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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.

Background Novel androgen receptor signaling inhibitors for prostate cancer (PC) impose the burden of self-administration on older patients overwhelmed by the requirement of many other concomitant medications. Patients and Methods This study evaluated the proportion of non-adherence in a 12-month follow-up period and the first 3 months to abiraterone (ABI) or enzalutamide (ENZ). In a prospective multicenter observational cohort study, patients with metastatic castration-resistant PC (mCRPC) aged ≥70 years receiving ABI or ENZ pre- or post-docetaxel were enrolled. Treatment monitoring included pill counting, a self-assessment questionnaire, and clinical diaries at each clinical visit. Non-adherence rates were based on proportions of missed/prescribed pills ratios by pill counting. Results Overall, 234 patients were recruited with median age of 78 years (range, 73–82); 86 (37%) were treated with ABI, and 148 (63%) with ENZ. The median follow-up for adherence was seven monthly cycles (IQR: 4–12). The two cohorts were well balanced for baseline characteristics. The percentage of non-adherence by pill counting was slightly higher for ABI than ENZ (5.2% vs. 4.2%, P < .001). By self-reporting, patients on ENZ tended to report more frequently than those with ABI forgetfulness as the reason for missing events (42% vs. 17%, P < .001). A lower Geriatric G8 score correlated with non-adherence (P = .004). Overall survival (OS) was 48.8 months. Patients on ABI had radiographic progression-free survival (rPFS) of 28.4 [24.2–32.5], while for ENZ patients, we reported a median rPFS of 23.1 [18.2–28.1] months. Conclusion Physicians tend to treat older mCRPC patients with ENZ. Non-adherence rate is relatively low overall but can be higher with ABI than with ENZ and correlates with the Geriatric G8 score. Forgetfulness is a potential barrier for ENZ.

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.

Immune checkpoint inhibitors have improved the treatment landscape of different tumors and one of the emerging issues is the reintroduction of immunotherapy after discontinuation. Scarce evidence is currently available and different definitions have been used. The case of a patient with pretreated advanced urothelial cancer, who responded to immunotherapy retreatment after long-term benefit from the previous course, is reported. Based on a review of the different clinical scenarios, a definition of immunotherapy retreatment was proposed, as rechallenge or reintroduction, based on the reasons of discontinuation of the previous course. Clinical factors potentially associated with clinical benefit from immunotherapy retreatment are discussed, even thoughLay abstract Immunotherapy is an effective treatment option for several types of cancer. It is unclear whether a rechallenge with this treatment could be effective following its discontinuation due to disease progression, treatment toxicity or completion. This is a relevant issue as patients with metastatic cancer have few therapeutic options. Therefore, we share our clinical experience and a literature review about this topic. We report the clinical course of a patient affected by metastatic urothelial cancer whose disease responded to retreatment with immunotherapy after a previous long-term benefit from the same treatment, which was discontinued after 2 years having reached the maximum established treatment duration. We describe the different clinical scenarios of immunotherapy retreatment and factors potentially associated with a benefit from this therapeutic strategy.

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.

688 Background: Pembrolizumab/axitinib (PAXI) combination is an approved option as first-line therapy of mRCC. The aim of this analysis is to evaluate safety profile of PAXI combo in the real-world experience in Italy. Methods: This is a prospective study including patients (pts) diagnosed with mRCC who received PAXI as first-line therapy in recruiting Italian Centers. Safety data about clinically significant adverse events (AEs), defined as AE requiring corticosteroids, hormone replacement, drug delay, discontinuation or dose reduction were collected. Results: Data from 122 pts treated from January 2021 to September 2022 have been analyzed. With a median follow-up of 10 mos (range 0.2 - 21) and treatment interruption in 35 pts (29%), at landmark 6-mos and 12-mos the treatment was ongoing in 76% (95%CI 0.67-0.83) and 66% of pts (95%CI 0.56-0.75) respectively. In 11% of pts a starting dose of Axi

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 .

Advanced non-clear cell renal cell carcinoma (nccRCC) has a poor prognosis and clinical data on the therapeutic options currently available, including immunotherapy, are generally limited highlighting an unmet clinical need. Moreover, the onset of rare adverse events raises the need of a better therapeutic management of limited treatment options. We report the clinical case of a 63-year-old man with the diagnosis of metastatic mucinous tubular and spindle cell carcinoma, a rare nccRCC, with sarcomatoid differentiation who developed two episodes of posterior reversible encephalopathy syndrome (PRES) to first-line sunitinib. It appeared after 5 months the start of the targeted therapy and reappeared at the reintroduction of the therapy. PRES is a rare and unusual adverse event to anti-vascular endothelial growth factor receptor (VEGFR) therapies, which is characterized by acute neurological disorders along with typical changes on neurological imaging, especially MRI. Moreover, this rare histotype of RCC experienced a long-term response to immunotherapy which is lasting more than 2 years. This clinical case is interesting for its rarity as a rare neurological adverse event developed twice in a rare type of RCC which also experienced an unusual long-term benefit to immunotherapy.

