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BackgroundImmune checkpoint inhibitors (ICIs) represent the standard of care as first- or second-line treatment in patients with renal cell carcinoma (RCC). Proton pump inhibitors (PPIs) are among the most prescribed drugs worldwide and are known to affect gut microbiota, which is gaining interest in its association with outcomes for patients on ICIs.ObjectiveThe aim of this study was to evaluate the impact of PPIs on outcomes in RCC patients receiving immunotherapy.Patients and MethodsWe retrospectively collected data from patients with metastatic RCC who received the combination of ipilimumab and nivolumab for first-line treatment (Cohort 1) or single-agent nivolumab for second-line or third-line treatment (Cohort 2) from five international centers with expertise in the treatment of RCC. Data about clinicopathological characteristics, PPI use, and outcome on ICIs were collected. Endpoints of the study were objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).ResultsTwo hundred and eighteen patients (71% male, median age 61 years) were included in the analysis, 62 in Cohort 1 (including 25 patients receiving PPIs) and 156 in Cohort 2 (including 88 patients receiving PPIs), and were followed up for a median of 42 months. In Cohort 1, no difference was observed in ORR (48% vs 57%; p = 0.203), PFS (12.2 vs 8.5 months; p = 0.928), or OS (not reached [NR] vs 27.3 months; p = 0.84). In Cohort 2, no difference was observed in ORR (32% vs 28%; p = 0.538), PFS (6.7 vs 9.0 months; p = 0.799), or OS (16.0 vs 26.0 months; p = 0.324).ConclusionsIn patients with RCC, concomitant PPI use did not seem to affect survival outcomes on ICIs, either as combination therapy or monotherapy.

Background Nowadays, different therapeutic options are available for the first-line treatment of metastatic renal cell carcinoma (mRCC). Immuno-combinations are the standard first-line therapy in all mRCC patients regardless of the International Metastatic RCC Database Consortium (IMDC) risk category, even though TKI monotherapy is still a therapeutic option in selected patients. However, comparisons between the different first-line treatment strategies are lacking and few real-world data are available in this setting. For this reason, the regimen choice represents an important issue in clinical practice and the optimal treatment sequence remains unclear. Methods The REGAL study is a multicentric prospective observational study enrolling mRCC patients treated with first-line systemic therapy according to clinical practice in a real-world setting. A retrospective cohort of mRCC patients who received first-line systemic therapy from the 1st of January 2021 will also be included. The primary objective is to identify potential prognostic and predictive factors that could help guide the treatment choice; secondary objectives included the assessment of the prognostic performance of the novel prognostic Meet-URO score (IMDC score + neutrophil-to-lymphocyte ratio + bone metastases) compared with the IMDC score and the comparison between treatment strategies according to response and survival outcomes and toxicity profile. Discussion Considering the high number of therapeutic first-line strategies available for mRCC, the identification of clinical prognostic and predictive factors to candidate patients to a preferable systemic therapy is still an unmet clinical need. The Meet-URO 33 study aims to provide a large-scale real-world database on mRCC patients, to identify the clinical predictive and prognostic factors and the different performances between the ICI-based combinations according to response, survival and toxicity. Trial Registration CESC IOV 2023-78.

