targeted drugs targeting 50 driver alterations. Most recommendations (346/411, 84%) referred to clinical trial data, while one-sixth (65/411, 16%) relied on case reports or preclinical studies. Clinical trials were mostly Phase I or Phase II (271/346, 78%), single arm (262/346, 76%), and evaluated overall response rate as the primary endpoint (271/346, 78%). Over half of target recommendations had Tier I target actionability (246/411, 60%), over one-third were Tier II or III (142/411, 35%), and the rest were undetermined (23/411, 6%). Among 267 scorable trials,12% (32/267) demonstrated substantial clinical benefit (ESMO-MCBS Grades 4-5) and 45% (121/267) were Grade 3. When combining both frameworks,12% (32/267) genomic-based cancer treatments were high-benefit and 33% (88/267) were promising-but-unproven. Conclusions: About one-eighth of genome-targeted cancer therapies recommended in NCCN guidelines received a high benefit rating, while one-third were identified as having a promising but unproven substantial benefit according to the ESCAT and ESMO-MCBS frameworks. Ensuring NCCN recommendations are aligned with well-documented clinical benefits is crucial for promoting informed, evidence-based genomic-guided treatment decisions.

Impact of next generation sequencing in high grade glioma management.

e14031 Background: Recent advances in genomic profiling have improved our understanding of the molecular pathogenesis of high grade gliomas. Increased availability of high-throughput Next Generation Sequencing (NGS) allows the identification of genetic alterations which could direct personalized cancer treatments for HGG patients. Methods: All patients with high grade glioma (WHO Grade ≥3 glioma by 2016 or 2022 classification) in our institution, who underwent NGS testing between 2019-2023, were identified from a prospectively maintained electronic database. NGS results, from the Oncomine Precision Assay, a multi-gene panel which tests for 50 different mutations, were collated. Medical records were systematically reviewed to collect demographic, treatment and survival data. Alterations detected on NGS were characterized using the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). Results: 53 patient samples underwent NGS testing (34 males [64%]; 19 females [36%]). Median age at diagnosis was 52 years (range: 20-72 years). Thirty patients (57%) had an ECOG PS 1 at first clinical review. 18 tumors (34%) were found to have MGMT promoter hypermethylation. 28 patients (53%) were found to have potentially actionable alterations according to the ESCAT scale; 19 (35%) EGFR mutations (ESCAT IIIA level evidence) were detected, 5 PIK3CA (9%) mutations (ESCAT IIIA), 3 FGFR3 (6%) alterations (ESCAT IIB), 2 patients with CDK 4 (4%) copy number gain (ESCAT IIIA), 2 PTPRZ1-MET (4%) fusions (ESCAT IIIA) and 1 BRAF V600E (2%) mutation (ESCAT IB). 4 patients were found to have multiple mutations on NGS. 1 sample had insufficient tissue for analysis. 2 patients (4%) were considered for targeted therapy based on NGS results (1 BRAF V600E mutation and 1 FGFR3 alteration) but both deteriorated in advance of commencing treatment. One patient received nivolumab for MSI-H recurrent GBM (ESCAT IIIB) but progressed within 3 months of commencing treatment. Conclusions: Despite advances in our understanding of the pathogenesis of these high grade gliomas and improved awareness of molecular targets, the delivery of targeted therapy to patients with HGG remains challenging. Rapid access to targeted therapy via compassionate access programmes and improved availability and access to clinical trials for patients with rare cancers and molecular alterations, is paramount.

Abstract PO4-14-03: Results of Comprehensive Genomic Profiling of Metastatic Breast Cancer Patients at a Single Institute in Japan

