Feasibility and outcome of genomics-guided treatment selection in advanced cancer – the MEGALiT explorative clinical trial
DOI:
https://doi.org/10.2340/1651-226X.2025.43366Keywords:
precision cancer medicine, genomics, clinical trial, targeted drug, PD-1/PD-L1inhibitorsAbstract
Background: Precision cancer medicine (PCM) is key to advancing cancer treatment beyond the standard of care. We performed an explorative clinical trial, MEGALiT, to investigate the feasibility, safety, and clinical benefit of genomics-based PCM in advanced cancer.
Methods: MEGALiT recruited adult patients with advanced solid tumors refractory to standard treatment. Tumor DNA from newly acquired biopsies or ctDNA were analyzed for alterations targetable with the PD-L1 inhibitor atezolizumab, the MEK inhibitor cobimetinib, the mTOR inhibitor everolimus, or the PARP-inhibitor niraparib. Any other ‘in study’ treatment was left to the discretion of the physician.
Results: Outcome data are reported for 153 patients. The median age was 65 years and the most common diagnoses were colorectal, prostate, and ovarian cancer. The median time from study inclusion to the Molecular Tumor Board was 35 days for tumor sampling by biopsy and 21 days by ctDNA. Of the 44 patients allocated to a study drug, 38 started treatment. The median follow-up was 1.9 years. Of the patients on a study drug and evaluable for tumor response, 6% (2/32) had partial remission, and 25% (8/32) had disease control at 16 weeks. Median overall survival for patients starting a study drug was longer, 7.4 months, compared to 2.7 months for the 61 untreated patients (HR 0.43; log-rank p < 0.0001), but shorter than for the 50 patients receiving treatment of physician’s choice, 11.8 months (HR 0.55; log-rank p = 0.012). No significant procedure- or drug-related severe adverse events were observed.
Interpretation: Genomics-guided treatment selection in advanced cancer is feasible and safe. However, evidence of patient benefit warrants further investigation.
Downloads
References
Tsimberidou AM, Fountzilas E, Nikanjam M, Kurzrock R. Review of precision cancer medicine: evolution of the treatment paradigm. Cancer Treat Rev. 2020;86:102019.
https://doi.org/10.1016/j.ctrv.2020.102019 DOI: https://doi.org/10.1016/j.ctrv.2020.102019
Mateo J, Chakravarty D, Dienstmann R, Jezdic S, Gonzalez-Perez A, Lopez-Bigas N, et al. A framework to rank genomic alterations as targets for cancer precision medicine: the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). Ann Oncol. 2018;29:1895–902.
https://doi.org/10.1093/annonc/mdy263 DOI: https://doi.org/10.1093/annonc/mdy263
Velden DL, Hoes LR, Wijngaart H, Henegouwen JMB, Werkhoven E, Roepman P, et al. The drug rediscovery protocol facilitates the expanded use of existing anticancer drugs. Nature. 2019;574:1–16.
https://doi.org/10.1038/s41586-019-1600-x DOI: https://doi.org/10.1038/s41586-019-1600-x
Trédan O, Wang Q, Pissaloux D, Cassier P, de la Fouchardière A, Fayette J, et al. Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial. Ann Oncol. 2019;30:757–65.
https://doi.org/10.1093/annonc/mdz080 DOI: https://doi.org/10.1093/annonc/mdz080
Kopetz S, Shaw KRM, Lee JJ, Zhang J, Litzenburger B, Holla V, et al. Use of a targeted exome next-generation sequencing panel offers therapeutic opportunity and clinical benefit in a subset of patients with advanced cancers. JCO Precis Oncol. 2019;3:1–14.
https://doi.org/10.1200/po.18.00213 DOI: https://doi.org/10.1200/PO.18.00213
Massard C, Michiels S, Ferté C, Deley M-CL, Lacroix L, Hollebecque A, et al. High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 trial. Cancer Discov. 2017;7:586–95.
https://doi.org/10.1158/2159-8290.cd-16-1396 DOI: https://doi.org/10.1158/2159-8290.CD-16-1396
Nakamura Y, Ozaki H, Ueno M, Komatsu Y, Yuki S, Esaki T, et al. Targeted therapy guided by circulating tumor DNA analysis in advanced gastrointestinal tumors. Nat Med. 2025;31:165–75.
https://doi.org/10.1038/s41591-024-03244-8 DOI: https://doi.org/10.1038/s41591-024-03244-8
Viller Tuxen I, Staal Rohrberg K, Oestrup O, Barlebo Ahlborn L, Yde Schmidt A, Spanggaard I, et al. Copenhagen prospective personalized oncology (CoPPO) – clinical utility of using molecular profiling to select patients to phase I trials. Clin Cancer Res. 2019;25:1–10.
