Cabozantinib is approved for patients with metastatic renal cell carcinoma on the basis of studies done in clear-cell histology. The activity of cabozantinib in patients with non-clear-cell renal ...cell carcinoma is poorly characterised. We sought to analyse the antitumour activity and toxicity of cabozantinib in advanced non-clear-cell renal cell carcinoma.
We did a multicentre, international, retrospective cohort study of patients with metastatic non-clear-cell renal cell carcinoma treated with oral cabozantinib during any treatment line at 22 centres: 21 in the USA and one in Belgium. Eligibility required patients with histologically confirmed non-clear-cell renal cell carcinoma who received cabozantinib for metastatic disease during any treatment line roughly between 2015 and 2018. Mixed tumours with a clear-cell histology component were excluded. No other restrictive inclusion criteria were applied. Data were obtained from retrospective chart review by investigators at each institution. Demographic, surgical, pathological, and systemic therapy data were captured with uniform database templates to ensure consistent data collection. The main objectives were to estimate the proportion of patients who achieved an objective response, time to treatment failure, and overall survival after treatment.
Of 112 identified patients with non-clear-cell renal cell carcinoma treated at the participating centres, 66 (59%) had papillary histology, 17 (15%) had Xp11.2 translocation histology, 15 (13%) had unclassified histology, ten (9%) had chromophobe histology, and four (4%) had collecting duct histology. The proportion of patients who achieved an objective response across all histologies was 30 (27%, 95% CI 19–36) of 112 patients. At a median follow-up of 11 months (IQR 6–18), median time to treatment failure was 6·7 months (95% CI 5·5–8·6), median progression-free survival was 7·0 months (5·7–9·0), and median overall survival was 12·0 months (9·2–17·0). The most common adverse events of any grade were fatigue (58 52%), and diarrhoea (38 34%). The most common grade 3 events were skin toxicity (rash and palmar-plantar erythrodysesthesia; five 4%) and hypertension (four 4%). No treatment-related deaths were observed. Across 54 patients with available next-generation sequencing data, the most frequently altered somatic genes were CDKN2A (12 22%) and MET (11 20%) with responses seen irrespective of mutational status.
While we await results from prospective studies, this real-world study provides evidence supporting the antitumour activity and safety of cabozantinib across non-clear-cell renal cell carcinomas. Continued support of international collaborations and prospective ongoing studies targeting non-clear-cell renal cell carcinoma subtypes and specific molecular alterations are warranted to improve outcomes across these rare diseases with few evidence-based treatment options.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In metastatic renal-cell carcinoma (mRCC), recent data have shown efficacy of first-line ipilimumab and nivolumab (ipi-nivo) as well as immuno-oncology (IO)/vascular endothelial growth factor (VEGF) ...inhibitor combinations. Comparative data between these strategies are limited.
To compare the efficacy of ipi-nivo versus IO-VEGF (IOVE) combinations in mRCC, and describe practice patterns and effectiveness of second-line therapies.
Using the International Metastatic Renal-cell Carcinoma Database Consortium (IMDC) dataset, patients treated with any first-line IOVE combination were compared with those treated with ipi-nivo.
All patients received first-line IO combination therapies.
First- and second-line response rates, time to treatment failure (TTF), time to next treatment (TNT), and overall survival (OS) were analysed. Hazard ratios were adjusted for IMDC risk factors.
In total, 113 patients received IOVE combinations and 75 received ipi-nivo. For IOVE combinations versus ipi-nivo, first-line response rates were 33% versus 40% (between-group difference 7%, 95% confidence interval CI –8% to 22%, p = 0.4), TTF was 14.3 versus 10.2 mo (p = 0.2), TNT was 19.7 versus 17.9 mo (p = 0.4), and median OS was immature but not statistically different (p = 0.17). Adjusted hazard ratios for TTF, TNT, and OS were 0.71 (95% CI 0.46–1.12, p = 0.14), 0.65 (95% CI 0.38–1.11, p = 0.11), and 1.74 (95% CI 0.82–3.68, p = 0.14), respectively. Sixty-four (34%) patients received second-line treatment. In patients receiving subsequent VEGF-based therapy, second-line response rates were lower in the IOVE cohort than in the ipi-nivo cohort (15% vs 45%; between-group difference 30%, 95% CI 3–57%, p = 0.04; n = 40), though second-line TTF was not significantly different (3.7 vs 5.4 mo; p = 0.4; n = 55). Limitations include the study’s retrospective design and sample size.
There were no significant differences in first-line outcomes between IOVE combinations and ipi-nivo. Most patients received VEGF-based therapy in the second line. In this group, second-line response rate was greater in patients who received ipi-nivo initially.
There were no significant differences in key first-line outcomes for patients with metastatic renal-cell carcinoma receiving immuno-oncology/vascular endothelial growth factor inhibitor combinations versus ipilimumab and nivolumab.