In the scenario of systemic treatment for advanced non-small cell lung cancer (NSCLC) patients, one of the most relevant breakthroughs is represented by targeted therapies. Throughout the last years, inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), c-Ros oncogene 1 (ROS1), and V-raf murine sarcoma viral oncogene homolog B (BRAF) have been approved and are currently used in clinical practice. However, other promising molecular drivers are rapidly emerging as therapeutic targets. This review aims to cover the molecular alterations with a potential clinical impact in NSCLC, including amplifications or mutations of the mesenchymal–epithelial transition factor (MET), fusions of rearranged during transfection (RET), rearrangements of the neurotrophic tyrosine kinase (NTRK) genes, mutations of the Kirsten rat sarcoma viral oncogene (KRAS) and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), as well as amplifications or mutations of human epidermal growth factor receptor 2 (HER2). Additionally, we summarized the current status of targeted agents under investigation for such alterations. This revision of the current literature on emerging molecular targets is needed as the evolving knowledge on novel actionable oncogenic drivers and targeted agents is expected to increase the proportion of patients who will benefit from tailored therapeutic approaches.

Simple Summary Despite immune checkpoint inhibitors’ (ICIs) improved overall survival in urothelial carcinoma patients, only a minority of them benefit from immunotherapy. Therefore, there is an unmet clinical need to identify biomarkers which are useful to select the patients who are most likely to respond to ICIs. This review describes the prognostic and predictive role, and potential clinical applicability, of patient- and tumour-related factors. These factors include new molecular classes, tumour mutational burden, mutational signatures, circulating tumour DNA, programmed death-ligand 1, inflammatory indices and clinical characteristics. This summary may help clinicians to assess patients who are considered for ICI treatment, and may drive further prospective research on these biomarkers. Abstract In recent years, the treatment landscape of urothelial carcinoma has significantly changed due to the introduction of immune checkpoint inhibitors (ICIs), which are the standard of care for second-line treatment and first-line platinum-ineligible patients with advanced disease. Despite the overall survival improvement, only a minority of patients benefit from this immunotherapy. Therefore, there is an unmet need to identify prognostic and predictive biomarkers or models to select patients who will benefit from ICIs, especially in view of novel therapeutic agents. This review describes the prognostic and predictive role, and clinical readiness, of clinical and tumour factors, including new molecular classes, tumour mutational burden, mutational signatures, circulating tumour DNA, programmed death-ligand 1, inflammatory indices and clinical characteristics for patients with urothelial cancer treated with ICIs. A classification of these factors according to the levels of evidence and grades of recommendation currently indicates both a prognostic and predictive value for ctDNA and a prognostic relevance only for concomitant medications and patients’ characteristics.

Simple Summary Radium-223 is an alpha-emitting radioisotope that selectively binds to increased bone turnover areas, such as metastatic sites, acting as a bone-seeking calcium mimetic drug. Its therapeutic function in metastatic castration-resistant prostate cancer patients relies on its capability to prolong overall survival, improve quality of life, and delay the first skeletal-related event. However, in the last few years, many studies showed that the survival benefit in the real-life patients might be lower than that initially reported, probably due to a suboptimal selection of patients with poorer prognostic clinical characteristics. In this scenario, it has emerged the urgent need for the identification of reliable biomarkers able to potentially identify patients most likely to benefit from Radium-223 since baseline. With this aim, this preliminary study is the first to combine the prognostic power of baseline FDG-PET/CT and systemic inflammation indexes in a cohort of metastatic castration-resistant prostate cancer patients undergoing Radium-223 administration. Abstract Over the last years has emerged the urgent need for the identification of reliable prognostic biomarkers able to potentially identify metastatic castration-resistant prostate cancer (mCRPC) patients most likely to benefit from Radium-223 (Ra-223) since baseline. In the present monocentric retrospective study, we analyzed the prognostic power of systemic inflammation biomarkers and 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG-PET)-derived parameters and their potential interplay in this clinical setting. The following baseline laboratory parameters were collected in 59 mCRPC patients treated with Ra-223: neutrophil-to-lymphocyte ratio (NLR), derived NLR (dNLR), lymphocyte-to-monocyte ratio (LMR), platelets-to-lymphocyte ratio (PLR), and systemic inflammation index (SII), while maximum Standardized Uptake Value, Metabolic Tumor Volume (MTV), and Total Lesion Glycolysis (TLG) were calculated in the 48 of them submitted to baseline FDG-PET. At the univariate analysis, NLR, dNLR, MTV, and TLG were able to predict the overall survival (OS). However, only NLR and MTV were independent predictors of OS at the multivariate analysis. Additionally, the occurrence of both increased NLR and MTV at baseline identified mCRPC patients at higher risk for lower long-term survival after treatment with Ra-223. In conclusion, the degree of systemic inflammation, the quantification of the metabolically active tumor burden and their combination might represent potentially valuable tools for identifying mCRPC patients who are most likely to benefit from Ra-223. However, further studies are needed to reproduce these findings in larger settings.