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2669 Background: An early crossing of the Kaplan-Meier overall survival curves in randomized clinical trials (RCTs) comparing ICI alone to standard treatments has been observed across different cancer types, suggesting the existence of an excess of mortality upon ICI. Whether ED reflects the natural history of the disease or it is a treatment specific phenomenon remains unclear. Therefore, we conducted a metanalysis of RCTs to analyze the association of ICI treatment with ED. Methods: PubMed, Embase and Cochrane were searched (until 12/2021) for RCTs comparing 1st-line PD-1/PD-L1 inhibitors +/- CTLA-4 inhibitors (ICI-only group) or the same drugs in combination with other non-ICI therapies (ICI+OT group) (experimental arms) vs non-ICI treatments (control arm) in patients (pts) with advanced solid cancers. ED was defined as death within the first 3 months of treatment. RCTs providing the number of pts in the intention-to-treat (ITT) population who were alive within 0-3 months from randomization were considered eligible. Primary outcome was ED rate both in the ICI-only and in the ICI+OT groups vs control arm. Secondary outcome was to compare ED risk between ICI-only group and ICI+OT group. Further analysis according to PD-L1 level were performed. The ED rates were estimated by risk-ratio (RR) with 95% confidence intervals (CI) and pooled by random effect model. Heterogeneity was assessed by I2 statistics. Results: 56 RCTs (n = 38697 pts) were eligible, 48.2% included pts with thoracic malignancies. In the ICI-only group (18 RCTs, n = 6638 pts) 50.5% of pts received anti-PD-1/PD-L1 monotherapy and 43.4% anti-PD-1/PD-L1 + anti-CTLA-4 agents. In the ICI+OT group (43 RCTs, n = 15421 pts) 80.1% of pts received ICI + chemotherapy. Compared to control arm, risk of ED was significantly higher for pts who received ICI-only therapies (RR 1.27, 95% CI 1.04-155, p = 0.02, I2: 73%), but significantly lower in ICI+OT group (RR 0.80, 95% CI 0.71-0.89, p < 0.00001, I2: 36%). Risk of ED was also significantly higher with ICI-only compared to ICI-OT (RR 1.59, 95% CI 1.26-2.00). ED risk was higher upon ICI-only also in pts with high PD-L1 expression (TPS ≥50%, TC or IC 3, CPS ≥10) and, after excluding Keynote-024, this result became statistically significant (7 RCTs, RR 1.54, 95% CI 1.13-2.10, p = 0.007) with I2 reducing from 63 to 46%. Conclusions: Across cancer types ED is a treatment specific phenomenon, increasing with first-line anti-PD-1/PD-L1 +/- CTLA-4 inhibitors and occurring also in pts with high PD-L1 expression, whereas it can be prevented by combining ICI with other non-ICI treatments.

e21601 Background: The introduction of Immunotherapy (IO) has dramatically improved the prognosis of patients (pts) with advanced Non-Small Cell Lung Cancer (NSCLC). However, data regarding the role of IO in ECOG Performance Status (PS) 2 pts are generally limited in randomized trials, and real-world evidences could support clinical decision-making. Methods: We retrospectively analyzed data about pts with stage IV NSCLC treated with IO between April 2013 and December 2019 in two Italian Centers. The aim of our study was to assess the impact of PS status (0-1 vs 2) on disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). Response was classified according to RECIST v1.1 criteria. PFS and OS were estimated by the Kaplan-Meier method. Chi-square test was used to compare clinical-pathological variables: gender, age ( < 70, 70-79, ≥80 years-old), smoking status, histology (squamous, non-squamous), PDL1 expression ( < 1%, ≥1%), IO line (1°, ≥2°), number (N) of metastatic sites (1, ≥2), presence of liver and/or brain metastasis. Their impact on survival was evaluated through Cox proportional hazard models. Results: Four-hundred-one pts (35.7% female) with median age of 65.4 years (range 27-88) were studied. Baseline PS was 0 in 134 pts (33.4%), 1 in 209 pts (52.1%) and 2 in 58 pts (14.5%). 