Using the International Metastatic Renal-cell Carcinoma Database Consortium database, we reviewed 188 patients with metastatic renal-cell carcinoma who received first-line ipilimumab and nivolumab (ipi-nivo) versus immuno-oncology/vascular endothelial growth factor (VEGF) combinations. There were no significant differences in first-line outcomes between groups. Response rates to second-line VEGF-based treatments were higher in patients who received ipi-nivo.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Tyrosine kinase inhibitors (TKIs) with antiangiogenic properties, such as sorafenib, have been the standard choice to systemically treat hepatocellular carcinoma for over a decade. More recently, ...encouraging results were obtained using immune checkpoint inhibitors, although head-to-head comparisons with sorafenib in phase 3 trials could not demonstrate superiority in terms of overall survival. The IMbrave150 was a breakthrough study that resulted in atezolizumab/bevacizumab, a combination of an antiangiogenic and an immune checkpoint inhibitor, as a new standard of care for advanced HCC. This review discusses the mode of action, clinical efficacy, and biomarker research for both drug classes and for the combination therapy. Moreover, the synergy between atezolizumab and bevacizumab is highlighted, unraveling pathophysiological mechanisms underlying an enhanced anticancer immunity by changing the immunosuppressed to a more immunoreactive tumor microenvironment (TME). This is achieved by upregulation of antigen presentation, upregulation of T-cell proliferation, trafficking and infiltration, impairing recruitment, and proliferation of immunosuppressive cells in the TME. However, more insights are needed to identify biomarkers of response that may improve patient selection and outcome.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Immunogenic cell death (ICD) refers to an immunologically distinct process of regulated cell death that activates, rather than suppresses, innate and adaptive immune responses. Such responses ...culminate into T cell-driven immunity against antigens derived from dying cancer cells. The potency of ICD is dependent on the immunogenicity of dying cells as defined by the antigenicity of these cells and their ability to expose immunostimulatory molecules like damage-associated molecular patterns (DAMPs) and cytokines like type I interferons (IFNs). Moreover, it is crucial that the host's immune system can adequately detect the antigenicity and adjuvanticity of these dying cells. Over the years, several well-known chemotherapies have been validated as potent ICD inducers, including (but not limited to) anthracyclines, paclitaxels, and oxaliplatin. Such ICD-inducing chemotherapeutic drugs can serve as important combinatorial partners for anti-cancer immunotherapies against highly immuno-resistant tumors. In this Trial Watch, we describe current trends in the preclinical and clinical integration of ICD-inducing chemotherapy in the existing immuno-oncological paradigms.
Abstract Background The use of third-line targeted therapy (TTT) in metastatic renal cell carcinoma (mRCC) is not well characterized and varies due to the lack of robust data to guide treatment ...decisions. This study examined the use of third-line therapy in a large international population. Objective To evaluate the use and efficacy of targeted therapy in a third-line setting. Design, setting, and participants Twenty-five international cancer centers provided consecutive data on 4824 mRCC patients who were treated with an approved targeted therapy. One thousand and twelve patients (21%) received TTT and were included in the analysis. Outcome measurements and statistical analysis Patients were analyzed for overall survival (OS) and progression-free survival using Kaplan-Meier curves, and were evaluated for overall response. Cox regression analyses were used to determine the statistical association between OS and the six factors included in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model. Subgroup analysis was performed on patients stratified by their IMDC prognostic risk status. Results and limitations Everolimus was the most prevalent third-line therapy (27.5%), but sunitinib, sorafenib, pazopanib, temsirolimus, and axitinib were all utilized in over ≥9% of patients. Patients receiving any TTT had an OS of 12.4 mo, a progression-free survival of 3.9 mo, and 61.1% of patients experienced an overall response of stable disease or better. Patients not receiving TTT had an OS of 2.1 mo. Patients with favorable- (7.2%) or intermediate-risk (65.3%) disease had the highest OS with TTT, 29.9 mo and 15.5 mo, respectively, while poor-risk (27.5%) patients survived 5.5 mo. Results are limited by the retrospective nature of the study. Conclusions TTT remains highly heterogeneous. The IMDC prognostic criteria can be used to stratify third-line patients. TTT use in favorable- and intermediate-risk patients was associated with the greatest OS. Patient summary Patients with favorable- and intermediate-prognostic criteria disease treated with third-line targeted therapy have an associated longer overall survival compared with those with poor risk disease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Abstract Background Sunitinib (SU) and pazopanib (PZ) are standards of care for first-line treatment of metastatic renal cell carcinoma (mRCC). However, how the efficacy of these drugs translates ...into effectiveness on a population-based level is unknown. Patients and methods We used the International mRCC Database Consortium (IMDC) to assess