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Background: The impact of tumour mutational burden (TMB) on outcome with molecularly matched therapy is unknown. Higher TMB could predict resistance to molecularly matched therapy through co-occurring driver mutations., Methods: One hundred and four patients with advanced cancers underwent molecular profiling in the DKTK-MASTER program. Fifty-five patients received systemic therapy excluding immunotherapy. Patients with molecularly matched (n = 35) or non-molecularly informed therapy (n = 20) were analysed for TMB and survival. Results were validated in an independent cohort of patients receiving molecularly matched (n = 68) or non-molecularly informed therapy (n = 40). Co-occurring driver mutations and TMB were analysed in the exploratory cohort and The Cancer Genome Atlas (TCGA) datasets., Results: Patients were stratified by the median TMB of 1.67 mutations per Megabase (mut/Mb) of 35 patients receiving molecularly matched therapy into TMB-high or TMB-low groups. Median overall survival (4 months [95% CI, 3.3-7.6] versus 12.8 months [95% CI, 10-not reached], p < 0.001) and progression-free survival (1.8 months [95% CI, 1.1-3.7] versus 7.9 months [95% CI, 2.8-17.0], p = 0.003) were significantly shorter in the TMB-high group compared to the TMB-low group. In the validation cohort, shorter OS and PFS were identified in the TMB-high group (TMB cut-off of 4 mut/Mb) treated with molecularly matched therapy. No differences were observed in patients receiving non-molecularly informed systemic therapy. A significant correlation between co-occurring driver mutations and TMB (n = 104, r = 0.78 [95% CI, 0.68-0.85], p < 0.001) was found in the exploratory cohort as well as the majority (24/33) of TCGA studies., Conclusion: A high TMB was associated with unfavourable outcome in patients receiving molecularly matched therapy, indicating untargeted resistance pathways. Therefore, TMB should be further investigated as a predictive biomarker in precision oncology programs., Competing Interests: Declaration of Competing Interest Till de Bortoli, Manuela Benary, Mario Lamping, Reinhold Schäfer and Frederick Klauschen report no potential conflicts of interest. Peter Horak reported consulting or advisory board membership for Platomics and honoraria from Platomics, Roche. Sebastian Stintzing has received honoraria/consulting or advisory role from Amgen, Bayer, Lilly, Merck KGaA, MSD, Pierre Fabre, Roche, Sanofi, Servier, Taiho Pharmaceuticals, Takeda, Boehringer Ingelheim, research funding from Merck Serono, Pierre Fabre, Roche Molecular Diagnostics, travel, accommodation and expenses support from Amgen, Bayer, Lilly, Merck KgaA, Pierre Fabre, Roche, Sanofi, Sirtex Medical and Takeda. Inge Tinhofer reports honoraria/consulting or advisory role for Merck KgaA and MerckSerono. Serge Leyvraz reports consulting or advisory role and travel expenses support from Bayer. Ulrich Keller reports a consulting role for Roche, Janssen-Cilag, Takeda, BMS, Gilead, Hexal, Pfizer, Astra-Zeneca, Pentixapharm and honoraria from Gilead, Amgen, Novartis, BMS, Roche, Takeda, MSD, as well as research funding from Celgene, Takeda, BMS, Roche, Astra-Zeneka, Novartis, MSD, Janssen-Cilag, Pfizer. Other support was declared from Roche, BMS, Gilead, Takeda, Janssen-Cilag and Celgene. Albrecht Stenzinger reported Advisory Board/Speaker’s Bureau from Aignostics, Astra Zeneca, AGCT, Bayer, BMS, Eli Lilly, Illumina, Incyte, Janssen, MSD, Novartis, Pfizer, Roche, Seattle Genetics, Takeda, Thermo Fisher and research grants from Bayer, BMS, Chugai, Incyte. Stefan Fröhling reported consulting or advisory board membership from Bayer, Illumina, Roche; honoraria: Amgen, Eli Lilly, PharmaMar, Roche and research funding from AstraZeneca, Pfizer, PharmaMar, Roche, as well as travel or accommodation expenses support from Amgen, Eli Lilly, Illumina, PharmaMar, Roche. Razelle Kurzrock has received research funding from Biological Dynamics, Boehringer Ingelheim, Debiopharm, Foundation Medicine, Genentech, Grifols, Guardant, Incyte, Konica Minolta, Medimmune, Merck Serono, Omniseq, Pfizer, Sequenom, Takeda, and TopAlliance; as well as consultant and/or speaker fees and/or advisory board for Actuate Therapeutics, AstraZeneca, Bicara Therapeutics, Biological Dynamics, EISAI, EOM Pharmaceuticals, Iylon, Merck, NeoGenomics, Neomed, Pfizer, Prosperdtx, Roche, TD2/Volastra, Turning Point Therapeutics, X-Biotech and has an equity interest in CureMatch Inc., CureMetrix, and IDbyDNA; She also serves on the Board of CureMatch and CureMetrix,and is a co-founder of CureMatch. Ulrich Keilholz has received advisory board/speaker bureau, trial support, research collaboration or research support from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Glycotope, Innate, Lilly, Medimmune, MerckSerono, MSD/Merck, Novartis, Pfizer, Roche/Genentech and Sirtex. Damian Rieke has received consultant and/or advisory board and/or speaker fees from Bayer, Bristol-Myers Squibb and Lilly. Ivan Jelas has received consultant and/or advisory board and/or speaker fees from Bristol-Myers Squibb, Merck and Roche., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Targeted therapies for metastatic uveal melanoma have shown limited benefit in biomarker-unselected populations. The Treat20 Plus study prospectively evaluated the feasibility of a precision oncology strategy in routine clinical practice., Patients and Methods: Fresh biopsies were analyzed by high-throughput genomics (whole-genome, whole-exome, and RNA sequencing). A multidisciplinary molecular and immunologic tumor board (MiTB) made individualized treatment recommendations based on identified molecular aberrations, patient