Abstract BACKGROUND. Comprehensive genomic profiling (CGP) was officially approved by the Japanese National Health Insurance System in June 2019. Currently, three CGP tests are available: FoundationOne CDx (F1CDx), OncoGuide NCC Oncopanel (NCC), and FoundationOne Liquid CDx (F1LCDx). This study examines the clinical significance of CGP testing in patients with metastatic breast cancer (mBC) in Japan. METHODS. The subjects were 105 patients (pts) who underwent CGP testing at our hospital from June 2019 to July 2023. Of these, 64 pts received tissue panels for F1CDx, 25 pts for F1LCDx, and 16 pts for others. Based on the reports from the testing companies and the expert panel committee's review, we evaluated the percentage of patients for whom matched therapy (MT) was recommended, whether MT was performed, and the prognosis of the group of patients for whom MT was performed. Overall survival was analyzed with the log-rank test. RESULTS. Of the 105 patients who underwent CGP testing, 47 pts (44.8%) were recommended MT corresponding to ESCAT(ESMO Scale for Clinical Actionability of molecular Targets) ranking I/II or clinical trials due to genetic alterations, and only 7 pts (6.7%) reached those treatments. Three HER2-negative patients were prescribed anti-HER2 therapy for ERBB2 amplification, one patient was prescribed entrectinib for NTRK fusion, and three patients participated in clinical trial for ERBB2 mutation and FGFR1 rearrangement. If ESCAT ranking beyond I/II and recommended therapy from FoundationOne report (e.g Abemaciclib for CCND1 amplification, Everolimus for PTEN loss)are added, 64 pts (60.1%) were considered these treatments, and 19 pts (18.1%) actually received these treatment. Among these 19 pts, overall survival was significant improved that of patientswho did not reach treatment (21.1 m vs 6.2 m, p=0.0097). CONCLUSIONS. We examined the rate of MT attainment by CGP in mBC at a single institute. We found that the rate of MT attainment with ESCAT ranking I/II, or clinical trials corresponding to genetic mutations, was low. The overall survival of patients who underwent MT, which can be performed by Japanese insurance, was significantly different from that of patients who did not undergo MT. Low accessibility of ESCAT ranking I/II MT may be because, in Japan, CGP testing is available only for patients who have completed or are expected to complete standard therapy. Early use of CGP testing and an increase in clinical trials will be desirable in Japan. Citation Format: Tomomi Kon, Hiroshi Tada, Minoru Miyashita, Akiko Ebata, Narumi Harada-Shoji, Yohei Hamanaka, Miku Sato, Mika Yanagaki, Satoko Tsunokake, Tokiwa Motonari, Asumi Yamazaki, Takanori Ishida. Results of Comprehensive Genomic Profiling of Metastatic Breast Cancer Patients at a Single Institute in Japan [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-14-03.

Abstract PO4-10-12: Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023

Abstract Title: Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023 Background: The number of FDA-approved genome-targeted cancer drugs for metastatic breast cancer has increased, providing the potential for personalized therapy. To help physicians, patients, and policymakers differentiate meaningful from trivial innovation in this field, we assessed the validity of the targets and value of the outcomes used in the pivotal trials supporting approval. Methods: We analyzed trials supporting genome-targeted breast cancer drugs FDA-approved between 2006-2023, defined as those using a genomic test in which the drug targeted a given genomic alteration. From FDA drug labels and trial reports, we extracted characteristics of pivotal trials. For Accelerated Approvals—a special FDA program allowing approval based on unvalidated surrogate measures—if the drug later received traditional approval based on a confirmatory trial, only the latter was analyzed. Strength of evidence supporting molecular targetability was evaluated using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT). Clinical benefit for approved indications was assessed using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Molecular targets qualifying for ESCAT category level I-A or I-B associated with ESMO-MCBS grade 4 or 5 were rated as high-benefit genomic-targeted breast cancer treatments. Results: Fifteen genome-targeted drugs covered 17 indications and targeted 8 driver alterations. Among the 17 pivotal trials supporting these indications, most were randomized (11, 65%), phase 3 (11, 65%) and open-label (14, 82%). The most common primary endpoint leading to approval (10, 59%) was progression-free survival. Eleven trials (65%) had a I-A ESCAT targetability, 5 (29%) had a I-C targetability score and 1 (6%) was categorized as II-A. ERBB2 amplification, germline BRCA1/2 mutations, PIK3CA mutations, and ESR1 mutation were classified as tier I-A due to randomized trials demonstrating the effectiveness of approved targeted therapies in patients with these alterations. RET fusions, NTRK fusions, and microsatellite instability were classified as tier I-C, while high-tumor mutational burden was categorized as tier II-A. Eighteen percent of trials (3/17) demonstrated ESMO-MCBS grades 4-5. Overall, 3 of 17 (18%) indications had high-benefit genomic-based cancer treatments. Conclusions: Among molecular-targeted cancer therapies approved for metastatic breast cancer, fewer than a fifth demonstrated substantial patient benefits at approval. Benefit frameworks like ESCAT and ESMO-MCBS can help stakeholders identify therapies with the greatest potential. Citation Format: Ariadna Tibau, Thomas J. Hwang, Consolacion Molto Valiente, Jerry Avorn, Aaron Kesselheim. Value of Molecular Targets and Genome-Targeted Therapies FDA-Approved for Metastatic Breast Cancer, 2006-2023 [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-10-12.