https://doi.org/10.1158/1078-0432.ccr-18-1780 DOI: https://doi.org/10.1158/1078-0432.CCR-18-1780
Sicklick JK, Kato S, Okamura R, Schwaederle M, Hahn ME, Williams CB, et al. Molecular profiling of cancer patients enables personalized combination therapy: the I-PREDICT study. Nat Med. 2019;15:863–21.
https://doi.org/10.1038/s41591-019-0407-5 DOI: https://doi.org/10.1038/s41591-019-0407-5
Rodón J, Soria J-C, Berger R, Miller WH, Rubin E, Kugel A, et al. Genomic and transcriptomic profiling expands precision cancer medicine: the WINTHER trial. Nat Med. 2019;2:1452–10.
https://doi.org/10.1038/s41591-019-0424-4 DOI: https://doi.org/10.1038/s41591-019-0424-4
Rothwell DG, Ayub M, Cook N, Thistlethwaite F, Carter L, Dean E, et al. Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study. Nat Med. 2019;2:1–20.
https://doi.org/10.1038/s41591-019-0380-z DOI: https://doi.org/10.1038/s41591-019-0380-z
Nakamura Y, Watanabe J, Akazawa N, Hirata K, Kataoka K, Yokota M, et al. ctDNA-based molecular residual disease and survival in resectable colorectal cancer. Nat Med. 2024;30:3272–83.
https://doi.org/10.1038/s41591-024-03254-6 DOI: https://doi.org/10.1038/s41591-024-03254-6
Puco K, Fagereng GL, Brabrand S, Niehusmann P, Blix ES, Steinskog ESS, et al. IMPRESS-Norway: improving public cancer care by implementing precision medicine in Norway; inclusion rates and preliminary results. Acta Oncol. 2024;63:28322.
https://doi.org/10.2340/1651-226x.2024.28322 DOI: https://doi.org/10.2340/1651-226X.2024.28322
Schneider BP, Jiang G, Ballinger TJ, Shen F, Chitambar C, Nanda R, et al. BRE12-158: a postneoadjuvant, randomized phase II trial of personalized therapy versus treatment of physician’s choice for patients with residual triple-negative breast cancer. J Clin Oncol. 2022;40:345–55.
https://doi.org/10.1200/jco.21.01657 DOI: https://doi.org/10.1200/JCO.21.01657
Andre F, Filleron T, Kamal M, Mosele F, Arnedos M, Dalenc F, et al. Genomics to select treatment for patients with metastatic breast cancer. Nature. 2022;610:343–8.
https://doi.org/10.1038/s41586-022-05068-3 DOI: https://doi.org/10.1038/s41586-022-05068-3
Tourneau CL, Delord J-P, Gonçalves A, Gavoille C, Dubot C, Isambert N, et al. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Lancet Oncol. 2015;16:1324–34.
https://doi.org/10.1016/s1470-2045(15)00188-6 DOI: https://doi.org/10.1016/S1470-2045(15)00188-6
Botticelli A, Scagnoli S, Conte P, Cremolini C, Ascierto PA, Cappuzzo F, et al. LBA7. The Rome trial from histology to target: the road to personalize targeted therapy and immunotherapy. Ann Oncol. 2024;35:S1202.
https://doi.org/10.1016/j.annonc.2024.08.2245 DOI: https://doi.org/10.1016/j.annonc.2024.08.2245
Kroeze LI, de Voer RM, Kamping EJ, von Rhein D, Jansen EAM, Hermsen MJW, et al. Evaluation of a hybrid capture–based pan-cancer panel for analysis of treatment stratifying oncogenic aberrations and processes. J Mol Diagn. 2020;22:757–69.
https://doi.org/10.1016/j.jmoldx.2020.02.009 DOI: https://doi.org/10.1016/j.jmoldx.2020.02.009
GMS560_synopsis.pdf. Available from: https://genomicmedicine.se/wpcontent/uploads/2023/11/GMS560_synopsis.pdf
Sanchez-Vega F, Mina M, Armenia J, Chatila WK, Luna A, La KC, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell. 2018;173:321–37.e10.
https://doi.org/10.1016/j.cell.2018.03.035 DOI: https://doi.org/10.1016/j.cell.2018.03.035
Friedman CF, Hainsworth JD, Kurzrock R, Spigel DR, Burris HA, Sweeney CJ, et al. Atezolizumab treatment of tumors with high tumor mutational burden from my pathway, a multicenter, open-label, phase 2a multiple basket study. Cancer Discov. 2021;12:654–69.
https://doi.org/10.1158/2159-8290.cd-21-0450 DOI: https://doi.org/10.1158/2159-8290.CD-21-0450
Woodhouse R, Li M, Hughes J, Delfosse D, Skoletsky J, Ma P, et al. Clinical and analytical validation of FoundationOne Liquid CDx, a novel 324-Gene cfDNA-based comprehensive genomic profiling assay for cancers of solid tumor origin. PLoS One. 2020;15:e0237802.