situation, drug, and clinical trial availability. Therapy selection was at the discretion of the treating physician. The primary endpoint was the feasibility of the precision oncology clinical program., Results: Molecular analyses were available for 39/45 patients (87%). The MiTB provided treatment recommendations for 40/45 patients (89%), of whom 27/45 (60%) received ≥1 matched therapy. First-line matched therapies included MEK inhibitors (n = 15), MET inhibitors (n = 10), sorafenib (n = 1), and nivolumab (n = 1). The best response to first-line matched therapy was partial response in one patient (nivolumab based on tumor mutational burden), mixed response in two patients, and stable disease in 12 patients for a clinical benefit of 56%. The matched therapy population had a median progression-free survival and overall survival of 3.3 and 13.9 months, respectively. The growth modulation index with matched therapy was >1.33 in 6/17 patients (35%) with prior systemic therapy, suggesting clinical benefit., Conclusions: A precision oncology approach was feasible for patients with metastatic uveal melanoma, with 60% receiving a therapy matched to identify molecular aberrations. The clinical benefit after checkpoint inhibitors highlights the value of tumor mutational burden testing., Competing Interests: Conflict of interest statement SL reports travel and advisory board support from Immunocore and Bayer. CP reports speaker honoraria from Bristol-Myers Squibb, Novartis, Daiichi-Sankyo, EUSA Pharma and Sirtex Medical and advisory honoraria from EUSA Pharma. MS is employee of Alacris Theranostics. TK is employee of Alacris Theranostics. SO reports consultancy fees from Astra Zeneca, Bristol-Myers Squibb, Janssen Biotech, Merck. DTR reports Honoraria from Lilly, Bristol-Myers Squibb and Advisory Honoraria from Bayer and Alacris Theranostics. KK reports advisory board and conference honoraria from Merck, Sanofi, Merck Sharp & Dohme, Glycotope, Roche, Novartis and Bristol-Myers Squibb. CU reports consulting fees from Sanofi, grant for educational activities form Galderma, Beiresdorf and Almirall. GP reports consulting fees and grant for educational activities from Amgen. Novartis, Sun Pharma. Bristol-Myers Squibb, Merck Sharp & Dohme. FK is co-founder of Aignostics GmbH and has received consulting support from Roche, Novartis, Bristol-Myers Squibb, Lilly, Agilent and Iomedico. AJ reports Consultant fees from Novartis, Roche, Boehringer, Allergan, Bayer. MLY is an employee and shareholder of Alacris Theranostics. UK reports consulting fees for Merck Sharp & Dohme, travel support from Merck Serono, Pfizer, grant for educational activities from Merck Serono, Bristol-Myers Squibb, Pierre-Fabre. FK, MD, ES, GD, ML, SB, RS have no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Reliable and reproducible interpretation of molecular aberrations constitutes a bottleneck of precision medicine. Evidence-based decision management systems may improve rational therapy recommendations. To cope with an increasing amount of complex molecular data in the clinical care of patients with cancer, we established a workflow for the interpretation of molecular analyses., Methods: A specialized physician screened results from molecular analyses for potential biomarkers, irrespective of the diagnostic modality. Best available evidence was retrieved and categorized through establishment of an in-house database and interrogation of publicly available databases. Annotated biomarkers were ranked using predefined evidence levels and subsequently discussed at a molecular tumour board (MTB), which generated treatment recommendations. Subsequent translation into patient treatment and clinical outcomes were followed up., Results: One hundred patients were discussed in the MTB between January 2016 and May 2017. Molecular data were obtained for 70 of 100 patients (50 whole exome/RNA sequencing, 18 panel sequencing, 2 immunohistochemistry (IHC)/microsatellite instability analysis). The MTB generated a median of two treatment recommendations each for 63 patients. Thirty-nine patients were treated: 6 partial responses and 12 stable diseases were achieved as best responses. Genetic counselling for germline events was recommended for seven patients., Conclusion: The development of an evidence-based workflow allowed for the clinical interpretation of complex molecular data and facilitated the translation of personalized treatment strategies into routine clinical care. The high number of treatment recommendations in patients with comprehensive genomic data and promising responses in patients treated with combination therapy warrant larger clinical studies., Competing Interests: Conflict of interest statement M.L., M.B., C.M., E.B., K.J., S.B., K.K., S.O., R.S., and F.K. reported no conflicts of interest. S.L. received support and consulting compensation from Bayer. M.L.Y., T.K. and M.S. are employees of Alacris Theranostics. D.L. is currently an employee of AstraZeneca and reported employment, stock ownership and patents/royalties/intellectual property for her spouse at Bayer. C.S. received honoraria from Merck Serono, I.T. took part in an advisory board by Merck Serono. D.B. is a shareholder of MicroDiscovery GmbH. U.K. reported research funding from Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, Roche, GlaxoSmithKline, AstraZeneca and Merck Serono and served as a consultant or as a member of the advisory board with Merck Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Merck Serono and GlaxoSmithKline. D.T.R. received payments as a consultant for Alacris Theranostics and honoraria from Bristol-Myers Squibb., (Copyright © 2019 Elsevier Ltd. All rights reserved.)