Abstract PO5-10-08: Clinical Value of Molecular Targets and Genome-Targeted Cancer Therapies Recommended by the National Comprehensive Cancer Network for Advanced Breast Cancer

Abstract Background: Genomic testing has expanded the possibilities of precision cancer medicine, particularly for advanced, treatment-resistant breast cancer cases. However, the clinical significance of most genetic alterations remains uncertain, potentially overestimating tailored therapies. The National Comprehensive Cancer Network (NCCN) guidelines are evidence-based cancer-specific recommendations used in clinical practice and that are often determinative for insurance coverage. In this study, we assessed the validity of the targets and the clinical benefit of genome-targeted cancer drugs recommended in the NCCN guidelines for metastatic breast cancer. Methods: We identified genome-targeted oncology therapies supporting advanced breast cancer recommendations in the most recent NCCN breast cancer guideline (version 4.2023). Genome-targeted drugs were defined as involving use of a genomic test in which the drug targeted a genomic alteration. We analyzed data from trials supporting advanced genome-targeted breast cancer drugs recommendations. When multiple (or overlapping) articles for the same study were identified, the most recent publication was included. We extracted key details of each trial, including trial design, blinding, phase of clinical trial and primary efficacy end points. We cross-referenced the FDA-approved indications as of 30 June 2023 with the NCCN recommendations for each drug. Strength of evidence supporting molecular targetability was evaluated using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT). Clinical benefit for genome-targeted oncology therapies was assessed using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). We considered a substantial clinical benefit as a grade of 4 or 5. Molecular targets qualifying for ESCAT category level I-A and I-B associated with substantial clinical benefit by ESMO-MCBS were rated as high-benefit genomic-targeted breast cancer treatments. Results: We identified 47 recommendations supporting 17 genome-targeted drugs, which targeted 11 driver alterations. Out of these recommendations, 29 (62%) aligned with the FDA indications. We associated 47 trials with these recommendations, most randomized (24, 51%), phase 3 (23, 49%) and open-label (42, 89%). The most common primary endpoint (22, 47%) was overall response rate, followed by progression-free survival/time to progression (21, 45%). Twenty-four trials (51%) had a I-A ESCAT targetability, 7 (15%) had a I-B targetability, 6 (13%) had a I-C targetability score and 10 (21%) were categorized as II-B. ERBB2 amplification, germline BRCA1/2 mutations, PIK3CA mutations, and ESR1 mutation were mainly classified as tier I-A based on randomized trials demonstrating the effectiveness of approved targeted therapies in patients with these alterations. By contrast, RET fusions, NTRK fusions, high-tumor mutational burden and microsatellite instability were ranked as tier I-C and somatic BRCA mutations, germline PALB2 mutations and HER-2 mutations as II-B. Six trials (14%, 6/42) supporting drug approval demonstrated substantial ESMO-MCBS clinical benefit. Overall, 6 recommendations (14%) had high-benefit genomic-based cancer treatments. Conclusions: Fewer than one-fifth of molecular-targeted cancer therapies recommended in NCCN guidelines for metastatic breast cancer demonstrated substantial patient benefits. Value frameworks like ESCAT and ESMO-MCBS can help stakeholders identify therapies with the greatest potential. Citation Format: Ariadna Tibau, Thomas J. Hwang, Jerry Avorn, Aaron Kesselheim. Clinical Value of Molecular Targets and Genome-Targeted Cancer Therapies Recommended by the National Comprehensive Cancer Network for Advanced Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-10-08.

Genomic spectrum of actionable alterations in serial cell free DNA (cfDNA) analysis of patients with metastatic breast cancer

We aimed to study the incidence and genomic spectrum of actionable alterations (AA) detected in serial cfDNA collections from patients with metastatic breast cancer (MBC). Patients with MBC who underwent plasma-based cfDNA testing (Guardant360®) between 2015 and 2021 at an academic institution were included. For patients with serial draws, new pathogenic alterations in each draw were classified as actionable alterations (AA) if they met ESCAT I or II criteria of the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). A total of 344 patients with hormone receptor-positive (HR+)/HER2-negative (HER2-) MBC, 95 patients with triple-negative (TN) MBC and 42 patients with HER2-positive (HER2 + ) MBC had a baseline (BL) cfDNA draw. Of these, 139 HR+/HER2-, 33 TN and 13 HER2+ patients underwent subsequent cfDNA draws. In the HR+/HER2- cohort, the proportion of patients with new AA decreased from 63% at BL to 27–33% in the 2nd-4th draws (p < 0.0001). While some of the new AA in subsequent draws from patients with HR+/HER2- MBC were new actionable variants in the same genes that were known to be altered in previous draws, 10-24% of patients had new AA in previously unaltered genes. The incidence of new AA also decreased with subsequent draws in the TN and HER2+ cohorts (TN: 25% to 0–9%, HER2 + : 38% to 14–15%). While the incidence of new AA in serial cfDNA decreased with subsequent draws across all MBC subtypes, new alterations with a potential impact on treatment selection continued to emerge, particularly for patients with HR+/HER2- MBC.

