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Immune checkpoint inhibitors have significantly improved the therapeutic scenario of many different advanced malignancies and could be an effective treatment strategy in synchronous or metachronous tumors. The authors describe the clinical case of a patient who experienced a long-lasting response of his metastatic renal cell carcinoma and an optimal response of his locally advanced cutaneous squamous cell carcinoma to immunotherapy. The systemic treatment was chosen based on a literature review of several clinical reports, since there was no prospective study on anti-PD-1 blockade activity in cutaneous squamous cell carcinoma when the patient started the treatment. This clinical case supports the growing evidence for immunotherapy as a valid treatment option across different types of advanced tumors.Immunotherapy is an effective treatment strategy across different cancer types and could be a valid treatment strategy in patients with multiple malignant tumors. In this scenario, in fact, the main challenge is to choose a systemic treatment which could be active on both tumors with an acceptable toxicity profile. The authors report the clinical case of a patient with metastatic renal cell carcinoma and a disfiguring cutaneous cancer of the zygomatic region who experienced a durable response of the renal tumor and almost a complete clinical response of the cutaneous cancer.

Recent studies have shown that immune-related adverse events (irAEs), occurring even after the discontinuation of immune checkpoint inhibitors (ICIs), may be associated with favorable disease outcomes, particularly in patients with melanoma and lung cancer. However, a few clinical cases have been described on the correlation between irAEs and ICIs efficacy in renal cell carcinoma (RCC) patients. This study reports the clinical case of a metastatic RCC patient who has experienced severe immune-related renal toxicity after 19 months of nivolumab use. Despite immunotherapy discontinuation, the patient has maintained clinical benefit and disease progression-free for 3 years. We examined the correlation between the occurrence and the severity of irAEs, treatment discontinuation and clinical benefits. The evidence on ICI retreatment following ICI discontinuation due to irAEs was also reviewed.Lay abstract Immunotherapy has profoundly changed the treatment scenario of cancer patients. However, similar to any oncological therapy, it may cause immune-related adverse events. Cancer patients experiencing immune-related adverse events have a higher probability of better survival outcomes. This correlation has been largely described in patients with melanoma and lung cancer, but only a few data have been reported for genitourinary tumor patients. Here, we report the clinical case of a metastatic renal cell carcinoma patient who has experienced a late-onset and severe immune-related renal toxicity after 19 months of immunotherapy, which led to treatment discontinuation. Despite this, the patient has maintained a clinical benefit and disease progression-free for more than 3.5 years. We reviewed the literature on the correlation between immunotherapy benefit and immune-related adverse events, considering the time of onset, the severity of the adverse events and the concepts of treatment discontinuation and retreatment.

Background: Prognostic and predictive factors for patients with metastatic renal cell carcinoma (mRCC) treated with immunotherapy are highly warranted, and the immune tumor microenvironment (I-TME) is under investigation. Methods: The Meet-URO 18 was a multicentric retrospective study assessing the I-TME in mRCC patients treated with ≥2nd-line nivolumab, dichotomized into responders and non-responders according to progression-free survival (≥12 months and ≤3 months, respectively). The primary objective was to identify differential immunohistochemical (IHC) patterns between the two groups. Lymphocyte infiltration and the expressions of different proteins on tumor cells (CD56, CD15, CD68, and ph-mTOR) were analyzed. The expression of PD-L1 was also assessed. Results: A total of 116 tumor tissue samples from 84 patients (59% were primary tumors and 41% were metastases) were evaluated. Samples from responders (N = 55) were significantly associated with lower expression of CD4+ T lymphocytes and higher levels of ph-mTOR and CD56+ compared with samples from non-responders (N = 61). Responders also showed a higher CD3+ expression (p = 0.059) and CD8+/CD4+ ratio (p = 0.084). Non-responders were significantly associated with a higher percentage of clear cell histology and grading. Conclusions: Differential IHC patterns between the tumors in patients who were responders and non-responders to nivolumab were identified. Further investigation with genomic analyses is planned.

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.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.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 (P0.001) 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).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.

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 analysed. 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), haemoglobin 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 couls be quickly adopted in clinical practice to inform patients about prognosis with immunotherapy and assess the benefit of novel immunotherapy combinations in clinical trials.

