The prognostic value of baseline and early variations of peripheral blood inflammatory ratios and their cellular components in patients with metastatic renal cell carcinoma treated with nivolumab: The Δ-Meet-URO analysis

Background: Treatment choice for metastatic renal cell carcinoma (mRCC) patients is still based on baseline clinical and laboratory factors. Methods: By a pre-specified analysis of the Meet-URO 15 multicentric retrospective study enrolling 571 pretreated mRCC patients receiving nivolumab, baseline and early dynamic variations (Δ) of neutrophil, lymphocyte, and platelet absolute cell counts (ACC) and their inflammatory ratios (IR) were evaluated alongside their association with the best disease response and overall (OS) and progression-free survival (PFS). Multivariable analyses on OS and PFS between baseline and Δ ACC and IR values were investigated with receiving operating curves-based cut-offs. Results: The analysis included 422 mRCC patients. Neutrophil-to-lymphocyte ratio (NLR) increased over time due to consistent neutrophil increase (p < 0.001). Higher baseline platelets (p = 0.044) and lower lymphocytes (p = 0.018), increasing neutrophil Δ (p for time-group interaction <0.001), higher baseline IR values (NLR: p = 0.012, SII: p = 0.003, PLR: p = 0.003), increasing NLR and systemic immune-inflammatory index (SII) (i.e., NLR x platelets) Δ (p for interaction time-group = 0.0053 and 0.0435, respectively) were associated with disease progression. OS and PFS were significantly shorter in patients with baseline lower lymphocytes (p < 0.001 for both) and higher platelets (p = 0.004 and p < 0.001, respectively) alongside early neutrophils Δ (p = 0.046 and p = 0.033, respectively). Early neutrophils and NLR Δ were independent prognostic factors for both OS (p = 0.014 and p = 0.011, respectively) and PFS (p = 0.023 and p = 0.001, respectively), alongside baseline NLR (p < 0.001 for both) and other known prognostic variables. Conclusions: Early neutrophils and NLR Δ may represent new dynamic prognostic factors with clinical utility for on-treatment decisions

1476P Immunohistochemical (mIHC) analyses of the immune tumor microenvironment (I-TME) in metastatic renal cell carcinoma (mRCC) patients (pts) receiving immunotherapy: Main results from the Meet-URO 18 study

Background The identification of biomarkers to select pts most likely to benefit from immunotherapy is still an unmet clinical need. The Meet-URO 18 study is a multicenter study assessing the I-TME in mRCC pts treated with ≥2nd line nivolumab divided according to clinical benefit in responders versus non-responders (progression-free survival ≥ 12 vs ≤ 3 months, respectively). Methods Histology and grading assessment and digital multitarget IHC analyses were performed on the I-TME of the primary tumor or the metastases assessing T-lineage (CD3, CD4, CD8, CD8/CD4 ratio, peritumoral T cells), macrophages (CD68) and granulocytes (CD15). Phosphorylated mTOR (ph-mTOR), CD56 and PD-L1 (SP263) expression on tumor cells were also assessed. Receiver operating curves (ROC) based on responses were used to identify cut-off values of the I-TME parameters. Differences between the two pts groups were reported as odds-ratios (OR) with the 95% CI and considered statistically significant with a p value of < 0.05. Results Overall, 116 tumor tissue samples (59% primary tumors, 41% metastases) were evaluated. Responders (N = 55) presented lower expression of CD4 and higher levels of ph-mTOR and CD56 compared to non responders. Responders showed also a tendency towards higher CD3 expression (≥40: 73% vs 56%, p=0.059) and CD8/CD4 ratio (median 1.74 vs 1.20, p=0.084). Non responders (N = 61) presented with clear cell histology (CCRCC) and higher grading. Statistically significant results are summarized in the table

IMMUNE TUMOR MICROENVIRONMENT (I-TME) ANALYSES IN METASTATIC RENAL CELL CARCINOMA (MRCC) PATIENTS (PTS) TREATED WITH SECOND LINE NIVOLUMAB: RESULTS FROM THE MEET-URO 18 STUDY

Background: To date, there are not well-established prognostic and predictive biomarkers able to predict response to immunotherapy for mRCC patients. Within the multicentric Meet-URO 18 study, we assessed the I-TME in mRCC pts treated with =2nd line nivolumab. Methods: Immunohistochemistry (IHC) analyses were performed on the primary tumor or the metastases assessing histology, grading and T-lineage (CD3, CD4, CD8, CD8/CD4 ratio, peritumoral T cells), macrophages (CD68) and granulocytes (CD15). Phosphorylated mTOR (ph-mTOR), CD56 and PD-L1 (SP263) expression on tumor cells were also assessed. Receiver operating curves (ROC) based on responses were used to identify cut-off values of IHC parameters. Patients were dichotomized in responders versus non responders according to progression-free survival (⩾ 12 vs ⩽ 3 months, respectively). Differences between the two pts groups were reported as odds ratios (OR) with the 95% CI and considered statistically significant with a p value of < 0.05. Results: Overall, 116 tumoral tissues (59% primary tumors, 41% metastases) were evaluated with responders (N = 55) presenting lower expression of CD4 and higher levels of ph-mTOR and CD56. Responders tended to have higher CD3 expression (⩾40: 73% vs 56%, p=0.059) and CD8/CD4 ratio (median 1.74 vs 1.20, p=0.084). Non responders (N = 61) presented with clear cell histology (CCRCC) and higher grading. Significant results are summarized in Table 1. Conclusions: In our study, responders to nivolumab were characterized by high expression of CD56, low levels of regulatory CD4 cells and other histologies than clear cell carcinoma. Phosphorylated mTOR could represent a new biomarker for immunotherapies to further investigate. Gene signature analyses are planned to integrate IHC analyses

A novel immunotherapy prognostic score for patients with pretreated advanced urInary TrAct CArcinoma from the subgroup analysis of the SAUL study: the ITACA Score

BACKGROUND: The current prognostic models for patients with advanced urinary tract cancers were developed and validated in the chemotherapy setting. As immunotherapy has become the backbone of novel treatments, updated prognostic scores are needed. METHODS: A comprehensive analysis of inflammatory indexes from peripheral blood and clinical factors was planned on the entire real-world cohort of pretreated patients with advanced urinary tract carcinoma receiving atezolizumab in the prospective, single-arm, phase IIIb SAUL study. Univariable and multivariable analyses with overall survival as the primary endpoint, bootstrap internal validation, Schneeweiss scoring system and calibration test were performed to develop a novel immunotherapy prognostic score. RESULTS: Thirteen clinical variables from 1001 patients were analyzed. The following eight prognostic factors were included in a model: ECOG PS, liver and bone metastases, histology, pre-treatment steroids, systemic immune-inflammatory index (i.e., neutrophils-to-lymphocytes ratio times platelets count), hemoglobin and lactate dehydrogenase. The prognostic model was able to stratify patients into five risk groups with significantly different (P<0.001) median overall survival of NR, 18.0, 8.7, 4.6 and 2.4 months, respectively. The c-index for OS was higher than the Bellmunt Score one (0.702 vs. 0.672). CONCLUSIONS: A novel 5-class prognostic model contemporary to immunotherapy provides robust prognostic discrimination of patients with advanced urinary tract carcinoma homogeneously treated with immunotherapy through baseline affordable and reproducible clinical and laboratory factors. It could be quickly adopted in clinical practice to inform patients about prognosis with immunotherapy and assess the benefit of novel immunotherapy combinations in clinical trials