Clinical Value of Molecular Targets and FDA-Approved Genome-Targeted Cancer Therapies

The number of new genome-targeted cancer drugs has increased, offering the possibility of personalized therapy, often at a very high cost. To assess the validity of molecular targets and therapeutic benefits of US Food and Drug Administration-approved genome-targeted cancer drugs based on the outcomes of their corresponding pivotal clinical trials. In this cohort study, all genome-targeted cancer drugs that were FDA-approved between January 1, 2015, and December 31, 2022, were analyzed. From FDA drug labels and trial reports, key characteristics of pivotal trials were extracted, including the outcomes assessed. The strength of evidence supporting molecular targetability was assessed using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT). Clinical benefit for their approved indications was evaluated using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Substantial clinical benefit was defined as a grade of A or B for curative intent and 4 or 5 for noncurative intent. Molecular targets qualifying for ESCAT category level I-A and I-B associated with substantial clinical benefit by ESMO-MCBS were rated as high-benefit genomic-based cancer treatments. A total of 50 molecular-targeted drugs covering 84 indications were analyzed. Forty-five indications (54%) were approved based on phase 1 or phase 2 pivotal trials, 45 (54%) were supported by single-arm pivotal trials, and 48 (57%) were approved on the basis of subgroup analyses. By each indication, 46 of 84 primary end points (55%) were overall response rate (median [IQR] overall response rate, 57% [40%-69%]; median [IQR] duration of response, 11.1 [9.2-19.8] months). Among the 84 pivotal trials supporting these 84 indications, 38 trials (45%) had I-A ESCAT targetability, and 32 (38%) had I-B targetability. Overall, 24 of 84 trials (29%) demonstrated substantial clinical benefit via ESMO-MCBS. Combining these ratings, 24 of 84 indications (29%) were associated with high-benefit genomic-based cancer treatments. The results of this cohort study demonstrate that among recently approved molecular-targeted cancer therapies, fewer than one-third demonstrated substantial patient benefits at approval. Benefit frameworks such as ESMO-MCBS and ESCAT can help physicians, patients, and payers identify therapies with the greatest clinical potential.

Use of next-generation sequencing in daily routine practice

Developments in molecular diagnosis and implementation of mutation-driven targeted therapy marked a milestone in cancer treatment. Next-generation sequencing allows sequencing of a high number of nucleotides in a short time and from a limited quantity of pathology or cytology specimens. This is a review of actual indications, utility of next-generation sequencing, and availability of targeted therapies in different neoplasms. We present the European Society for Medical Oncology Precision Medicine Working Group recommendations for tumor multigene sequencing use with the Scale for Clinical Actionability of molecular Targets ranking determined for each alteration.

Clinical implication of genetic intratumor heterogeneity for targeted therapy in head and neck cancer

Background Genomic profiling is increasingly used both in therapeutic decision-making and as inclusion criteria for trials testing targeted therapies. However, the mutational landscape may vary across different areas of a tumor and intratumor heterogeneity will challenge treatments or clinical decisions based on single tumor biopsies. The purpose of this study was to assess the clinical relevance of genetic intratumor heterogeneity in head and neck squamous cell carcinomas (HNSCC) using the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT). Materials and methods This prospective study included 33 whole tumor specimens from 28 patients with primary or recurrent HNSCC referred for surgery. Three tumor blocks were selected from central, semi-peripheral, and peripheral positions, mimicking biopsies in three different locations. Genetic analysis of somatic copy number alterations (SCNAs) was performed on the three biopsies using Oncoscan, focusing on 45 preselected HNSCC genes of interest. Clinical relevance was assessed using the ESCAT score to investigate whether and how treatment decisions would change based on the three biopsies from the same tumor. Results The SCNAs identified among 45 preselected genes within the three tumor biopsies derived from the same tumor revealed distinct variations. The detected discrepancies could potentially influence treatment approaches or clinical decisions in 36% of the patients if only one tumor biopsy was used. Recurrent tumors exhibited significantly higher variation in SCNAs than primary tumors (p = .024). No significant correlation between tumor size and heterogeneity (p = .7) was observed. Conclusion In 36% of patients diagnosed with HNSCC, clinically significant intratumor heterogeneity was observed which may have implications for patient management. This finding substantiates the need for future studies that specifically investigate the clinical implications associated with intratumor heterogeneity.

Multigene panel next generation sequencing in metastatic colorectal cancer in an Australian population.

