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

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.

References

Novello S, Kowalski D, Luft A, Gumus M, Vicente D, Mazieres J . Pembrolizumab Plus Chemotherapy in Squamous Non-Small-Cell Lung Cancer: 5-Year Update of the Phase III KEYNOTE-407 Study. J Clin Oncol. 2023; 41(11):1999-2006. PMC: 10082300. DOI: 10.1200/JCO.22.01990. View

Paz-Ares L, Ciuleanu T, Cobo M, Schenker M, Zurawski B, Menezes J . First-line nivolumab plus ipilimumab combined with two cycles of chemotherapy in patients with non-small-cell lung cancer (CheckMate 9LA): an international, randomised, open-label, phase 3 trial. Lancet Oncol. 2021; 22(2):198-211. DOI: 10.1016/S1470-2045(20)30641-0. View

Vallejo J, Singh H, Larkins E, Drezner N, Ricciuti B, Mishra-Kalyani P . Impact of Increasing PD-L1 Levels on Outcomes to PD-1/PD-L1 Inhibition in Patients With NSCLC: A Pooled Analysis of 11 Prospective Clinical Trials. Oncologist. 2024; 29(5):422-430. PMC: 11067805. DOI: 10.1093/oncolo/oyae006. View

Paz-Ares L, Luft A, Vicente D, Tafreshi A, Gumus M, Mazieres J . Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer. N Engl J Med. 2018; 379(21):2040-2051. DOI: 10.1056/NEJMoa1810865. View

Ricciuti B, Arbour K, Lin J, Vajdi A, Vokes N, Hong L . Diminished Efficacy of Programmed Death-(Ligand)1 Inhibition in STK11- and KEAP1-Mutant Lung Adenocarcinoma Is Affected by KRAS Mutation Status. J Thorac Oncol. 2021; 17(3):399-410. PMC: 10980559. DOI: 10.1016/j.jtho.2021.10.013. View

Garassino M, Gadgeel S, Speranza G, Felip E, Esteban E, Domine M . Pembrolizumab Plus Pemetrexed and Platinum in Nonsquamous Non-Small-Cell Lung Cancer: 5-Year Outcomes From the Phase 3 KEYNOTE-189 Study. J Clin Oncol. 2023; 41(11):1992-1998. PMC: 10082311. DOI: 10.1200/JCO.22.01989. View

Reck M, Rodriguez-Abreu D, Robinson A, Hui R, Csoszi T, Fulop A . Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016; 375(19):1823-1833. DOI: 10.1056/NEJMoa1606774. View

Zhou Y, Lin Z, Zhang X, Chen C, Zhao H, Hong S . First-line treatment for patients with advanced non-small cell lung carcinoma and high PD-L1 expression: pembrolizumab or pembrolizumab plus chemotherapy. J Immunother Cancer. 2019; 7(1):120. PMC: 6500047. DOI: 10.1186/s40425-019-0600-6. View

Cortellini A, Buti S, Agostinelli V, Bersanelli M . A systematic review on the emerging association between the occurrence of immune-related adverse events and clinical outcomes with checkpoint inhibitors in advanced cancer patients. Semin Oncol. 2019; 46(4-5):362-371. DOI: 10.1053/j.seminoncol.2019.10.003. View

10.

Passaro A, Spitaleri G, Gyawali B, de Marinis F . Immunotherapy in Non-Small-Cell Lung Cancer Patients With Performance Status 2: Clinical Decision Making With Scant Evidence. J Clin Oncol. 2019; 37(22):1863-1867. DOI: 10.1200/JCO.18.02118. View

11.

Nishio M, Barlesi F, West H, Ball S, Bordoni R, Cobo M . Atezolizumab Plus Chemotherapy for First-Line Treatment of Nonsquamous NSCLC: Results From the Randomized Phase 3 IMpower132 Trial. J Thorac Oncol. 2020; 16(4):653-664. DOI: 10.1016/j.jtho.2020.11.025. View

12.

Velcheti V, Rai P, Kao Y, Chirovsky D, Nunes A, Liu S . 5-Year Real-World Outcomes With Frontline Pembrolizumab Monotherapy in PD-L1 Expression ≥ 50% Advanced NSCLC. Clin Lung Cancer. 2024; 25(6):502-508.e3. DOI: 10.1016/j.cllc.2024.05.002. View

13.

Castelo-Branco L, Pellat A, Martins-Branco D, Valachis A, Derksen J, Suijkerbuijk K . ESMO Guidance for Reporting Oncology real-World evidence (GROW). Ann Oncol. 2023; 34(12):1097-1112. DOI: 10.1016/j.annonc.2023.10.001. View

14.

Garon E, Hellmann M, Rizvi N, Carcereny E, Leighl N, Ahn M . Five-Year Overall Survival for Patients With Advanced Non‒Small-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study. J Clin Oncol. 2019; 37(28):2518-2527. PMC: 6768611. DOI: 10.1200/JCO.19.00934. View

15.

Reck M, Rodriguez-Abreu D, Robinson A, Hui R, Csoszi T, Fulop A . 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(21):2339-2349. PMC: 8280089. DOI: 10.1200/JCO.21.00174. View

16.

Ricciuti B, Wang X, Alessi J, Rizvi H, Mahadevan N, Li Y . Association of High Tumor Mutation Burden in Non-Small Cell Lung Cancers With Increased Immune Infiltration and Improved Clinical Outcomes of PD-L1 Blockade Across PD-L1 Expression Levels. JAMA Oncol. 2022; 8(8):1160-1168. PMC: 9204620. DOI: 10.1001/jamaoncol.2022.1981. View

17.

Cortellini A, Tiseo M, Banna G, Cappuzzo F, Aerts J, Barbieri F . Clinicopathologic correlates of first-line pembrolizumab effectiveness in patients with advanced NSCLC and a PD-L1 expression of ≥ 50. Cancer Immunol Immunother. 2020; 69(11):2209-2221. PMC: 11027629. DOI: 10.1007/s00262-020-02613-9. View

18.

Guyot P, Ades A, Ouwens M, Welton N . Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2012; 12:9. PMC: 3313891. DOI: 10.1186/1471-2288-12-9. View

19.

Pathak R, de Lima Lopes G, Yu H, Aryal M, Ji W, Frumento K . Comparative efficacy of chemoimmunotherapy versus immunotherapy for advanced non-small cell lung cancer: A network meta-analysis of randomized trials. Cancer. 2020; 127(5):709-719. DOI: 10.1002/cncr.33269. View

20.

Cortellini A, Cannita K, Tiseo M, Cortinovis D, Aerts J, Baldessari C . 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. View