Background: The addition of neutrophil-to-lymphocyte ratio (NLR) and bone metastases to the International Metastatic RCC Database Consortium (IMDC) score (by the Meet-URO score) has been shown to better stratify pretreated metastatic renal cell carcinoma (mRCC) patients receiving nivolumab. This study aimed to validate the Meet-URO score in patients receiving cabozantinib to assess its predictivity and prognostic role. Methods: A multicenter retrospective analysis evaluated mRCC patients receiving ⩾second-line cabozantinib. NLR, IMDC score and bone metastases were assessed before the start of cabozantinib. The primary endpoint was overall survival (OS). Harrell’s c-index was calculated to compare the accuracy of the prediction of the two scores. Results: Overall, 174 mRCC patients received cabozantinib as second and third line (51.7% and 48.3%, respectively) with a median follow-up of 6.8 months. A shorter median overall survival (mOS) was observed for the IMDC poor-risk group, NLR ⩾3.2 and the presence of bone metastases, while the IMDC intermediate-risk group had a similar mOS to the favourable-risk one. Applying the Meet-URO score, three risk groups were identified: group 1 (55.2% of patients) with a score of 0–3, group 2 (38.5%) with a score of 4–8 and group 3 (6.3%) with a score of 9. Compared to group 1 (mOS: 39.4 months), a statistically significant worse mOS was observed in group 2 (11.2 months) and group 3 (3.2 months) patients, respectively. The Meet-URO c-index score was 0.640, showing a higher discriminative ability than the IMDC score (c-index: 0.568). Conclusion: This analysis showed that the Meet-URO score provides a more accurate prognostic stratification than the IMDC score in mRCC patients treated with ⩾second-line cabozantinib besides nivolumab. Moreover, it is an easy-to-use tool with no additional costs for clinical practice (web-calculator is available at: https://proviso.shinyapps.io/Meet-URO15_score/). Future investigations will include the application of the Meet-URO score to the first-line immunotherapy-based combination therapies.

BackgroundAngiogenesis has been recognized as the most important factor for tumor invasion, proliferation, and progression in metastatic renal cell carcinoma (mRCC). However, few clinical data are available regarding the efficacy of cabozantinib following immunotherapy.ObjectiveTo describe the outcome of cabozantinib in patients previously treated with immunotherapy.Patients and methodsPatients with mRCC who received cabozantinib immediately after nivolumab were included. The primary endpoint was to assess the outcome in terms of efficacy and activity.ResultsEighty-four mRCC patients met the criteria to be included in the final analysis. After a median follow-up of 9.4 months, median overall survival was 17.3 months. According to the IMDC criteria, the rates of patients alive at 12 months in the good, intermediate, and poor prognostic groups were 100%, 74%, and 33%, respectively (p < 0.001). The median progression-free survival (PFS) was 11.5 months (95% CI 8.3–14.7); no difference was found based on duration of previous first-line therapy or nivolumab PFS. The overall response rate was 52%, stable disease was found as the best response in 25.3% and progressive disease in 22.7% of patients. Among the 35 patients with progressive disease on nivolumab, 26 (74.3%) patients showed complete/partial response or stable disease with cabozantinib as best response after nivolumab. The major limitations of this study are the retrospective nature and the short follow-up.ConclusionsCabozantinib was shown to be effective and active in patients previously receiving immune checkpoint inhibitors. Therefore, cabozantinib can be considered a valid therapeutic option for previously treated mRCC patients, irrespective of the type and duration of prior therapies.

Purpose of ReviewTherapeutic alternatives to treat metastatic renal cell carcinoma (mRCC) are increasing, and combination therapies, including antiangiogenic agents and tyrosine kinase/mTOR/immune checkpoint inhibitors, are identified as the gold standard driven by the results of recent clinical studies. Nevertheless, the real-world RCC population is very heterogeneous, with categories of patients not represented in the enrolled trial population who may not benefit more from these treatments. The purpose of this expert review is to assess the rationale on which tyrosine kinase alone may still be a viable first-line treatment option for some subgroups of patients with mRCC.Recent FindingsThe first-line treatment with tyrosine kinase inhibitor monotherapy can still be considered an effective tool for addressing selected mRCCs, as highlighted by the successful outcome in a range of subjects such as favorable-risk patients, the ones suffering from autoimmune diseases, those with pancreatic or lung metastases, or previously undergoing organ transplantation and elderly subjects.SummarySome selected categories of patients may still benefit from monotherapy with TKI, and smart sequential therapies can also be considered instead of a combination strategy. Tyrosine kinase inhibitors can also act as immune modulator agents, boosting the immune response to facilitate and potentiate the therapeutic effectiveness of subsequent immunotherapy.

