Determinants of 5-year survival in patients with advanced NSCLC with PD-L1≥50% treated with first-line pembrolizumab outside of clinical trials: results from the Pembro-real 5Y global registry
Authors: Alessio Cortellini, Leonardo Brunetti, Giuseppina Rita Di Fazio, Edoardo Garbo, David J Pinato, Jarushka Naidoo, Artur Katz, Monica Loza, Joel W Neal, Carlo Genova, Scott Gettinger, So Yeon Kim, Ritujith Jayakrishnan, Talal El Zarif, Marco Russano, Federica Pecci, Alessandro Di Federico, Mark Awad, Joao V Alessi, Michele Montrone, Dwight Hall Owen, Diego Signorelli, Mary Jo Fidler, Mingjia Li, Andrea Camerini, Andrea De Giglio, Lauren Young, Bruno Vincenzi, Giulio Metro, Francesco Passiglia, Sai Yendamuri, Annalisa Guida, Michele Ghidini, Nichola O Awosika, Andrea Napolitano, Claudia A M Fulgenzi, Salvatore Grisanti, Francesco Grossi, Armida D’Incecco, Eleni Josephides, Mieke Van Hemelrijck, Alessandro Russo, Alain Gelibter, Gianpaolo Spinelli, Monica Verrico, Bartłomiej Tomasik, Raffaele Giusti, Thomas Newsom-Davis, Emilio Bria, Martin Sebastian, Maximilian Rost, Martin Forster, Uma Mukherjee, Lorenza Landi, Francesca Mazzoni, Avinash Aujayeb, Manuel Dupont, Alessandra Curioni-Fontecedro, Rita Chiari, Francesco Pantano, Alessandro Morabito, Alessandro Leonetti, Alex Friedlaender, Alfredo Addeo, Federica Zoratto, Michele De Tursi, Luca Cantini, Elisa Roca, Giannis Mountzios, Luigi Della Gravara, Sukumar Kalvapudi, Alessandro Inno, Paolo Bironzo, Rafael Di Marco Barros, David O’Reilly, Jack Bell, Eleni Karapanagiotou, Isabelle Monnet, Javier Baena, Marianna Macerelli, Margarita Majem, Francesco Agustoni, Diego Luigi Cortinovis, Giuseppe Tonini, Gabriele Minuti, Chiara Bennati, Laura Mezquita, Teresa Gorría, Alberto Servetto, Teresa Beninato, Giuseppe Lo Russo, Jacobo Rogado, Laura Moliner, Federica Biello, Frank Aboubakar Nana, Anne-Marie Dingemans, Joachim G J V Aerts, Roberto Ferrara, Valter Torri, Taher Abu Hejleh, Kazuki Takada, Abdul Rafeh Naqash, Marina Garassino, Solange Peters, Heather Wakelee, Amin H Nassar, Biagio Ricciuti
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Pembrolizumab monotherapy is an established front-line treatment for advanced non-small cell lung cancer (NSCLC) with programmed cell death-ligand 1 (PD-L1) tumor proportion score (TPS)≥50%. However, real-world data on its long-term efficacy remains sparse. Methods This study assessed 5-year outcomes of first-line pembrolizumab monotherapy in a large, multicenter, real-world cohort of patients with advanced NSCLC and PD-L1 TPS≥50%, referred to as Pembro-real 5Y. Individual patient-level data (IPD) from the experimental arm of the KEYNOTE-024 trial were extracted (KN024 IPD cohort) to compare the long-term outcomes between the two cohorts. To further assess the reproducibility of clinical trial results, we reconstructed the “KN024 look-alike” cohort by excluding patients with an Eastern Cooperative Oncology Group-performance status (ECOG-PS)≥2, those requiring corticosteroids with doses ≥10 mg of prednisolone/equivalent, patients with positive/unknown epidermal growth factor receptor/anaplastic lymphoma kinase genotype, and those with pre-existing autoimmune disease. We additionally provided a hierarchical organization of determinants of long-term benefit through a conditional inference tree analysis. Results The study included 1050 patients from 61 institutions across 14 countries, with a median follow-up of 70.3 months. The 5-year survival rate was 26.9% (95% CI: 23.8% to 30.2%), and median OS was 21.8 months (95% CI: 19.1 to 25.7), while 32 (3.0%) patients who achieved a complete response remained progression-free at the data cut-off. The KN024 look-alike cohort had a 5-year survival rate of 29.3% (95% CI: 25.5% to 33.6%) and a median OS of 27.5 months (95% CI: 22.8 to 31.3). Neither the overall study population nor the KN024 look-alike cohort exhibited significantly different OS compared with the KN024 IPD cohort. By the data cut-off, 1015 patients (96.7%) had permanently discontinued treatment: 659 (64.9%) due to progressive disease, 156 (15.4%) due to toxicity, 77 (7.6%) due to treatment completion, and 106 (10.4%) due to other reasons. Overall, 222 participants (21.1%) were treated for a minimum period of 24 months, among them the 5-year survival rates were: 31.7%, 72.7%, 78.6%, 84.2% for patients who discontinued treatment due to progressive disease, toxicity, treatment completion, and other reasons, respectively. Conclusion This study provides valuable real-world evidence that confirms the long-term efficacy of pembrolizumab outside of clinical trials. Hierarchical organization indicates ECOG-PS, age and PD-L1-TPS as the most important predictors of 5-year survival, potentially informing clinical practice.