Next generation sequencing (NGS) is increasingly used in standard clinical practice to identify patients with potentially actionable mutations. Stratification of NGS mutation tiers is currently based on the European Society of Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT[E]) Tier I-V & X. Allele frequency is also increasingly recognised as an important prognostic tool in advanced cancer. The aim of this study was to determine the genomic mutations in metastatic colorectal cancer (CRC) in an Australian multicultural population and their influence on survival outcomes. Next generation sequencing with the 50-gene panel Oncomine Precision Assay™ was used on 180 CRC tissue samples obtained across six Sydney hospitals between June 2021 and March 2022. From 180 samples, 147 (82%) had at least one gene mutation identified with 68 (38%) having two or more concurrent mutations. Tier I variants included RAS wild-type [EI] in 73 (41%) and BRAF V600E [EIA] in 27 (15%). Non-tier I variants include 2 (1%) ERBB2 amplification [EIIB], 26 (15%) PIK3CA hotspot mutations [EIIIA] and 9 (5%) MET focal amplifications [EIIIA]. NGS testing revealed an additional 22% of cases with Tier II & III mutations. 43% of patients also presented with potentially actionable Tier III & IV mutations. Patients with concurrent TP53 and RAS mutations had significantly reduced overall survival (6.1 months versus 21.1 months, p <0.01). High KRAS allele frequency, as defined by those with over 20% variant allele frequency (VAF), also demonstrated reduced overall survival (12.1 months versus 42.9 months, p = 0.04). In addition to identifying patients with genomic alterations suitable for clinically proven standard of care therapeutic options, the 50 gene NGS panel has significant potential in identifying potentially actionable non-tier 1 mutations and therefore may become future standard clinical practice.

Reimbursement in the Context of Precision Oncology Approaches in Metastatic Breast Cancer: Challenges and Experiences

Background: Precision oncology programs using next-generation sequencing to detect predictive biomarkers are extending therapeutic options for patients with metastatic breast cancer (mBC). Regularly, based on the recommendations of the interdisciplinary molecular tumor board (iMTB), an inclusion in a clinical trial is not possible. In this case, the German health insurance system allows for the application of reimbursement for an off-label drug use. Here, we describe the current challenges and our experience with reimbursement of molecular therapies in mBC. Methods: A total of 100 applications for reimbursement of off-label therapies recommended by an iMTB were filed for patients with mBC, of which 89 were evaluable for this analysis. The approval rate was correlated with the molecular level of evidence of the respective therapy according to the National Center for Tumor Diseases (NCT) and European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) classification as well as with pretreatment therapy lines. Findings: Overall, 53.9% (48/89) of reimbursement applications were approved. Applications for therapies based on level of evidence m1 (NCT classification), tier I and II (ESCAT classification) had a significantly and clinically relevant increased chance of reimbursement, while a greater number of previous treatment lines had no significantly increased chance of approval, though a trend of approval toward higher treatment lines was detectable. Interpretation: Currently, the German jurisdiction seems to aggravate the clinical implementation of clinically urgently needed molecular therapies.

Real world evidence reveals improved survival outcomes in biliary tract cancer through molecular matched targeted treatment

Biliary tract cancers are rare cancers with poor prognosis due to a lack of therapeutic options, especially after the failure of first-line systemic treatment. Targeted treatments for this clinical situation are promising and have entered clinical practice. We aimed to describe the overall survival of matched targeted treatment after first-line treatment in patients with biliary tract cancers in an Austrian real-world multicenter cohort. We performed a multicenter retrospective chart review of patients with biliary tract cancer between September 2015 and January 2022. Data, including comprehensive molecular characteristics—next generation sequencing (NGS) and immunohistochemistry (IHC), clinical history, surgical procedures, ablative treatments, patient history, and systemic chemotherapy, were extracted from the records of the participating institutions. Targeted treatment was matched according to the ESMO scale for the clinical actionability of molecular targets (ESCAT). We identified 159 patients with the available molecular characteristics. A total of 79 patients underwent second-line treatment. Of these, 36 patients received matched targeted treatment beyond the first-line and were compared with 43 patients treated with cytotoxic chemotherapy in terms of efficacy outcomes. For Tier I/II alterations, we observed a progression free survival ratio (PFStargeted/PFSpre-chemotherapy) of 1.86, p = 0.059. The overall survival for patients receiving at least two lines of systemic treatment significantly favored the targeted approach, with an overall survival of 22.3 months (95% CI 14.7–29.3) vs. 17.5 months (95% CI 1.7–19.8; p = 0.048). Our results underscore the value of targeted treatment approaches based on extended molecular characterization of biliary tract cancer to improve clinical outcomes.

Utility of multigene panel next-generation sequencing in routine clinical practice for identifying genomic alterations in newly diagnosed metastatic nonsmall cell lung cancer.