Multigene germline panel testing is recommended for Pancreatic Cancer (PC) patients; however, for non-BRCA1/2 genes, the clinical utility is unclear. A comprehensive multi-gene assessment in unselected Italian PC patients is missing. We evaluated the prevalence and impact of Pathogenic Variants (PV) in 51 PC susceptibility genes in a real-world series of 422 Italian PC patients unselected for Family History (FH), compared the clinical characteristics and conducted survival analyses. 17% of patients had PVs (70/422), mainly in BRCA1/2 (4.5%, all 50 y), ATM (2.1%). PV carriers were younger (64 vs. 67; p = 0.02) and had more frequent personal/FH of PC, melanoma and breast/ovarian cancer (all p < 0.05). The Overall Survival (OS) was longer in patients carrying PVs (HR 0.78; p = 0.090), comprising ATM carriers (HR 0.33; p = 0.054). In the oxaliplatin-treated subset, PV carriers showed better control of the disease, although this was not statistically significant (67% vs. 56%). CDKN2A, BRCA2 and ATM were the most frequently altered genes. ATM PVs were positively associated with OS in 41% of PV carriers, 60% of whom carried CDKN2A,BRCA2 or ATM PVs, had negative FH and would have been missed by traditional referral. Thus, CDKN2A and ATM should be added to BRCA1/2 testing regardless of FH.

Major advances have been made in CRC treatment in recent years, especially in molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do not benefit from these treatments and their prognosis remains poor. The landscape of DNA damage response (DDR) alterations is emerging as a novel target for treatment in different cancer types. PARP inhibitors have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancers carrying deleterious BRCA1/2 pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on the emerging role of HRD in CRC and showed that alterations in these genes, either germline or somatic, are carried by up to 15–20% of CRCs. However, the role of HRD is still widely unknown, and few data about their clinical impact are available, especially in CRC patients. In this review, we report preclinical and clinical data currently available on DDR inhibitors in CRC. We also emphasize the predictive role of DDR mutations in response to platinum-based chemotherapy and the potential clinical role of DDR inhibitors. More preclinical and clinical trials are required to better understand the impact of DDR alterations in CRC patients and the therapeutic opportunities with novel DDR inhibitors.

Gastrointestinal stromal tumors (GISTs) are one of the most common mesenchymal tumors characterized by different molecular alterations that lead to specific clinical presentations and behaviors. In the last twenty years, thanks to the discovery of these mutations, several new treatment options have emerged. This review provides an extensive overview of GISTs’ molecular pathways and their respective tailored therapeutic strategies. Furthermore, current treatment strategies under investigation and future perspectives are analyzed and discussed.

TPS753 Background: Several studies suggested that response to immunotherapy may be influenced by many factors, including peripheral blood biomarkers, the composition of I-TME and different molecular expression pathways. In mRCC patients, immunotherapy has become part of clinical practice, but the identification of patients most likely to respond to checkpoint inhibitors is still an unmet clinical need. Moreover, there are no validated and clinically applicable gene expression panels as prognostic and/or predictive response biomarkers. To date, three major groups of immune-related gene expression were identified in mRCC: the angiogenesis pathway, the T-effector pathway and the mixed pathway (doi: 10.1038/s41598-020-58804-y). Each group of gene expression seems to be responsible for a different type of immune response in the I-TME. However, a significant association with treatment response to immunotherapy has not yet been demonstrated. Methods: The Meet-URO 18 is a multicentric retrospective translational study aimed at identifying distinctive molecular patterns of the I-TME with a prognostic and predictive role in mRCC (primary objective). Pretreated mRCC patients receiving ≥2nd line nivolumab have been divided according to clinical benefit in responders (PFS ≥ 12 months) versus non-responders (PFS ≤ 3 months). Secondary objectives include the correlation between primary tumor and metastases to identify a potential inter-tumor heterogeneity and the correlation with survival and response outcomes. Histological samples of primary tumors and/or metastases have been collected for the transcriptomic analyses together with clinical data of patients from medical records. The transcriptomic characterization of the I-TME of the primary tumor and/or metastases will be performed using the analytical platform "nCounter" of NanoString®, which analyzes the expression of 71 genes involved in angiogenesis, immunomodulation mediated by T-effector response, mechanisms of tumor invasion and mechanisms of calcium channel flows. The gene-panel include a group of 66 genes previously demonstrated to be related in the immune-response in mRCC (doi: 10.1038/s41598-020-58804-y) and 5 housekeeping genes (RPS13, PPIA, RPL27, RP2, B-ACT).