Background Severe immune-related Adverse Events (irAEs) develop in 10–27% of patients treated with Immune-Oncology (IO) [Powles (Lancet 391:748–757, 2018); Galsky (Lancet 395:1547–1557, 2020); Haanen (Ann Oncol 28:119–142, 2017)]. The aim of our study was to evaluate efficacy and clinical outcome of metastatic renal cell carcinoma (mRCC) patients who stopped Immune Checkpoint Inhibitors (ICIs) due to early Grade (G) 3-G4 irAEs. Methods We retrospectively collected data from 204 mRCC patients treated with ICIs in 6 Italian referral centers adhering to the Meet-Uro group, between February 2017 and January 2020. To properly weight the results, patients who did not report early G3–G4 toxicities have been included as control group. Primary endpoint was to evaluate 6 months Progression Free Survival (PFS) after early treatment interruption for Grade (G) 3–4 toxicities compared to the control group. Secondary endpoints were to evaluate Time to treatment failure (TTF) and overall survival (OS) in both groups. All statistical analyses were performed using SPSS software (version 19.00, SPSS, Chicago). Results 18/204 (8.8%) patients had early treatment interruption for serious (G3-G4) irAEs. Early was defined as interruption of IO after only one or two administrations. Immune related nephritis and pancreatitis were the most common irAE that lead to treatment interruption. 6/18 patients received IO-IO combination whereas 12/18 patients antiPD1. In the study group, 12/18 (66.6%) were free from progression at 6 months since IO interruption, TTF was 1.6 months (95% CI 1.6–2.1), mPFS was 7.4 months (95% CI 3.16–11.6) and mOS was 15.5 months (5.1–25.8). In the control group 111/184 (60.3%) patients were free from progression at 6 months, TTF was 4.6 months (95% CI 3.5–5.6), mPFS was 4.6 months (95% CI 3.5–5.6) and mOS was 19.6 months (95% CI 15.1–24.0). In the overall population, mPFS was 5.0 months (95% CI 4.0–5.9) and mOS was 19.6 months (95% CI 15.1–24.0). Conclusions ICIs seem to maintain efficacy even after early interruption due to severe irAE.

Background: Although the relationship between androgen deprivation therapy (ADT) for prostate cancer (PC) and the biological mechanisms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection remains unequivocally unclear, it is possible that exposure to the virus may influence PC evolution by altering TMPRSS2 expression. This study aims to evaluate the long-term oncological outcomes of patients with metastatic PC who were undergoing medical therapy at the time of contracting SARS-CoV-2 and who resumed/continued anticancer treatment after recovery. Methods: We retrospectively evaluated a consecutive series of 151 metastatic PC patients who developed SARS-CoV-2 infection while receiving one active systemic anticancer therapy (125 metastatic castration-resistant PC (mCRPC) patients and 26 metastatic hormone-sensitive PC (mHSPC) patients). We evaluated variables that influence the ability to maintain or resume the ongoing therapy. For the maintained/resumed therapies, we calculated the post-infection overall survival (piOS) and the overall survival (OS). Results: Of the patients, 12.6% died due to SARS-CoV-2 infection, 10.6% recovered from the infection but failed to maintain/resume the ongoing anticancer treatment, and the remaining 76.8% maintained/resumed the treatment after recovery. Hospitalization, duration of infection, and the type of ongoing anticancer agent influenced these treatment changes. In the cohort of mCRPC patients, the median piOS was 32 months, and the median OS was 67.8 months. The median piOS was not achieved in the cohort of mHSPC patients, while the median OS was 122 months. The outcomes of single anticancer agents were in line with those of pivotal trials. Conclusions: Although observed in a highly selected population of PC patients who survived SARS-CoV-2 infection and were able to resume/maintain anticancer therapy, the survival outcomes of this study appear to be in line with those reported in pivotal studies, and SARS-CoV-2 infection does not seem to have adversely affected long-term oncological outcomes.