The standard of care in newly diagnosed metastatic non-small cell lung cancer (NSCLC) is to test for aberrations in three genes for driver mutations - ALK, ROS1 and epidermal growth factor receptor (EGFR) - and also for immunohistochemistry to be performed for programmed death-ligand 1 expression level. Next-generation sequencing (NGS), with or without RNA fusion testing, is increasingly used in standard clinical practice to identify patients with potentially actionable mutations. Stratification of NGS mutation tiers is currently based on the European Society of Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT) Tiers I-V and X. Our aim was to analyse NSCLC tumour samples for the prevalence of Tiers I-V mutations to establish guidance for current and novel treatments in patients with metastatic disease. NGS was performed employing the Oncomine Precision Assay (without RNA fusion testing) that interrogates DNA hotspot variants across 45 genes to screen 210 NSCLC tissue samples obtained across six Sydney hospitals between June 2021 and March 2022. In our cohort, 161 of 210 (77%) had at least one gene mutation identified, with 41 of 210 (20%) having two or more concurrent mutations. Tier I mutations included 42 of 210 (20%) EGFR mutations (EIA) and five of 210 (3%) MET exon 14 skipping mutations (EIB). Non-Tier I variants included 22 of 210 (11%) KRAS G12C hotspot mutations (EIIB), with a further 47 of 210 (22%) having non-G12C KRAS (EX) mutations. NGS testing revealed an additional 15% of cases with Tier II ESCAT mutations in NSCLC. Forty-six percent of patients also demonstrated potential Tier III and IV mutations that are currently under investigation in early-phase clinical trials. In addition to identifying patients with genomic alterations suitable for clinically proven standard-of-care therapeutic options, the 45-gene NGS panel has significant potential in identifying potentially actionable non-Tier 1 mutations that may become future standard clinical practice in NSCLC.

P17.06.B TARGETED THERAPY MATCHED TO GENOMIC ALTERATIONS (BRAFV600E, NTRK, FGFR, ROS1, PIK3CA, PTEN) IN PATIENTS WITH RECURRENT IDH WILDTYPE GLIOBLASTOMA: A REAL-LIFE COHORT ANALYSIS FROM VENETO INSTITUTE OF ONCOLOGY, PADUA (ITALY)

Abstract BACKGROUND The use of next-generation sequencing (NGS) allows the identification of subgroups of patients that may respond to personalized targeted therapies (TT). Despite the acquired deep knowledge about biology, there are only a few data available regarding TT efficacy and feasibility for patients with glioblastoma (GBM). MATERIAL AND METHODS We retrospectively analyzed a cohort of patients with recurrent GBM treated at Veneto Institute of Oncology, Padua (Italy) with TT based on their individual NGS profile. NGS was obtained with FoundationOne®CDx on formalin-fixed paraffin-embedded (FFPE) tissue samples. We identified 6 druggable genomic alterations, classified according to ESCAT (ESMO Scale for Clinical Actionability of molecular Targets): BRAFV600E mutation (IB), NTRK1-2-3 fusions (IC), FGFR1-2-3 alterations (IIB), ROS1 fusions (IIIA), PIK3CA mutations (IIIA) and PTEN loss/mutations (IIIA). TT was given as agnostic approval, part of compassionate use programs or in clinical trials. Response assessment was based on RANO (Response Assessment in Neuro-Oncology) criteria. RESULTS Between March 2020 and December 2022, 34 patients with recurrent glioblastoma received TT (19 males, 15 females, median age of 54 years at time of TT initiation). ECOG PS was 0-1 in 29 pts. All patients received radiotherapy and temozolomide as first-line therapy. The median line of therapy with TT was 3 (range 2-7). TT was dabrafenib/trametinib (9 pts), larotrectinib (2 pts), erdafitinib (4 pts), entrectinib (1 pt), alpelisib (6 pts), ipatasertib+/-atezolizumab (12 pts). At data cut-off (March 2023), 19 patients had died. In the entire cohort, median overall survival and progression-free survival (PFS) after starting TT was 8.72 and 2.14 months, respectively. The dabrafenib/trametinib subgroup had the longest median PFS (5.23 months), a disease control rate (DCR) of 77%, an objective response rate of 22%, and a median duration of response of 22.5 months. 7/9 pt had died and 2 pts are continuing dabrafenib/trametinib. The pt with ROS1-GOCP fusion maintained a complete response for 12 months with entrectinib. Among the others, no complete/partial responses were detected. DCR due to stable disease was 50% in larotrectinib and erdafitinib, 8.3% in ipatasertib+/-atezolizumab, 0% in alpelisib subgroup. No toxicities were reported in dabrafenib/trametinib subgroup. Among all patients, no grade 4 drug-related adverse events were observed and in any case TT was interrupted for toxicity. CONCLUSION Our results confirm the activity of dabrafenib/trametinib in BRAFV600E mutant glioblastoma pts and might suggest deeper explorations in targeting ROS1 and FGFR. Further correlation among patients' outcome, molecular characteristics and TT timing are still under investigation.

Whole Exome Analysis to Select Targeted Therapies for Patients with Metastatic Breast Cancer - A Feasibility Study.

