Correlation Study On Predictors Of Fast Progression Of Non-Small Cell Lung Cancer After Immunotherapy

Objective: Immunotherapy has brought a revolutionary breakthrough in lung cancer and has become an indispensable treatment method.However,some patients experience a phenomenon that exacerbates tumor growth after receiving single-agent immunotherapy,also known as hyperprogression or fast progression(FP),with very poor prognosis.At present,the understanding of FP after immunotherapy is very limited,and there is a lack of biomarkers for predicting FP.Hence,identification of predictors of fast progress has become an urgent clinical problem.Therefore,we conducted a systematic and comprehensive study of patients’ clinicopathological factors,tumor genomic characteristics,and the tumor immune microenvironment,aiming to explore the predictive factors of the FP after immunotherapy.Methods: Part 1: The case data of patients with advanced NSCLC at Jilin Cancer Hospital from January 2015 to December 2019 were retrospectively collected.Patients were divided into the immunotherapy cohort(PD-1/PD-L1 inhibitor monotherapy in the second or later line)and the chemotherapy cohort(single-agent chemotherapy in the second or later line).FP was defined as disease progression,assessed on imaging,within <2 months of treatment initiation,considering the following parameters:(1)the total diameter of target lesions after treatment increased by ≥50% compared to baseline,(2)the total diameter of the target lesions increased by ≥20% compared to baseline,accompanied by significant progression of non-target lesions or more than two new lesions.According to the definition of FP,patients after immunotherapy or chemotherapy were divided into the FP group and the Non-FP group.The differences in baseline clinicopathological variables of patients in the FP and Non-FP groups of the two cohorts were compared,and survival analysis was performed.Part 2: We collected genomics information of patients in the immunotherapy cohort and performed next-generation sequencing(NGS)on the archived formalin-fixed paraffin-embedded(FFPE)specimens.We compared the differences in tumor genomic characteristics and tumor mutational burden between the FP and Non-FP groups and analyzed the predictive factors for survival.Part 3: In the immunotherapy cohort,immunohistochemical staining was performed on FFPE specimens to detect the expression of PD-L1,CD8,and Foxp3 in the tumor parenchymal and stromal areas,as well as detect the PD-L1+ tumor and immune cell density,CD8+ T cell density,and Foxp3+ Tregs density.The differences in the expression status and cell density of immune markers between the FP group and the Non-FP group were compared,and survival analysis was performed on the predictive factors.Results: Part 1: In total,92 patients were enrolled in the immunotherapy cohort,and86 patients were enrolled in the chemotherapy cohort.The incidence rate of FP in the immunotherapy and chemotherapy cohorts was 22.8% and 10.5%,respectively.The median OS in the FP and Non-FP groups in the immunotherapy cohort was 6.2 and17.5 months,respectively(P < 0.0001).The median OS of patients with FP and radiological PD was 6.2 and 7.8 months,respectively(P = 0.0242),suggesting that FP has a worse prognosis than radiological PD.The median OS in the FP and Non-FP groups in the chemotherapy cohort was 5.2 and 10.1 months,respectively(P <0.0001).The median OS of patients with FP and radiological PD was 5.2 and 6.7months,respectively(P = 0.1777),suggesting that there was no significant difference in survival time between FP and radiological PD.Multivariate analysis of the immunotherapy cohort indicated that tumor metastasis sites ≥3 and peripheral blood NLR ≥3 were independent predictors of FP;however,there was no predictors of FP in the chemotherapy cohort.In the immunotherapy cohort,the median OS of patients with tumor metastasis sites <3 and ≥3 was 21.7 and 10.7 months,respectively(P =0.0008),while that of patients with NLR <3 and ≥3 was 17.0 and 9.5 months,respectively(P = 0.0038).Part 2: In the immunotherapy cohort,69 adenocarcinoma patients had EGFR and ALK gene test results available,and 38 FFPE samples were tested for NGS,including15 patients with FP and 23 patients without FP.EGFR or ALK mutations were associated with FP.The median PFS of EGFR/ALK gene-negative and-positive patients was 5.6 and 1.8 months,respectively(P = 0.0027),while the median OS of EGFR/ALK gene-negative and-positive patients was 16.8 and 9.5 months,respectively(P = 0.0720).Part 3: In the immunotherapy cohort,35 FFPE specimens were stained by immunohistochemistry,including 13 in the FP group and 22 in the non-FP group.Tumor stroma PD-L1+ cell density,tumor parenchymal PD-L1-and CD8-,low tumor parenchymal PD-L1+ cell density as well as high Foxp3+ Tregs density,and low tumor parenchymal CD8+ cell density as well as high Foxp3+ Tregs density are predictors of FP.The median OS of patients with low tumor stroma PD-L1+cell density and high PD-L1+ cell density was 10.5 and 19.7 months,respectively(P =0.0080).The median OS of PD-L1-and CD8-patients and PD-L1+ and/or CD8+patients with tumor parenchyma was 6.6 and 18.6 months,respectively(P=0.0103).The median OS of patients with low tumor parenchyma PD-L1+ cell density and high Foxp3+ Tregs density and patients with high PD-L1+ cell density and/or low Foxp3+cell density was 8.6 and 19.7 months,respectively(P = 0.0078).The median OS of patients with low tumor parenchyma CD8+ T cell density and high Foxp3+ Tregs density and those with high CD8+ cell density and/or low Foxp3+ Tregs density was8.6 and 19.7 months,respectively(P = 0.0311).Conclusion: The FP phenomenon after immunotherapy is different from that after chemotherapy,and the prognosis of patients with FP after immunotherapy is worse.In patients with tumor metastasis sites ≥3,NLR ≥3,EGFR/ALK gene mutations,low tumor stromal PD-L1+ cell density,tumor parenchymal PD-L1-and CD8-,low tumor parenchymal PD-L1+ cell density as well as high Foxp3+ Tregs density,and low tumor parenchyma CD8+ T cell density as well as high Foxp3+ Tregs density,the clinical use of single-agent immunotherapy should be cautious,and the occurrence of FP should be monitored.The results of this study need to be further validated in prospective clinical studies.