Histologieagnostische Tumortherapie – Abschied von den Entitäten?

Die Diagnostik und zielgenaue therapeutische Adressierung molekularer Veränderungen hat zu einer erheblichen Verbesserung der Prognose vieler onkologischer Erkrankungen geführt. Dennoch beschränkt sich die Zulassung moderner Krebstherapeutika meist auf einzelne Tumorentitäten mit rekurrenten molekularen Alterationen. Dabei zeigen Beispiele wie NTRK-Inhibitoren das enorme Potenzial einer histologieagnostischen, molekular stratifizierten Krebstherapie.

Abstract

Considerable efforts concerning the molecular characterization and targeted treatment of cancer have significantly improved treatment options and prognosis of tumor patients. Nevertheless, in tumor entities without recurrent genetic alterations the application of molecular testing for potentially targetable lesions remains heterogeneous and, in most cases, the approval of targeted therapies is still restricted to defined tumor entities harboring corresponding predictive biomarkers.

The broad genomic analysis of different tumor entities including rare cancers within several genome sequencing initiatives and precision oncology programs has revealed the occurrence of addressable molecular alterations across many tumor entities, although their incidence may differ significantly in the context of the underlying cancer type. The treatment of molecularly defined patient cohorts demonstrated an impressive tumor-agnostic efficacy of certain therapeutics such as NTRK inhibitors, while the outcome of other targeted therapies, such as ERBB or BRAF inhibitors, varied in the context of the underlying disease.

In the meantime, a handful targeted therapeutics addressing NRTK and RET fusions, the BRAF V600E mutation or different features of defective DNA mismatch repair and high tumor mutational burden has been approved for histology-agnostic treatment of tumors harboring these target lesions. Ongoing molecularly stratified basket trials will further investigate the tumor-agnostic efficacy of different targeted treatment approaches.

Kernaussagen

• Molekular stratifizierte Therapien sind bereits Bestandteil der Leitlinien zu zahlreichen Tumorentitäten.

• Aufgrund entitätenübergreifender Distribution gut adressierbarer Biomarker besteht eine Indikation zur breiten molekularen Analyse seltener Tumorentitäten und fortgeschrittener Stadien.

• Erste zielgerichtete Therapien, wie z.B. die NTRK-Inhibitoren, wurden bereits tumoragnostisch zugelassen.

• Eine Loslösung von tumorspezifischen Therapiekonzepten ist aufgrund der zum Teil indikationsabhängigen Wirksamkeit potenter Behandlungsschemata aktuell nicht absehbar.

• Zielgerichtete Therapieempfehlungen – auf Basis einer breiten molekularen Diagnostik – sollten insbesondere außerhalb zugelassener Indikationen in interdisziplinären, molekularen Tumorboards diskutiert werden.

Schlüsselwörter

Tumorgenetik - zielgerichtete Therapie - Histologie-agnostische Behandlung - molekulares Tumorboard

Keywords

cancer genetics - targeted therapy - histology-agnostic treatment - molecular tumor board

