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714 Background: Intermediate IMDC group is the largest and most heterogeneous group of mRCC. Current first-line (1L) therapy options for these patients (pts) are based on either an anti-angiogenic agent (VEGFR-TKI) combined with immunotherapy (IO), or a combo of IO (ipilimumab+nivolumab [I/N]). No biomarkers (BM) for selecting the most effective regimen have been identified so far. Methods: Immunohistochemical expression of PBRM1, PD-L1, CD31, and CD4/CD8 ratio was evaluated on histological samples of intermediate-risk mRCC pts treated with VEGFR-TKI monotherapy, and then in pts receiving a VEGFR-TKI-based therapy or the immune doublet I/N. PBRM1 positivity score was based on the percentage of positive cells and on the intensity of nuclear expression; PD-L1 positivity was defined as CPS≥10; CD31 high-density had moderate to strong nuclear staining; and the CD4/CD8 ratio cut-off for positivity was >0.2. Cox model was used to assess the correlation between BM and outcomes; PFS and OS were estimated by Kaplan-Meier method. Results: After screening of tumor tissues from 150 pts, a total of 111 were included in the final analysis (Table). In pts treated with VEGFR-TKI monotherapy, a significant correlation with PFS was observed with loss of PBRM1 expression (HR 0.58, p=0.035), PD-L1 negativity (HR 0.44, p=0.048), and high CD4/CD8 ratio (HR 0.62, p=0.073). CD31 density did not significantly correlate with PFS. A profile potentially predictive of angiogenesis (AP+) was defined based on the PBRM1 loss, PD-L1 negative, and high CD4/CD8. In pts treated with VEGFR-TKI monotherapy, tumors with the AP+ (43% of all cases) had a significantly longer median PFS (mPFS 23.8 vs. 11.8 months, p=0.003) and mOS (41.5 vs. 26.9 months, p=0.024) compared to the others. The AP+ retained its significant correlation with PFS (mPFS 23.8 vs. 11.1 months, p

e14529 Background: PD-L1 is the only biomarker that has been accepted to identify patients who could potentially benefit from immune checkpoint inhibitors (ICIs) administration, but also PD-L1 negative tumors respond to immunotherapy. However, other biomarkers have been proposed but they are too expensive and actually, there is not a consensus for detection and analytical methods. Thus, there is an urgent need for inexpensive and reproducible tests to better optimize the clinical use of ICIs. Recent findings suggest that host parameters may help to select patients to treat with ICIs: performance status (PS) and some laboratory parameters, such as lactate dehydrogenase (LDH) and blood cells count. Inflammation and inflammatory response have been considered surrogate biomarkers of host immunity. An elevated neutrophil-to-lymphocyte (NLR), myeloid-to-lymphocyte (MLR) and platelet-to-lymphocyte (PLR) ratio have been associated with systemic inflammation and some evidences suggest that these biomarkers could play a role as prognostic factors. Methods: We performed a retrospective analysis of 250 patients treated with ICIs at our institution. The associations between basal NLR, MLR and PLR, clinicopathological features and their impact on progression free survival (PFS), overall survival (OS) and toxicities were assessed. Results: From May 2015 to January 2022, 250 patients were screened, of whom 66 were excluded from the analysis. A total of 184 patients (64.7% men), with a median age of 68 years (37-90) a PS 0 (52.2%), 1 (39.7%) and 2 (8.1%), were enrolled. The primary tumor origin was lung (93 adenocarcinoma, 19 squamous, 14 small cell lung cancer), urothelial (33), melanoma (4) and renal (21). Nivolumab was used in 103 patients, Pembrolizumab in 67 and atezolizumab in 18. At 24 months median follow up there were 131 progression diseases and 122 deaths. Overall, the median value of NLR, PLR and MLR was 3.15 (1-41), 168 (4-797) and 3.5 (0-245), respectively. Lower values of NLR and PLR were associated with a better median PFS (HR for NLR 1.7, 95% CI 1.2-2.4, p = 0.002; HR for PLR 2.2, 95% CI, 1.6 - 3.2, p < 0.0001) and OS (HR for NLR 1.5, 95%CI 1.1-2.2, p = 0.017; HR for PLR 1.9, 95%CI 1.3-2.7 p < 0.0001). MLR was not statistically significant. According to primary tumor origin, renal cancer reported a value significantly under the median of NLR and PLR (p = 0.015 and p = 0.021 respectively). Toxicity and clinico-pathological factors showed a significant association between female sex and both severe fatigue (p = 0.002) and pain (p = 0.018). Pain was also related to younger age (p = 0.009) and to a PS ≥2 (p = 0.003). Conclusions: Our study shows that NLR and PLR represent inexpensive, reproducible and reliable markers that may help identifying patients who can have a greater benefit from immunotherapy.