The purpose of this feasibility study was to select targeted therapies according to "ESMO Scale for Clinical Actionability of molecular Targets (ESCAT)". Data interpretation was further supported by a browser-based Treatment Decision Support platform (MH Guide, Molecular Health, Heidelberg, Germany). We applied next generation sequencing based whole exome sequencing of tumor tissue and peripheral blood of patients with metastatic breast cancer (n=44) to detect somatic as well as germline mutations. In 32metastatic breast cancer patients, data interpretation was feasible. We identified 25 genomic alterations with ESCAT Level of Evidence I or II in 18/32 metastatic breast cancer patients, which were available for evaluation: three copy number gains in HER2 , two g BRCA1 , two g BRCA2 , six PIK3CA, one ESR1 , three PTEN , one AKT1 and two HER2 mutations. In addition, five samples displayed Microsatellite instability high-H. Resulting treatment options were discussed in a tumor board and could be recommended in a small but relevant proportion of patients with metastatic breast cancer (7/18). Thus, this study is a valuable preliminary work for the establishment of a molecular tumor board within the German initiative "Center for Personalized Medicine" which aims to shorten time for analyses and optimize selection of targeted therapies.

SYST-20 TARGETED THERAPY MATCHED TO GENOMIC ALTERATIONS (BRAFV600E, NTRK, FGFR, ROS1, PIK3CA, PTEN) IN PATIENTS WITH RECURRENT IDH WILDTYPE GLIOBLASTOMA: A REAL-LIFE COHORT ANALYSIS FROM VENETO INSTITUTE OF ONCOLOGY, PADUA (ITALY)

Abstract We retrospectively analyzed 34 patients (pts) [19 males, 15 females, median age 54] with recurrent IDH wildtype glioblastoma treated with target therapy (TT) based on their next-generation sequencing (NGS) profile, between March2020 and December2022 at Veneto Institute of Oncology, Padua (Italy). ECOG PS was 0-1 in 29 pts. All pts received previous radiotherapy and temozolomide. NGS was obtained with FoundationOne®CDx on formalin-fixed paraffin-embedded samples. We identified 6 druggable genomic alterations, classified according to ESCAT (ESMO Scale for Clinical Actionability of molecular Targets): BRAFV600E mutation (IB), NTRK1-2-3 fusions (IC), FGFR1-2-3 alterations (IIB), ROS1 fusions (IIIA), PIK3CA mutations (IIIA) and PTEN loss/mutations (IIIA). The median line of therapy with TT was 3 (range 2-7). TT was dabrafenib/trametinib (9 pts), larotrectinib (2 pts), erdafitinib (4 pts), entrectinib (1 pt), alpelisib (6 pts), ipatasertib+/-atezolizumab (12 pts). At data cut-off (March2023), 19 patients had died. In the entire cohort, median overall survival and progression-free survival (PFS) after starting TT was 8.72 and 2.14 months, respectively. The dabrafenib/trametinib subgroup had the longest median PFS (5.23 months), a disease control rate (DCR) of 77%, an objective response rate of 22%, and a median duration of response of 22.5 months. 7/9 pt had died and 2 pts are continuing dabrafenib/trametinib. The pt with ROS1-GOCP fusion maintained a complete response for 12 months with entrectinib. Among the others, no complete/partial responses were detected. DCR due to stable disease was 50% in larotrectinib and erdafitinib subgroups and 8.3% in ipatasertib+/-atezolizumab subgroup. No toxicities were reported in dabrafenib/trametinib subgroup. Among all patients, no grade 4 drug-related adverse events were observed and in any case TT was interrupted for toxicity. Our results confirm the activity of dabrafenib/trametinib in BRAFV600E mutant glioblastoma pts and might suggest further explorations in targeting ROS1 and FGFR.

Actionable molecular alterations in newly diagnosed and recurrent IDH1/2 wild-type glioblastoma patients and therapeutic implications: a large mono-institutional experience using extensive next-generation sequencing analysis

BackgroundNext-generation sequencing (NGS) panels enable the identification of alterations in cancer-related genes. This may guide a molecularly targeted strategy for the treatment of glioblastoma (GBM). Material and methodsWe retrospectively analysed data obtained using FoundationOne®CDx in a large cohort of IDH1/2 wild-type GBM. We aimed to 1) identify potentially actionable molecular alterations at diagnosis and/or recurrence based on ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT) defined categories of targetability, 2) understand the clinical implications of NGS in terms of access to and activity of targeted therapies. ResultsIn 442 samples, an NGS profile was available in 98.2%. The median time from diagnosis to NGS profiling was 7.4 months (interquartile range (IQR): 3.4–13.2). Although about half of the patients had at least one actionable molecular alteration, only 3.4% of them were classified as ESCAT IB–IC and 6.7% as ESCAT IIB. Only 36 patients (10.5%) received personalised treatment in clinical trials or as off-label/compassionate use from second-line (median line 3). Most patients did not receive targeted therapy due to clinical deterioration/death (49.6%). Patients treated with dabrafenib/trametinib (9 patients) had the highest disease control rate of 77% and an objective response rate of 22%, with a median progression-free survival (PFS) of 5.2 months. No complete/partial responses were seen with the other regimens. 4/9 (44.4%) patients on anti-BRAF/anti-MEK, 2/4 patients (50%) on erdafitinib and 1/1 patient on capmatinib had a PFS ratio > 1.3. One recurrent GBM patient with ROS1-GOCP fusion maintained a complete response for 11.3 months on entrectinib. ConclusionsOur study demonstrated the feasibility of NGS in GBM samples. As the number of clinically relevant targets was limited and only a small group of GBM patients were treated with targeted therapy, NGS testing should be performed in the context of clinical trials. Our results support the activity of anti-BRAF/anti-MEK, while for the other agents prospective study results are needed to draw solid conclusions.

