Prognostic value of tumor microenvironment (TME) features in advanced, EGFR-mutant non-small cell lung cancer (NSCLC)

Abstract Background: Prognostic role of tumor microenvironment (TME) features, although well-studied in the context of immunotherapy responses, remains unclear for oncogene-driven non-small cell lung cancer (NSCLC). Here, we interrogate the impact of TME features on survival outcomes of patients with advanced EGFR-mutant NSCLC. Methods: A single-center, retrospective study was carried out on patients with advanced EGFR-mutant (exon 19 deletion/L858R) NSCLC who underwent first-line targeted therapy or chemotherapy. Clinical, radiological, molecular, pathological data were collected. Hematoxylin-eosin diagnostic tissue slides, digitalized at 20x magnification, were analyzed by an expert pathologist and a medical oncologist, blinded to clinical data, to describe TME. Tumor-infiltrating lymphocytes (TILs), excluding polymorphonucleates, were assessed in the stromal compartment as positive (+) or negative (-), with positivity threshold of 10% of stromal tissue area. Fibrosis, necrosis, tertiary lymphoid structures (TLSs) and lymphangitis were assessed with a positivity threshold of 1%. Progression free survival (PFS) and overall survival (OS) were calculated from the start of first-line therapy and compared by log-rank test. Multivariable analysis by Cox regression model for OS included age, gender, PS-ECOG, number (n) of metastatic sites, presence of brain metastases and TME features. Results: A total of 118 patients were included: 52 treated with first-line osimertinib, 47 with gefitinib/erlotinib, 19 with platinum-based chemotherapy. The patient population included 84 (71%) females, 77 (65%) never smokers. Median age was 64 years (range 34-91), median n of metastatic sites was 2, PS ECOG was <2 in 91 (77%) and brain metastases were present in 48 (41%) cases. Most common biopsy site was lung (70%). Fibrosis, TILs, lymphangitis, necrosis, TLSs were found in 76/95 (80%), 34/93 (37%), 35/95 (37%), 28/94 (30%), and 12/92 (13%) of evaluable samples, respectively. After a median follow-up of 50.3 months (m), median OS was 35.2 (95%CI 27.8-41.6) m in the overall population; 23.1 (95%CI 18.2-39.3) vs 36.3 (95%CI 32.1-51.3) m (p=0.007) in necrosis+ vs -; 27.7 (95%CI 26.6- not reached, NR) vs 35.5 (95% CI 27.8-48.5) m (p=0.85) in TILs+ vs TILs-; 38.1 (95%CI 36.6-NR) vs 32.1 (95%CI 27-44.7) m (p=0.94) in TLS+ vs TLS-. Nine (26%) TILs+ tumors were also necrosis+. Necrosis (HR 2.05, p=0.026) and PS>1 (HR 2.52, p<0.01) were independently associated with worse OS in the multivariable analysis. In necrosis+ vs -, median PFS to first-line was 11.4 (95%CI 3,6-NR) vs 11.2 (95%CI 9.3-NR) m in osimertinib (p=0.67) and 7.8 (95%CI 5.4-NR) vs 13 (95%CI 8.7-20.1) in erlotinib/gefitinib group (p=0.84). Conclusions: Necrosis emerges as a negative prognostic factor for EGFR-mutant NSCLC. The role of osimertinib in counteracting the impact of necrosis should be elucidated on a larger scale to yield more substantial data. Further analyses will be performed on patients treated with anti-angiogenic agents. Citation Format: Lodovica Zullo, Maria Rosa Ghigna, Wael Salem Zrafi, Arianna Marinello, Damien Vasseur, Maxime Frelaut, Pamela Abdayem, Marco Tagliamento, Pernelle Lavaud, Anas Gazzah, Jean-Yves Scoazec, Jordi Remon, Fabrice Barlesi, Benjamin Besse, David Planchard, Mihaela Aldea. Prognostic value of tumor microenvironment (TME) features in advanced, EGFR-mutant non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C168.