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Multicenter Study
. 2025 Feb 4;13(2):e010674.
doi: 10.1136/jitc-2024-010674.

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

Alessio Cortellini  1   2   3 , Leonardo Brunetti  4   2   3 , Giuseppina Rita Di Fazio  4   3 , Edoardo Garbo  5 , David J Pinato  2   6 , Jarushka Naidoo  7   8   9 , Artur Katz  10 , Monica Loza  11 , Joel W Neal  11 , Carlo Genova  12 , Scott Gettinger  13 , So Yeon Kim  13 , Ritujith Jayakrishnan  13 , Talal El Zarif  13 , Marco Russano  4 , Federica Pecci  5 , Alessandro Di Federico  5 , Mark Awad  5 , Joao V Alessi  5 , Michele Montrone  14 , Dwight Hall Owen  15   16 , Diego Signorelli  17 , Mary Jo Fidler  18 , Mingjia Li  15 , Andrea Camerini  19 , Andrea De Giglio  20 , Lauren Young  21 , Bruno Vincenzi  4   3 , Giulio Metro  22 , Francesco Passiglia  23 , Sai Yendamuri  24 , Annalisa Guida  25 , Michele Ghidini  26 , Nichola O Awosika  2 , Andrea Napolitano  27 , Claudia A M Fulgenzi  2 , Salvatore Grisanti  28 , Francesco Grossi  29 , Armida D'Incecco  30 , Eleni Josephides  31 , Mieke Van Hemelrijck  31   32 , Alessandro Russo  33 , Alain Gelibter  34 , Gianpaolo Spinelli  35 , Monica Verrico  36 , Bartłomiej Tomasik  37 , Raffaele Giusti  38 , Thomas Newsom-Davis  39 , Emilio Bria  40   41 , Martin Sebastian  42 , Maximilian Rost  42 , Martin Forster  43 , Uma Mukherjee  43 , Lorenza Landi  44 , Francesca Mazzoni  45 , Avinash Aujayeb  46 , Manuel Dupont  47 , Alessandra Curioni-Fontecedro  47 , Rita Chiari  48 , Francesco Pantano  4   3 , Alessandro Morabito  49 , Alessandro Leonetti  50 , Alex Friedlaender  51 , Alfredo Addeo  52 , Federica Zoratto  53 , Michele De Tursi  54 , Luca Cantini  55 , Elisa Roca  56 , Giannis Mountzios  57 , Luigi Della Gravara  58 , Sukumar Kalvapudi  24 , Alessandro Inno  59 , Paolo Bironzo  23 , Rafael Di Marco Barros  31 , David O'Reilly  7 , Jack Bell  7 , Eleni Karapanagiotou  31 , Isabelle Monnet  60 , Javier Baena  61 , Marianna Macerelli  62 , Margarita Majem  63 , Francesco Agustoni  64 , Diego Luigi Cortinovis  65   66 , Giuseppe Tonini  4   3 , Gabriele Minuti  44 , Chiara Bennati  67 , Laura Mezquita  68 , Teresa Gorría  68 , Alberto Servetto  69 , Teresa Beninato  70 , Giuseppe Lo Russo  70 , Jacobo Rogado  71 , Laura Moliner  72 , Federica Biello  6 , Frank Aboubakar Nana  73 , Anne-Marie Dingemans  74 , Joachim G J V Aerts  74 , Roberto Ferrara  75   76 , Valter Torri  77 , Taher Abu Hejleh  78   79 , Kazuki Takada  80 , Abdul Rafeh Naqash  81 , Marina Garassino  82 , Solange Peters  83 , Heather Wakelee  11 , Amin H Nassar  13 , Biagio Ricciuti  5
Affiliations
Multicenter Study

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

Alessio Cortellini et al. J Immunother Cancer. .

Abstract

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.

Keywords: Immune Checkpoint Inhibitor; Immunotherapy; Lung Cancer.