TPS407 Background: Renal cell carcinoma (RCC) is the 6° most common cancer in men and the 8° in women in the USA. In Italy RCC incidence was 11,500 new cases in 2017, while mortality was 3,371 cases in 2015. Increasing evidence suggests that response to immune checkpoint inhibitors (ICIs), a novel treatment for advanced RCC (aRCC) and other epithelial tumors, can be influenced by the patient gut microbiota. Fecal microbiota transplantation (FMT) is a novel treatment option aimed to restore healthy gut microbiota, and is the most effective therapy for recurrent C. difficile infection. Preliminary nonrandomized findings show that FMT is able to improve efficacy of ICIs in patients with advanced melanoma. The aim of this study is to evaluate, through a double-blinded placebo-controlled randomized clinical trial, the efficacy of targeted FMT (from donors who are responding to ICIs) in improving response rates to ICIs in subjects with aRCC. Methods: 50 patients who are about to receive, or have started by 12 months) responders to ICIs, and will be selected by following protocols recommended by international guidelines. Patients in the FMT group will always receive feces from the same donor throughout the three fecal transplants. Frozen fecal batches and frozen fecal capsules will be manufactured according to international guidelines. Patients will be followed-up 7, 15, 30, 90, 180, 270, and 360 days after randomization for clinical evaluation and collection of stool samples. Patients will also undergo radiological assessment at 90, 180, 270 and 360 days after randomization. Microbiome analysis will be performed with shotgun metagenomics. The primary endpoint is the progression-free survival (PFS) at 12 months. Secondary endpoints are: objective response rate at 12 months; overall survival at 12 months; adverse events after FMT; microbiome changes after FMT. Sample size calculation was based on the hypothesis that FMT can improve the 1-year PFS rate from 60% (reported 1-year PFS for SOC) to 80% wen associated to SOC. Clinical trial information: NCT04758507.

e18508 Background: Immunotherapy is the standard of care in the treatment of platinum-refractory recurrent/metastatic head and neck squamous cell carcinoma (R/M-HNSCC). Previous loco-regional treatment could have an impact on the immune system and response to Nivolumab. The aim of this study is to evaluate the efficacy and safety of Nivolumab in a real world population, identifying the impact of the clinic-pathological characteristics and previous treatment in prediction of early progression. Methods: This is a observational, multicenter retrospective/prospective study including patients (pts) with platinum refractory R/M HNSCC who received Nivolumab 240 mg every 2 weeks until disease progression or unacceptable toxicity, from October 2018 to October 2019. We analyzed treatment outcomes in term of early progression (within 3 months), clinical benefit, progression free survival (PFS) and overall survival (OS). To determine the influence on outcomes, the following variables were investigated: primary tumor sub-site, age, gender, ECOG, previous loco-regional treatment, previous systemic therapy, metastatic site. Results: Data from 61 pts were reviewed: 15 oral cavity, 14 oropharynx, 7 hyphofarynx, 19 larynx, 6 paranasal sinus. Median age was 66 years (29-82), 48 pts were men. Forty-nine pts (80%) had performance status (ECOG) ≥ 1 at baseline evaluation. Eleven pts (18%) had only loco-regional recurrence, while 50 pts (82%) had one or more metastatic site. 32 (52%) and 17 pts (28%) had smoking and alcohol abuse history, respectively. 44 pts (72%) received surgery followed by adjuvant radiant treatment at standard dose (28, 46%) or concomitant definitive radiotherapy (16, 26%) as upfront treatment with curative intent. With a median follow up of 4 months (range 1-11), early progression occurred in 39 pts during Nivolumab treatment (64%), while clinical benefit (stable disease and partial response) was achieved in 22 pts (36%). No G3-G4 toxicities occurred. Early progression to Nivolumab was significantly associated to previous loco-regional treatment both at univariate and multivariate analysis (p=0.003 and p= 0.04, respectively). Conclusions: Nivolumab in R/M HNSCC is effective and safe even though burdened with a high early progression rate. Loco-regional treatment, including wide neck dissection and high dose radiotherapy, may compromise the efficacy of Nivolumab, distorting the anatomy of the local lymphatic system and hindering the priming of immune response.