312 pts had non-squamous NSCLC, 89 squamous NSCLC. Clinical-pathological variables were uniformly distributed across PS groups except for a higher rate of liver metastasis in PS2 pts ( p= 0.046). Response evaluation was available for 386 pts. DCR was 49.7% in PS0-1 pts and 25.9% in PS2 pts ( p= 0.006). At a median follow-up of 29 months (mos), median PFS was 3.0 mos (95% CI 2.63-4.00) and 2.04 mos (95% CI 1.84-3.00) in pts with PS0-1 and 2 ( p< 0.0001). Median OS was 13.2 mos (95% CI 11.18-15.78) and 4.0 mos (95% CI 2.66-5.62) in pts with PS 0-1 and 2 respectively ( p< 0.0001). Univariate analysis showed significant correlation of PS2 status, negative PDL1, IO line ≥2, N of metastatic sites ≥2 and liver metastasis, for both PFS and OS. Multivariate analysis confirmed an independent association of PS ( p= 0.0013 for PFS, p< 0.0001 for OS), PDL1 ( p= 0.0002 for PFS, p= 0.02 for OS) and liver metastasis ( p= 0.017 for PFS, p= 0.02 for OS). The incidence of Grade 3/4 adverse events was 10.5% in PS 0-1 pts and 13.7% in PS 2 pts ( p= 0.41). Conclusions: Our data confirm reduced efficacy of IO in pts with poor PS, regardless of the N of prior therapy lines or PDL1 expression. Despite IO appears to be safe and tolerable its role remains uncertain in PS2 pts based on worse survival outcomes.

9547 Background: HPD occurs in ≃10-25% of NSCLC pts upon single-agent ICI and correlates with poor prognosis. High circulating neutrophil count and neutrophils/lymphocytes ratio have been associated with shorter survival and HPD in NSCLC pts. In mouse lung cancer models, interleukin-17 (IL-17) promoted tumour growth upon ICI increasing intratumoral neutrophils. The role of specific circulating and/or tumour-associated neutrophils in driving HPD is currently unknown. Methods: NSCLC pts treated with single agent ICI were assessed for HPD and circulating neutrophils’ phenotype. Conventional PD was defined by RECIST 1.1. HPD required 3 tumour assessments (2 before ICI, 1 upon ICI) and was defined as delta tumour growth rate (TGR) (TGR upon ICI – TGR before ICI) > 50% and/or TGR ratio (TGR upon ICI/ TGR before ICI) ≥2. Correlations with continuous variables were performed by Mann-Whitney test. Circulating low density neutrophils (LDNs) subtypes were assessed by flow cytometry (FC) on peripheral blood mononuclear cells (PBMCs) from fresh blood samples. LDNs were defined as CD66b+CD15+ cells among CD11b+ PBMCs. Immature subtypes were defined as CD10− and CD10−CD16− LDNs. The occurrence of HPD upon anti-PD-1 treatment was tested in C57BL/6 immune competent mice bearing Lewis Lung Carcinoma and treated with anti-murine PD-1. Tumour associated neutrophils’ phenotype was assessed by FC. Results: Of 52 NSCLC, 65% were > 65 years, 83% had stage IV, 25% PD-L1 on tumour cells ≥50%, 67% received 1st line ICI. PD and HPD occurred in 21 (40%) and 5 (10%) pts, respectively. Before ICI start, HPD pts had higher circulating immature neutrophils measured as median percentage of CD10− LDNs [41.9 (min 26.7; max 83.5) vs 10.1 (min 0.69; max 79.3), p = 0.01] and of CD16− cells among CD10− LDNs [93 (min 89.5; max 98.4) vs 86.3 (min 24.2; max 99), p = 0.03] compared to conventional PD pts. PD and HPD occurred in 17 (71%) and 3 (12.5%) of 24 immune competent mice treated with anti-murine PD-1. The median percentage of IL-17+ tumour associated neutrophils (Gr1highLy6Clow) was significantly higher in HPD compared to PD mice [0.25 (min 0.14; max 0.63) vs 0.06 (min 0.02; max 0.32), p = 0.02]. Conclusions: Circulating immature (CD10− and CD10− CD16−) LDNs and IL-17+ tumour associated neutrophils discriminate HPD from conventional PD upon ICI in NSCLC pts and in vivo models, respectively. Functional characterization of specific neutrophil subsets is ongoing.