BackgroundIn preclinical studies, combining M9241 (a novel immunocytokine containing interleukin (IL)-12 heterodimers) with avelumab (anti-programmed death ligand 1 antibody) resulted in additive or synergistic antitumor effects. We report dose-escalation and dose-expansion results from the phase Ib JAVELIN IL-12 trial investigating M9241 plus avelumab.MethodsIn the dose-escalation part of JAVELIN IL-12 (NCT02994953), eligible patients had locally advanced or metastatic solid tumors; in the dose-expansion part, eligible patients had locally advanced or metastatic urothelial carcinoma (UC) that had progressed with first-line therapy. Patients received M9241 at 4, 8, 12, or 16.8 µg/kg every 4 weeks (Q4W) plus avelumab 10 mg/kg every 2 weeks (Q2W, dose levels (DLs) 1–4) or M9241 16.8 µg/kg Q4W plus avelumab 800 mg once a week for 12 weeks followed by Q2W (DL5/dose expansion). Primary endpoints for the dose-escalation part were adverse events (AEs) and dose-limiting toxicities (DLTs), and those for the dose-expansion part were confirmed best overall response (BOR) per investigator (Response Evaluation Criteria in Solid Tumors V.1.1) and safety. The dose-expansion part followed a two-stage design; 16 patients were enrolled and treated in stage 1 (single-arm part). A futility analysis based on BOR was planned to determine whether stage 2 (randomized controlled part) would be initiated.ResultsAt data cut-off, 36 patients had received M9241 plus avelumab in the dose-escalation part. All DLs were well tolerated; one DLT occurred at DL3 (grade 3 autoimmune hepatitis). The maximum-tolerated dose was not reached, and DL5 was declared the recommended phase II dose, considering an observed drug–drug interaction at DL4. Two patients with advanced bladder cancer (DL2 and DL4) had prolonged complete responses. In the dose-expansion part, no objective responses were recorded in the 16 patients with advanced UC; the study failed to meet the criterion (≥3 confirmed objective responses) to initiate stage 2. Any-grade treatment-related AEs occurred in 15 patients (93.8%), including grade ≥3 in 8 (50.0%); no treatment-related deaths occurred. Exposures for avelumab and M9241 concentrations were within expected ranges.ConclusionsM9241 plus avelumab was well tolerated at all DLs, including the dose-expansion part, with no new safety signals. However, the dose-expansion part did not meet the predefined efficacy criterion to proceed to stage 2.

Immune-checkpoint inhibitors (ICIs) have significantly improved metastatic renal cell carcinoma (mRCC) prognosis, although their efficacy in patients with bone metastases (BMs) remains poorly understood. We investigated the prognostic role of natremia in pretreated RCC patients with BMs receiving immunotherapy. This retrospective multicenter study included RCC patients with BMs receiving nivolumab as second-line therapy or beyond. Inclusion criteria involved baseline sodium levels (pre-ICI) and sodium levels after 4 weeks of nivolumab initiation (post-ICI). The population was divided into two groups based on the median value, and response rates, progression-free survival (PFS), and overall survival (OS) were assessed. Among 120 eligible patients, those with pre-treatment sodium levels ≥140 mEq/L showed longer OS (18.7 12.0 months, p=0.04). Pre-treatment sodium levels ≥140 mEq/L were associated with better OS compared to levels <140 mE/L (18.7 12.0, p=0.04). Post-treatment sodium levels ≥140 mEq/L were associated with improved PFS (9.6 . 3.2 months) and OS (25.1 8.8 months) (p=0.05 and p<0.01, respectively). Patients with consistent sodium levels ≥140 mEq/L at both time points exhibited the best outcomes compared to those with lower values (PFS 11.5 3.3 months and OS 42.2 9.0 months, respectively, p<0.01). Disease control rate was significantly higher in the latter group (p<0.01). Multivariate analysis confirmed the prognostic significance of sodium levels. Elevated sodium levels (≥140 mEq/L) pre- and post-ICI treatment correlate with better survival outcomes in mRCC patients with BMs. This finding suggests sodium level assessment as a potential prognostic factor in these patients and warrants further investigation, particularly in combination immunotherapy settings.

The role of percutaneous tumour biopsies had gain importance in the management of renal cell carcinoma to provide diagnostic specimen for the patients with metastatic disease that could benefit a systemic treatment. Among the possible complications of this procedure, however, there is the risk of tumoral cells seeding along the biopsy’s tract; this complication, albeit being reported as anecdotal, could have devastating effects. Here we report a case of a young male who developed subcutaneous chest metastasis of renal cell carcinoma after a biopsy of a lung nodule. We subsequently reviewed other cases reported in literature