https://doi.org/10.1371/journal.pone.0237802 DOI: https://doi.org/10.1371/journal.pone.0237802
Nakamura Y, Taniguchi H, Ikeda M, Bando H, Kato K, Morizane C, et al. Clinical utility of circulating tumor DNA sequencing in advanced gastrointestinal cancer: SCRUM-Japan GI-SCREEN and GOZILA studies. Nat Med. 2020;26:1859–64.
https://doi.org/10.1038/s41591-020-1063-5 DOI: https://doi.org/10.1038/s41591-020-1063-5
Verdaguer H, Saurí T, Acosta DA, Guardiola M, Sierra A, Hernando J, et al. ESMO scale for clinical actionability of molecular targets driving targeted treatment in patients with cholangiocarcinoma. Clin Cancer Res. 2022;28:clincanres.2384.2021.
https://doi.org/10.1158/1078-0432.ccr-21-2384 DOI: https://doi.org/10.1158/1078-0432.CCR-21-2384
Martin-Romano P, Mezquita L, Hollebecque A, Lacroix L, Rouleau E, Gazzah A, et al. Implementing the European Society for Medical Oncology Scale for clinical actionability of molecular targets in a comprehensive profiling program: impact on precision medical oncology. JCO Precis Oncol. 2022;6:e2100484.
https://doi.org/10.1200/PO.21.00484 DOI: https://doi.org/10.1200/PO.21.00484
Taskén K, Mohammad SFH, Fagereng GL, Falk RS, Helland Å, Barjesteh van Waalwijk van Doorn-Khosrovani S et al. Collaboration for implementation of precision cancer medicine in Europe. Acta Oncol. 2024;63:34791.
https://doi.org/10.2340/1651-226x.2024.34791 DOI: https://doi.org/10.2340/1651-226X.2024.34791
Mohammad SFH, Timmer HJL, Zeverijn LJ, Geurts BS, Spiekman IAC, Verkerk K, et al. The evolution of precision oncology: the ongoing impact of the Drug Rediscovery Protocol (DRUP). Acta Oncol. 2024;63:34885.
https://doi.org/10.2340/1651-226x.2024.34885 DOI: https://doi.org/10.2340/1651-226X.2024.34885
Klute KA, Rothe M, Garrett-Mayer E, Mangat PK, Nazemzadeh R, Yost KJ, et al. Cobimetinib plus vemurafenib in patients with colorectal cancer with BRAF mutations: results from the targeted agents and profiling utilization registry (TAPUR) study. JCO Precis Oncol. 2022;6:e220019.
https://doi.org/10.1200/PO.22.00191 DOI: https://doi.org/10.1200/PO.22.00191
O’Dwyer PJ, Gray RJ, Flaherty KT, Chen AP, Li S, Wang V, et al. The NCI-MATCH trial: lessons for precision oncology. Nat Med. 2023;29:1349–57.
https://doi.org/10.1038/s41591-023-02379-4 DOI: https://doi.org/10.1038/s41591-023-02379-4
Glimelius B, Lahn M. Window-of-opportunity trials to evaluate clinical activity of new molecular entities in oncology. Ann Oncol. 2011;22:1717–25.
https://doi.org/10.1093/annonc/mdq622 DOI: https://doi.org/10.1093/annonc/mdq622
Andrei P, Battuello P, Grasso G, Rovera E, Tesio N, Bardelli A. Integrated approaches for precision oncology in colorectal cancer: the more you know, the better. Semin Cancer Biol. 2022;84:199–213.
https://doi.org/10.1016/j.semcancer.2021.04.007 DOI: https://doi.org/10.1016/j.semcancer.2021.04.007
Letai A, Bhola P, Welm AL. Functional precision oncology: testing tumors with drugs to identify vulnerabilities and novel combinations. Cancer Cell. 2022;40:26–35.
https://doi.org/10.1016/j.ccell.2021.12.004 DOI: https://doi.org/10.1016/j.ccell.2021.12.004
Beumer JH, Chu E, Salamone SJ. All optimal dosing roads lead to therapeutic drug monitoring – why take the slow lane. JAMA Oncol. 2022;8(12):1733–5.
https://doi.org/10.1001/jamaoncol.2022.4452 DOI: https://doi.org/10.1001/jamaoncol.2022.4452
Additional Files
Published
How to Cite
Issue
Section
Categories
License
Copyright (c) 2025 Lars Ny, Henrik Fagman, Johan Botling, Loviisa Mantovaara, Peter Asplund, Hannah Karlsson, Jennie Aust, Edvard Abel, Mats Hellström, Joakim Crona, Peter Nygren
This work is licensed under a Creative Commons Attribution 4.0 International License.