637 Background: The combination of neutrophil to lymphocyte (NLR), bone metastases and IMDC score in the novel prognostic Meet-URO score has shown a higher prognostic performance than the IMDC score alone in mRCC pts receiving ≥2nd line nivolumab or cabozantinib in two retrospective analyses and 1st line nivolumab-ipilimumab in a real-world prospective study [http://bit.ly/Meet-URO15_score]. Further validation is needed since this score represents an easy prognostic tool for clinical practice with no additional costs. Methods: A real-world analysis of elderly (≥70 yo) mRCC pts treated with any line cabozantinib was conducted in the multicenter observational prospective Zebra study. Baseline Meet-URO score was assessed. The primary endpoint was overall survival (OS) and the Harrell’s c-index was calculated to compare accuracy of survival prediction of the Meet-URO and IMDC scores. Results: 104 mRCC pts received cabozantinib as 1st (38%), 2nd (20%), 3rd (33%) and 4th (8%) line, with a median follow-up of 11.2 months (mo) and a median overall survival (mOS) of 18.4 mo. According to the IMDC score, favorable- (15%), intermediate- (65%) and poor-risk (19%) pts had a mOS not reached (NR), 15.6 and of 5.7 mo, respectively (p = 0.011). Reclassifying the population according to the Meet-URO score, we observed that group 1 (10%) and group 2 (25%) had both mOS NR, whereas group 3 (33%), group 4 (25%) and group 5 (8%) had a mOS of 13.6, 12.5 and 3.7 mo, respectively (p = 0.001). Moreover, the Meet-URO score maintained its discrimination ability also merging group 1-2 vs 3-4 vs 5 (p < 0.001). NLR < 3.2 was the heaviest component of the score (p < 0.001, mOS 24.8 vs 11.5 mo). The Meet-URO score (using both original with 5 groups and modified with 3 groups) has shown a higher prognostic power than the IMDC score alone (c-index of 0.686 and 0.676 vs 0.622). Conclusions: This analysis confirmed the higher accuracy in survival stratification of the Meet-URO score compared with the IMDC score alone also in a specific population like elderly mRCC pts treated with cabozantinib. NLR was confirmed as a strong prognostic factor with cabozantinib. Further applications of the Meet-URO score in mRCC pts treated with first-line immune-combinations are planned and highly awaited. Clinical trial information: 2018/116/PU .

Objective Androgen deprivation therapy alters body composition promoting a significant loss in skeletal muscle (SM) mass through inflammation and oxidative damage. We verified whether SM anthropometric composition and metabolism are associated with unfavourable overall survival (OS) in a retrospective cohort of metastatic castration-resistant prostate cancer (mCRPC) patients submitted to 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG PET/CT) imaging before receiving Radium-223. Patients and methods Low-dose CT were opportunistically analysed using a cross-sectional approach to calculate SM and adipose tissue areas at the third lumbar vertebra level. Moreover, a 3D computational method was used to extract psoas muscles to evaluate their volume, Hounsfield Units (HU) and FDG retention estimated by the standardized uptake value (SUV). Baseline established clinical, lab and imaging prognosticators were also recorded. Results SM area predicted OS at univariate analysis. However, this capability was not additive to the power of mean HU and maximum SUV of psoas muscles volume. These factors were thus combined in the Attenuation Metabolic Index (AMI) whose power was tested in a novel uni- and multivariable model. While Prostate-Specific Antigen (PSA), Alkaline Phosphatase (ALP), Lactate Dehydrogenase and Hemoglobin, Metabolic Tumor Volume, Total Lesion Glycolysis and AMI were associated with long-term OS at the univariate analyses, only PSA, ALP and AMI resulted in independent prognosticator at the multivariate analysis. Conclusion The present data suggest that assessing individual 'patients' SM metrics through an opportunistic operator-independent computational analysis of FDG PET/CT imaging provides prognostic insights in mCRPC patients candidates to receive Radium-223. Graphical abstract