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Conflict of interest statement

Competing interests: AC received grants for consultancies/advisory boards from MSD, BMS, OncoC4, IQVIA, AstraZeneca, REGENERON, Access Infinity, Ardelis Health, Alpha Sight, Guidepoint, Roche; speaker fees from AstraZeneca, Pierre-Fabre, MSD, Sanofi/REGENERON; payment for writing/editorial activity from BMS, MSD; travel support from Sanofi/REGENERON, MSD. JB declares honoraria/consulting or advisory role from AstraZeneca, BMS, Roche, Access Oncology, travel support from MSD, Roche, Janssen Oncology. GPS has received payment or honoraria for advisory boards from Novartis, Roche, Bayer, unrelated to this project. DO’R has received conference attendance support from Takeda, Janssen, Servier, MSD. EB has received grants or contracts from AstraZeneca, Roche and honoraria for lectures from Merck-Sharp & Dome, AstraZeneca, Pfizer, Eli-Lilly, Bristol Myers Squibb, Novartis, Takeda and Roche; EB has been member of Data Safety Monitoring Board or Advisory Board of Merck-Sharp & Dome, Pfizer, Novartis, Bristol Myers Squibb, AstraZeneca, Celltrion and Roche. AA declares consulting or advisory role for Bristol Myers Squibb, AstraZeneca, Boehringer Ingelheim, Roche, MSD, Pfizer, Eli Lilly, Astellas, Takeda, and Amgen; speaker’s bureau for Eli Lilly, and AstraZeneca. AR has received advisory board or speaker bureau honoraria from AstraZeneca, MSD, Novartis, Pfizer, BMS, Takeda, and Amgen; compensated activity for editorial projects from AstraZeneca, MSD, Novartis, Roche, and Regeneron. AL has received speakers’ fee for AstraZeneca, MSD, Sanofi and Takeda; he also received travel support from MSD and Novartis, has been on advisory board for AstraZeneca, BeiGene, Novartis and Sanofi, and has attended editorial activities sponsored by Eli Lilly and Roche. FM received honorary for advisory board roles with MDS, BMS, Takeda, Roche, AstraZeneca, Novartis. Paolo Bironzo served as consultant/advisory board for Regeneron, Pierre-Fabre, Janssen, Seagen. DO declares research funding/grants (to institution) from BMS, Merck, Palobiofarma, Pfizer, Genentech, AstraZeneca, Nuvalent, AbbVie, Onc.AI. TN-D received support to attend educational conferences from AbbVie, AstraZeneca, BMS, Boehringer Ingelheim, Lilly, MSD, Otsuka, Roche, Takeda; advisory roles for AbbVie, Amgen, Bayer, AstraZeneca, BMS, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Eli-Lilly, EQRx, Gilead, GSK, Janssen, Merck, MSD, Novartis, Novocure, Otsuka, Pfizer, Roche, Sanofi, Takeda; speaker bureau from Amgen, AstraZeneca, Chugai, Gilead, Janssen, Lilly, Medscape, Guardant, Merck, MSD, Roche, Takeda; trial steering committees’ member for AstraZeneca, Roche. BT received lecture fees from Pfizer. LC is an employee of Fortrea. BT declares honoraria from Roche. IM declares travel support from Takada, MSD, Pfizer, Oxyvie and speaker fees from Regeneron. A-MD declares research grants from Amgen, the Dutch Cancer Society and HANART, consulting fees from Amgen, Bayer, Boehringer Inglheim, Sanofy, Roche, Janssen and AstraZeneca, speaker fees from Janssen, Pfizer, AstraZeneca, Lilly and Takeda, advisory board role for Takeda and Roche. GLR declares fees for advisory boards, travel support, consultancies from MSD, BMS, Roche, Sanofi, Regeneron, Lilly, AstraZeneca, Janssen, Pfizer, Novartis, Bayer, Takeda, Amgen, GSK, Daichii. TAH declares stock interests for GlaxoSmithKline and honoraria from Novartis. BR served as consultant/advisory board for AMGEN, Regeneron, AstraZeneca, Capvision. Speaker fee: AstraZeneca. Received honoraria from Targeted Oncology, SITC. All other authors declare no conflicts of interest associated with the present study.