Publikationsverlauf

Artikel online veröffentlicht:
01. September 2023

• Literatur

• 1 Chapman PB, Robert C, Larkin J. et al. Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study. Ann Oncol Off J Eur Soc Med Oncol 2017; 28: 2581-2587
• 2 Dummer R, Ascierto PA, Gogas HJ. et al. Overall survival in patients with BRAF-mutant melanoma receiving encorafenib plus binimetinib versus vemurafenib or encorafenib (COLUMBUS): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2018; 19: 1315-1327
• 3 Busaidy NL, Konda B, Wei L. et al. Dabrafenib Versus Dabrafenib + Trametinib in BRAF-Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial. Thyroid Off J Am Thyroid Assoc 2022; 32: 1184-1192 DOI: 10.1089/thy.2022.0115. (PMID: 35658604)
• 4 Planchard D, Besse B, Groen HJM. et al. Phase 2 Study of Dabrafenib Plus Trametinib in Patients With BRAF V600E-Mutant Metastatic NSCLC: Updated 5-Year Survival Rates and Genomic Analysis. J Thorac Oncol Off Publ Int Assoc Study Lung Cancer 2022; 17: 103-115
• 5 Salama AKS, Li S, Macrae ER. et al. Dabrafenib and Trametinib in Patients With Tumors With BRAFV600E Mutations: Results of the NCI-MATCH Trial Subprotocol H. J Clin Oncol Off J Am Soc Clin Oncol 2020; 38: 3895-3904
• 6 Marabelle A, Le DT, Ascierto PA. et al. Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol 2020; 38 (01) 1-10
• 7 Meric-Bernstam F, Hainsworth J, Bose R. et al. MyPathway HER2 basket study: Pertuzumab (P) + trastuzumab (H) treatment of a large, tissue-agnostic cohort of patients with HER2-positive advanced solid tumors. J Clin Oncol 2021; 39 (Suppl. 15) 3004
• 8 Doebele RC, Drilon A, Paz-Ares L. et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1–2 trials. Lancet Oncol 2020; 21: 271-282 DOI: 10.1016/S1470-2045(19)30691-6. (PMID: 31838007)
• 9 Drilon A, Laetsch TW, Kummar S. et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 2018; 378: 731-739 DOI: 10.1056/NEJMoa1714448. (PMID: 29466156)
• 10 Subbiah V, Wolf J, Konda B. et al. Tumour-agnostic efficacy and safety of selpercatinib in patients with RET fusion-positive solid tumours other than lung or thyroid tumours (LIBRETTO-001): a phase 1/2, open-label, basket trial. Lancet Oncol 2022; 23: 1261-1273 DOI: 10.1016/S1470-2045(22)00541-1. (PMID: 36108661)
• 11 Laskin J, Liu SV, Tolba K. et al. NRG1 fusion-driven tumors: biology, detection, and the therapeutic role of afatinib and other ErbB-targeting agents. Ann Oncol Off J Eur Soc Med Oncol 2020; 31: 1693-1703 DOI: 10.1016/j.annonc.2020.08.2335. (PMID: 32916265)
• 12 Schram AM, Odintsov I, Espinosa-Cotton M. et al. Zenocutuzumab, a HER2xHER3 Bispecific Antibody, Is Effective Therapy for Tumors Driven by NRG1 Gene Rearrangements. Cancer Discov 2022; 12: 1233-1247 DOI: 10.1158/2159-8290.CD-21-1119. (PMID: 35135829)
• 13 Massard C, Michiels S, Ferté C. et al. High-Throughput Genomics and Clinical Outcome in Hard-to-Treat Advanced Cancers: Results of the MOSCATO 01 Trial. Cancer Discov 2017; 7: 586-595 DOI: 10.1158/2159-8290.CD-16-1396. (PMID: 28365644)
• 14 Trédan O, Wang Q, Pissaloux D. et al. Molecular screening program to select molecular-based recommended therapies for metastatic cancer patients: analysis from the ProfiLER trial. Ann Oncol Off J Eur Soc Med Oncol 2019; 30: 757-765
• 15 Horak P, Heining C, Kreutzfeldt S. et al. Comprehensive Genomic and Transcriptomic Analysis for Guiding Therapeutic Decisions in Patients with Rare Cancers. Cancer Discov 2021; 11: 2780-2795 DOI: 10.1158/2159-8290.CD-21-0126. (PMID: 34112699)
• 16 Hyman DM, Puzanov I, Subbiah V. et al. Vemurafenib in Multiple Nonmelanoma Cancers with BRAF V600 Mutations. N Engl J Med 2015; 373: 726-736
• 17 Prahallad A, Sun C, Huang S. et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012; 483: 100-103
• 18 Tabernero J, Grothey A, Van Cutsem E. et al. Encorafenib Plus Cetuximab as a New Standard of Care for Previously Treated BRAF V600E-Mutant Metastatic Colorectal Cancer: Updated Survival Results and Subgroup Analyses from the BEACON Study. J Clin Oncol Off J Am Soc Clin Oncol 2021; 39: 273-284
• 19 Ahn ER, Mangat PK, Garrett-Mayer E. et al. Palbociclib in Patients With Non-Small-Cell Lung Cancer With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study. JCO Precis Oncol 2020; 4: 757-766
• 20 Al Baghdadi T, Halabi S, Garrett-Mayer E. et al. Palbociclib in Patients With Pancreatic and Biliary Cancer With CDKN2A Alterations: Results From the Targeted Agent and Profiling Utilization Registry Study. JCO Precis Oncol 2019; 3: 1-8