Genomically matched therapy in refractory colorectal cancer according to ESMO Scale for Clinical Actionability of Molecular Targets: experience of a comprehensive cancer center network.

Efficiency of expanded genomic profiling (EGP) programmes in terms of final inclusion of patients in genomically matched therapies is still unknown. Fit patients with advanced and refractory colorectal cancer (CRC) were selected for an EGP programme. Next-generation sequencing (NGS) analysis from formalin-fixed paraffin-embedded tumour samples was performed. The purpose was to describe the prevalence of genomic alterations defined by the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT), as well as the percentage of patients finally included in genomically guided clinical trials. In total, 187 patients were recruited. Mutational profile was obtained in 177 patients (10 patients were failure due to insufficient tumour sample), copy number alterations in 41 patients and fusions in 31 patients. ESCAT-defined alterations were detected in 28.8% of the intention-to-analyse population. BRAF V600E was clustered in ESCAT I, with a prevalence of 3.7%, KRAS G12C and ERBB2 amplification were clustered in ESCAT II, whose prevalence was 4.2% and 1.6%, respectively. Most alterations were classified in ESCAT III (mutations in ERBB2, PIK3CA or FGFR genes and MET amplification) and IV (mutations in BRAF non-V600E, ERBB3, FBXW7, NOTCH, RNF43), with a single prevalence under 5%, except for PIK3CA mutation (9%).The final rate of inclusion into genomically guided clinical trials was 2.7%, including therapies targeting BRAF V600E or RNF43 mutations in two patients each, and ERBB2 mutation in one patient. In conclusion, EGP programmes in patients with advanced CRC are feasible and identify a subset of patients with potentially druggable genomic alterations. However, further efforts must be made to increase the rate of patients treated with genomically guided therapies.

Usefulness and real-world outcomes of next generation sequencing testing in patients with cancer: an observational study on the impact of selection based on clinical judgement.

Next Generation Sequencing (NGS) panels are increasingly used in advanced patients with cancer to guide therapy. There is, however, controversy about when should these panels be used, and about their impact on the clinical course. In an observational study of 139 patients with cancer having an NGS test [from January 1st, 2017 to December 30th, 2020, in two hospitals (Hospital Universitario de La Princesa and Hospital Universitario Quironsalud Madrid) from Spain], we evaluated whether the clinical course (progression-free survival, PFS) was influenced by drug-based criteria [druggable alterations, receiving a recommended drug, having a favourable ESCAT category (ESMO Scale for Clinical Actionability of molecular Targets)] or clinical judgement criteria. In 111 of 139 cases that were successfully profiled, PFS was not significantly influenced by either having druggable alterations [median PFS for patients with druggable alterations was 170 (95% C.I.: 139-200) days compared to 299 (95% C.I.: 114-483) for those without; p=0.37], receiving a proposed matching agent [median PFS for patients receiving a genomics-informed drug was 195 days (95% C.I.: 144-245), compared with 156 days for those that did not (95% C.I.: 85-226); p=0.50], or having favourable ESCAT categories [median PFS for patients with ESCAT I-III was 183 days (95% C.I.: 104-261), compared with 180 (95% C.I.:144-215) for patients with ESCAT IV-X; p=0.87]. In contrast, NGS testing performed within clinical judgement showed a significantly improved PFS [median PFS for patients that were profiled under the recommended scenarios was 319 days (95% C.I.: 0-658), compared to 123 days (95% C.I.: 89-156) in the non-recommended categories; p=0.0020]. According to our data, real-world outcomes after NGS testing provide evidence of the benefit of clinical judgement in patients with either advanced cancers that routinely need multiple genetic markers, patients with advanced rare cancers, or patients that are screened for molecular clinical trials. By contrast, NGS does not seem to be valuable when performed in cases with a poor PS, rapidly progressing cancer, short expected lifetime, or cases with no standard therapeutic options. RC, NR-L and MQF are recipients of the PMP22/00032 grant, funded by the ISCIII and co-funded by the European Regional Development Fund (ERDF). The study also received funds from the CRIS Contra el Cancer Foundation.