e15021Background: Immune checkpoint inhibitors have revolutionized treatment and outcome of NSCLC. Unfortunately, only 25-30% of patients have a long-term benefit, while the remaining 70-75% demons...

e13076Background: mCHT is the minimum biologically effective dose of a CHT agent, given at regular dosing regimen with no prolonged drug free interval. Aim of this observational retrospective study...

e15158Background: The combination of external-beam radiotherapy (EBRT) and PD-1 inhibitors may enhance antitumor immune responses. The aim of this study was to assess the outcome of NSCLC pts who h...

177 Background: RT-induced abscopal effect seems increase the efficacy of immunotherapy. The aim of this study was to evaluate the outcome of patients (pts) with NSCLC previously undergone to RT before receiving PD-1 inhibitors. Methods: We conducted an observational, retrospective analysis of 63 consecutive pts with advanced NSCLC who received RT followed by PD-1 inhibitors at five Italian institutions. Tumor response to treatment was defined according to Response Evaluation Criteria in Solid Tumors version 1.1. Median overall survival (OS) and the 95% confidence interval (CI) were estimated with the Kaplan -Meier method. Results: 63 pts (median age 66 years; male:60.3%) with advanced NSCLC (adenocarcinoma [adc]:71.4%; squamous cells [sqc]:28.6%) were treated with PD-1 inhibitors after RT. RT was delivered a median of 70 days before the start of immunotherapy.47 pts(74.5%)received extracranical RT and 16 pts (25.7%) performed cranial irradiation. Median OS was 11.7 months (mo) [95% CI, 4.7-18.7] (adc: 13.0 mo [95% CI,7.3-18.7], sqc 5.1 mo [95%CI,2.9-7.3]). Median progression free survival (PFS) was 5.1 mo [95% CI,2.5-7.7] (adc: 9.0 mo[ 95% CI,2.6-15.3]; sqc: 3.5 mo [95% CI,2.0-5.1]). A better performance status (PS) according to ECOG scale was associated with an improved OS (PS 0[21 pts]: 15.4 mo [95% CI,10.8-19.9]; PS1[33 pts]: 11.7 mo [95%CI,4.0-19.4]; PS2[9 pts]: 4.1 mo [95% CI,0.9-7.3]). Median OS in 46 pts who received ≤ 1 previous systemic therapy was 13.0 mo [95% CI, 9.4-16.6] and in 17 pts who received ≥2 previous treatments was 7.4 mo [95% CI, 3.1-11.7]. Median OS in 45 pts aged < 70 years was 11.7 mo [95% CI, 4.7-18.7] and in 18 elderly (≥ 70 years) was 6.5 mo [95% CI, 0.0-17.7]. 9(14.3%) partial response, 23(36.5%) stable disease and 25(39.7%) progressive disease have been observed. Conclusions: The synergic combination of RT and PD-1 inhibitors leads to an enhancement of systemic antitumor immune responses, triggering the abscopal effect, resulting in prolonged OS.