Figures

Figure 1
Figure 1. (A) ESMO Guidance for Reporting Oncology real-World Evidence (ESMO-GROW) flow chart for the study population. (B) Geographical distribution of participating centers. ALK, anaplastic lymphoma kinase; ECOG-PS, Eastern Cooperative Oncology Group-performance status; EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer.
Figure 2
Figure 2. Sankey diagram reporting the descriptive conditional inference tree analysis performed using an alpha level of 0.1. Patients with EGFR mutation/ALK translocation were excluded a priori, patients with missing variables were excluded. Included covariates were: age at pembrolizumab initiation (<70 vs ≥70 years old); biological sex (male vs female); ethnicity (white vs any other ethnicity); Eastern Cooperative Oncology Group-performance status (ECOG-PS) (0–1 vs≥ 2); PD-L1 TPS value (≥90% vs <90%); smoking status (never smokers vs former smokers (≥1 year) vs current smokers); primary tumor histology (non-squamous cell carcinoma vs squamous cell carcinoma); number of metastatic sites (>3 vs ≤3); corticosteroids administration at baseline within the 30 days before treatment commencement (none/doses <10 mg/day prednisolone or equivalent vs doses ≥10 mg/day prednisolone or equivalent vs none). Variables not included in the final model were those that did not produce significant splits in 5-year survival within the population. PD-L1, programmed cell death-ligand 1; TPS, tumor proportion score.
Figure 3
Figure 3. Kaplan-Meier survival estimates. (A) Overall survival and 5-year survival rates for the Pembro-real 5Y cohort and the KN024 look alike cohort; (B) overall survival and 5-year survival rates for the Pembro-real 5Y cohort and the KN024 IPD cohort; (C) overall survival and 5-year survival rates for the KN024 look alike cohort and the KN024 IPD cohort. IPD, individual patient-level data.
Figure 4
Figure 4. (A) Histogram plot reporting the 5-year survival rate with 95% CI for the whole population and the KN024 look alike cohort (light blue), for the overall study population according to the reason for treatment discontinuation (light red) and for patients with a minimum treatment duration of 24 months according to the reason for treatment discontinuation (red), p value computed with the χ2 test. (B) Kaplan-Meier survival estimates for overall survival according to the reason for discontinuation among patients with a minimum treatment duration of 24 months. P value computed with the log-rank test.
Figure 5
Figure 5. (A) Histogram plot reporting the cumulative incidence of real-world immune-related adverse events (rw-irAEs) of any grade occurred during the first 2 years of treatment among the whole study population and those occurred after the first 2 years of treatment among patients with a minimum treatment duration of 24 months. (B) Histogram plot reporting the cumulative incidence of grade 3/4 rw-irAEs occurred during the first 2 years of treatment among the whole study population and those occurred after the first 2 years of treatment among patients with a minimum treatment duration of 24 months. (C) Histogram plot reporting the cumulative incidence of rw-irAEs of any grade occurred during the first 2 years of treatment among the KN 024 look alike population and those occurred after the first 2 years of treatment among patients with a minimum treatment duration of 24 months. (D) Histogram plot reporting the cumulative incidence of grade 3/4 rw-irAEs occurred during the first 2 years of treatment among the KN 024 look alike population and those occurred after the first 2 years of treatment among patients with a minimum treatment duration of 24 months. Details reported in online supplemental table 4 and 5. irAEs, immune related adverse events; GI, gastrointestinal.
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References

    1. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016;375:1823–33. doi: 10.1056/NEJMoa1606774. - DOI - PubMed
    1. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Five-Year Outcomes With Pembrolizumab Versus Chemotherapy for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50. J Clin Oncol. 2021;39:2339–49. doi: 10.1200/JCO.21.00174. - DOI - PMC - PubMed
    1. Cortellini A, Tiseo M, Banna GL, et al. Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50. Cancer Immunol Immunother. 2020;69:2209–21. doi: 10.1007/s00262-020-02613-9. - DOI - PMC - PubMed
    1. Cortellini A, Cannita K, Tiseo M, et al. Post-progression outcomes of NSCLC patients with PD-L1 expression ≥ 50% receiving first-line single-agent pembrolizumab in a large multicentre real-world study. Eur J Cancer. 2021;148:24–35. doi: 10.1016/j.ejca.2021.02.005. - DOI - PubMed
    1. Velcheti V, Rai P, Kao Y-H, et al. 5-Year Real-World Outcomes With Frontline Pembrolizumab Monotherapy in PD-L1 Expression ≥ 50% Advanced NSCLC. Clin Lung Cancer. 2024;25:502–8. doi: 10.1016/j.cllc.2024.05.002. - DOI - PubMed

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