Federica Pecci, Medical Oncologist of Department of Thoracic Oncology at the European Institute of Oncology (IEO), shared on LinkedIn:
“Glad to share our manuscript just published in JTO investigating the clinicogenomic determinants of earlier progression with osimertinib monotherapy in EGFR-mutant NSCLC.
To study early osimertinib progression further, we conducted a large international multicenter real-world study which included 1,488 patients treated with first-line osimertinib monotherapy. We investigated baseline clinicogenomic determinants of progression over time, aiming to develop a dynamic and clinically applicable framework for risk stratification.
The major strengths and findings of our study include:
- Time-dependent risk stratification: rather than only evaluating biomarkers for overall progression-free survival, we investigated when each biomarker exerts its greatest prognostic impact (6, 12, 18, 24 months), providing a dynamic model for risk of progression.
- PD-L1 TPS emerged as the strongest predictor of early progression, consistently demonstrating the greatest contribution to prediction models during the first year of treatment across multiple complementary statistical approaches.
- Integration of TP53 and tumor suppressor gene (TSG) alterations significantly improved prognostic stratification beyond individual biomarkers for progression-free survival.
- Distinct genomic determinants according to EGFR subtype: TP53 mutations had greater prognostic relevance in EGFR exon 19 deletion tumors, whereas concurrent TSG alterations were particularly informative in EGFR L858R disease, highlighting important biological differences between the two molecular subgroups.
- Biological characterization of EGFR-mutant PD-L1 positive tumors: PD-L1-positive tumors were associated with increased MET protein and transcriptomic expression together with enrichment of proliferative, inflammatory, metabolic and EMT pathways. Furthermore, tumors with PD-L1 TPS ≥50% were enriched for TP53 and TSG mutations, providing further understanding for the adverse prognostic impact associated with high PD-L1 expression.
Validation of these findings in the current first-line intensification strategies is needed.
Special thanks to Pasi Jänne, Mark Jeng, Alessandro Di Federico, Helena Yu, patients, and all the friends and colleagues across the world that made this work possible.”
Title: Clinicogenomic determinants of early progression on first-line osimertinib in EGFR-mutant NSCLC
Authors: Federica Pecci, Mark Y. Jeng, Alessandro Di Federico, Emanuele Mazzola, Marianna Peroni, Federico Monaca, Emanuele Claudio Mingo, Lodovica Zullo, Daniele Marinelli, Andrea Torchia, Francesca Colamartini, Silvia Teresa Riva, Minh Tri Le, Ayesha Aijaz, Maisam Makarem, Eleonora Gariazzo, Biagio Ricciuti, Valentina Santo, Mihaela Aldea, Edoardo Garbo, Francesco Paoloni, Ilit Turgeman, Igor Gomez-Randulfe, Andrea De Giglio, Irene Zannini, Sara Stumpo, Francesco Mantuano, Alessandro Leonetti, Michela Verzè, Roberta Minari, Marco Russano, Francesco Facchinetti, Seshiru Nakazawa, Cassio Murilo Hidalgo-Filho, Stefano Scalera, Marcello Maugeri-Saccà, Amanda Pupo, Stacey Frumm, Xinan Wang, Molly Bogardus, Jose Avila, Raphael Liautaud, Sara Baglivo, Danielle Haradon, Mizuki Nishino, Igor Odintsov, Lynette M. Sholl, Ullas Batra, Nishant Gandhi, Marzia Capelletti, Andrew Elliott, Joe Murray, George Sledge, Soo-Ryum Yang, Julia Rotow, Jaclyn LoPiccolo, Abdul Rafeh Naqash, Mark M. Awad, Antoine Desilets, Benjamin Besse, David Planchard, Alessio Cortellini, Roberto Ferrara, Giulio Metro, Federico Cappuzzo, Raffaele Califano, Andrea Ardizzoni, Marcello Tiseo, Helena Yu, Pasi A. Jänne.
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