485 Background: Currently there are no biomarkers to predict either toxicity or activity of targeted therapy in mRCC. The aim of this study was to correlate single nucleotide polymorphisms (SNPs) of genes encoding for efflux transporters and metabolizing enzymes with sunitinib toxicity in metastatic renal cell carcinoma (mRCC) patients (pts). Methods: We conducted an observational, retrospective analysis of 60 Caucasian pts who received sunitinib for mRCC from 2 Italian institutions. Correlation between adverse events (AE, according to CTCAE v.4.0) and 4 polymorphisms in 3 genes (ABCB1 [1236C>T, 3435C>T], CYP3A5*3 6986A>G, CYP3A4*1B-392A>G) was analyzed. SNPs were detected in blood samples using pyrosequencing technique. Association between SNPs and toxicities was evaluated using the Chi Square test. Results: 60pts (median age: 61 years; male: 63.3%) with mRCC (clear cell: 85%, other histologies: 15%) were treated with sunitinib (83.3% as first-line). The most common AE (any-grade) reported were: hypertension (85%), asthenia (83.3%), hypothyroidism (65%), anemia (61.6%), nausea/vomiting (60%), stomatitis (58.3%), diarrhoea (48.3%), neutropenia (48.3%), thrombocytopenia (46.7%), leukopenia (46.7%), hypertriglyceridemia (45%), hyperglycaemia (38.4%), hypercholesterolemia (35%), and hand-foot syndrome (35%). Treatment was discontinued and sunitinib dose was reduced due to AE in 28.3% and 61.7% of pts, respectively. The G/A-variant in CYP3A5*3 was associated with thrombocytopenia (any grade, p=0.03); homozygous C/C alleles in ABCB1 1236C>T significantly correlated with leukopenia (any grade, p=0.01), while the C/C genotype in ABCB1 3435C>T was associated with hypertension (grade≥3, p=0.05); hypertriglyceridemia showed a trend towards increased prevalence in the presence of the C allele (grade≥3, p=0.08). Conclusions: Polymorphisms in ABCB1 and CYP3A5*3 are predictive of toxicity, as hypertension, leukopenia, and thrombocytopenia in pts with mRCC treated with sunitinib. This analysis could support the selection of the more appropriate drug to the individual patient.

174 Background: Abiraterone Acetate (AA), an effective treatment for metastatic castration resistant prostate cancer (mCRPC), is highly variable in its effectiveness and it is well known that form of primary and acquired resistance to this agent, exist. This resistance may partly depend on the increased capacity of CRPC cells to synthesize testosterone and dihydrotestosterone from weak adrenal androgens (i.e. DHEA, DHEA-S) or de novo from cholesterol, in response to a chronic exposition to a low-testosterone environment. The organic anion-transporting polypeptides (OATPs) encoded by SLCO genes, mediate the cellular uptake of many compounds, including adrenal androgens. We hypothesized that germ-line variants of the androgen transporter gene SLCO2B1 (solute carrier organic anion transporter family member 2B1), altering the ability of the prostate cancer cell to stock adrenal precursors, may influence the response to AA of mCRPC patients. Methods: Three single nucleotide polymorphisms (SNPs), exonic SNP rs12422149 and intronic SNPs rs1789693 and rs1077858, were genotyped in a cohort of 21 consecutive patients with mCRPC who were treated with AA at the Sant’Andrea Hospital of Rome, Italy. The SNPs were detected in blood samples using pyrosequencing technique. The median TTBP (Time to Biochemical Progression), PFS (Progression Free Survival) and OS (Overall Survival) was estimated using the Kaplan-Meier method, with 95% CI. To test the association between SNPs and TTBP, PFS and OS the log-rank test was used. Results: The intronic polymorphism of SLCO2B1 rs1077858A > G was associated with TTBP (p = 0.03) and PFS (p = 0.04) of mCRPC patients on AA therapy. Patients carrying the SLCO2B1 rs1077858 risk genotype (GG) exhibited a TTBP that was 8 months shorter than that of patients with the major allele of SNP rs1077858 (AA or GA) (TTBP: A/A+G/A = 12 (95% CI: 12-NA) vs G/G = 4 (95% CI: NA) months). Patients carrying genotype GG of SNP rs1077858 also showed an 11 months shorter PFS on AA therapy than patients with AA or GA genotype (PFS: GG = 5.1 (95% CI:NA) vs AA+GA = 16.7 (95%CI:14.9-NA) months). Conclusions: Genetic variants of SLCO2B1 may function as pharmacogenomic determinants of resistance to AA in mCRPC.