Background
Immune 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.
Objective
The aim of this study was to evaluate the impact of PPIs on outcomes in RCC patients receiving immunotherapy.
Patients and Methods
We 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).
Results
Two 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).
Conclusions
In patients with RCC, concomitant PPI use did not seem to affect survival outcomes on ICIs, either as combination therapy or monotherapy.
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
Background
Angiogenesis 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.
Objective
To describe the outcome of cabozantinib in patients previously treated with immunotherapy.
Patients and methods
Patients with mRCC who received cabozantinib immediately after nivolumab were included. The primary endpoint was to assess the outcome in terms of efficacy and activity.
Results
Eighty-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.
Conclusions
Cabozantinib 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.
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.
Purpose of Review
Therapeutic 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 Findings
The 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.
Summary
Some 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.
Instrumental activities of daily living (IADL) are significant health indicators closely related to executive functions and able to detect mild cognitive impairment. A decline in IADL usually ...precedes ADL limitation, including taking medications, and may therefore predict a cognitive decline. We aimed to investigate the association of patients' IADL score with other clinical factors, with a particular focus on the presence of a caregiver, and the impact on adherence to androgen receptor pathway inhibitors (ARPIs) and survival outcomes within the Meet-URO 5-ADHERE study. It was a large prospective multicentre observational cohort study monitoring adherence to ARPIs in 234 metastatic castrate-resistant PC (mCRPC) patients aged ≥ 70. We observed an association between impaired IADL and lower geriatric G8 scores (p < 0.01), and lower adherence to ARPIs whether assessed by pill counting (p = 0.01) or self-reported by the patient himself (p = 0.03). The combination of an IADL < 6 and the absence of a caregiver resulted in a significantly high risk of non-adherence to the ARPIs at the multivariable analysis (HR 9.23, 95% confidence interval 2.28-37.43, p = 0.01). IADL alongside the geriatric G8 scales represent essential tools to identify frail and less auto-sufficient patients who are extremely vulnerable particularly if not supported by a caregiver and have the highest risk of nonadherence to ARPIs.
Background: Non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous group of cancer. Treatment recommendations are extrapolated from ccRCC and lack solid evidence. Here, we review advanced ...nccRCC patients treated at our institute. Patients and methods: We collected retrospective data on all advanced nccRCC pts treated at the Istituto Oncologico Veneto from January 2008. We compared overall response rate (ORR), progression free survival (PFS) and overall survival (OS) according to histological subtypes and type of systemic treatments. Kaplan-Meier method, log-rank test and Cox regression were used to estimate and compare PFS and OS. Results: Of 1370 RCC patients, 289 had a diagnosis of nccRCC and 121 were eligible for the analysis. Fifty-three pts showed papillary histology (pRCC), 15 chromophobe; 37 unclassified RCC (NOS-RCC), 16 other histologies. Pts with chromophobe and other hystologies showed poorer survival rates compared to pRCC and NOS-RCC (mOS 10.7 vs. 20.7 vs. 30.7, p = 0.34). Pts treated with combination regimens achieved a better OS (30.7 vs. 13.7, p = 0.10), PFS (12.7 vs. 6.4, p = 0.10) and ORR (42.4% vs. 13.9%, p = 0.002) than those treated with monotherapy. IMDC and Meet-URO score retained their prognostic value. Conclusion: Our retrospective real-life cohort of advanced nccRCC patients shows that immunotherapy-based combinations could improve ORR, PFS and OS compared to TKI monotherapy. Prospective trials for nccRCC patients utilizing novel therapies are ongoing and their results eagerly awaited.
Abstract
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.
Metabolic reprogramming is a hallmark of clear cell renal cell carcinoma (ccRCC) progression. Here, we used genome-scale metabolic modeling to elucidate metabolic reprogramming in 481 ccRCC samples ...and discovered strongly coordinated regulation of glycosaminoglycan (GAG) biosynthesis at the transcript and protein levels. Extracellular GAGs are implicated in metastasis, so we speculated that such regulation might translate into a non-invasive biomarker for metastatic ccRCC (mccRCC). We measured 18 GAG properties in 34 mccRCC samples versus 16 healthy plasma and/or urine samples. The GAG profiles were distinctively altered in mccRCC. We derived three GAG scores that distinguished mccRCC patients with 93.1%–100% accuracy. We validated the score accuracies in an independent cohort (up to 18 mccRCC versus nine healthy) and verified that the scores normalized in eight patients with no evidence of disease. In conclusion, coordinated regulation of GAG biosynthesis occurs in ccRCC, and non-invasive GAG profiling is suitable for mccRCC diagnosis.
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•Coordinated regulation of glycosaminoglycan (GAG) biosynthesis is observed in ccRCC•The plasma and urine GAG profile is strongly altered in metastatic ccRCC•Three non-invasive GAG scores accurately predict the occurrence of metastatic ccRCC•The GAG scores normalize in patients with no evidence of disease
Gatto et al. computationally uncovered altered and coordinated regulation of glycosaminoglycan biosynthesis in clear cell renal cell carcinoma, resulting in altered metabolite levels in plasma and urine that, in turn, could be used to diagnose the occurrence of the disease.
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