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