overall survival (OS), progression-free survival (PFS), response rate (RR) and performed proportional hazard regression adjusting for IMDC prognostic groups. Second-line OS (OS2) and second-line PFS (PFS2) were also evaluated. Results We obtained data from 7438 patients with mRCC treated with either first-line SU (n = 6519) or PZ (n = 919) with an overall median follow-up of 40.4 months (95% confidence interval CI 39.2–42.1). There were no significant differences in IMDC prognostic groups (p = 0.36). There was no OS difference between SU and PZ (22.3 versus 22.6 months, respectively, p = 0.65). When adjusted for IMDC criteria, the hazard ratio (HR) of death for PZ versus SU was 1.03 (95% CI 0.92–1.17, p = 0.58). There was no PFS difference between SU and PZ (8.4 versus 8.3 months, respectively, p = 0.17). When adjusted for IMDC criteria, the HR for PFS for PZ versus SU was 1.08 (95% CI 0.981–1.19, p = 0.12). There was no difference in RR between SU and PZ (30% versus 28%, respectively, p = 0.15). We also found no difference in any second-line treatment between either post-SU or post-PZ groups for OS2 (13.1 versus 11 months, p = 0.27) and PFS2 (3.7 versus 5.0 months, p = 0.07). Conclusions We confirmed in real-world practice that SU and PZ have similar efficacy in the first-line setting for mRCC and do not affect outcomes with subsequent second-line treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Clear-cell renal cell carcinomas (ccRCC) can be divided into four transcriptomic subtypes, two of which have a favorable and two an unfavorable prognosis. To assess mechanisms driving these subtypes, ...we investigated their miRNA expression patterns. miRNAs are master regulators of mRNAs, that are widely deregulated in cancer. Unsupervised clustering in our dataset (n = 128) and The Cancer Genome Atlas (TCGA) validation set identified two distinct miRNA clusters that overlapped with the transcriptomic subtypes, underscoring the validity of these subtypes on a multi-omics level and suggesting a driving role for miRNAs. Discriminatory miRNAs for the favorable subtypes repressed epithelial-to-mesenchymal transition, based on gene set enrichment analysis and target-mRNA expression levels. Strikingly, throughout the entire dataset, miRNAs associated with favorable subtypes were also associated with longer overall survival after diagnosis, and miRNAs associated with unfavorable subtypes with shorter overall survival (Pearson r = -0.54, p<0.0001). These findings indicate a general shift in miRNA expression between more and less aggressive tumors. This adds to current literature, which usually suggests only a small subset of miRNAs as markers of aggressive disease. In conclusion, this study reveals distinct mRNA expression patterns underlying transcriptomic ccRCC-subtypes, whereby miRNAs associated with favorable subtypes counteract epithelial-to-mesenchymal transition. There is a general shift in miRNA expression in ccRCC, between more and less aggressive tumors.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In clear cell renal cell carcinoma (ccRCC), first-line treatment combines nivolumab (anti-PD-1) and ipilimumab (anti-CTLA4), yielding long-term remissions but with only a 40% success rate. Our study ...explored the potential of enhancing ccRCC treatment by concurrently using CXCR2 inhibitors alongside immunotherapies.
We analyzed ELR + CXCL levels and their correlation with patient survival during immunotherapy. RCT001, a unique CXCR2 inhibitor, was examined for its mechanism of action, particularly its effects on human primary macrophages. We tested the synergistic impact of RCT001 in combination with immunotherapies in both mouse models of ccRCC and human ccRCC in the presence of human PBMC.
Elevated ELR + CXCL cytokine levels were found to correlate with reduced overall survival during immunotherapy. RCT001, our optimized compound, acted as an inverse agonist, effectively inhibiting angiogenesis and reducing viability of primary ccRCC cells. It redirected M2-like macrophages without affecting M1-like macrophage polarization directed against the tumor. In mouse models, RCT001 enhanced the efficacy of anti-CTLA4 + anti-PD1 by inhibiting tumor-associated M2 macrophages and tumor-associated neutrophils. It also impacted the activation of CD4 T lymphocytes, reducing immune-tolerant lymphocytes while increasing activated natural killer and dendritic cells. Similar effectiveness was observed in human RCC tumors when RCT001 was combined with anti-PD-1 treatment.
RCT001, by inhibiting CXCR2 through its unique mechanism, effectively suppresses ccRCC cell proliferation, angiogenesis, and M2 macrophage polarization. This optimization potentiates the efficacy of immunotherapy and holds promise for significantly improving the survival prospects of metastatic ccRCC patients.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose
The aim of this study was to investigate the impact of acid suppressive therapy on clinical efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma (mRCC).
Methods
A ...single-center retrospective study was carried out. Charts of mRCC patients who received pazopanib as first-line treatment were reviewed and concomitant use of proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA) was studied. Two groups of patients were identified, namely patients receiving PPI/H2RA and patients without acid suppressive therapy. Both groups were compared with regard to progression free survival (PFS), overall survival (OS), tumor response, and time to dose reduction of pazopanib.
Results
Ninety-one patients were included. Median PFS was 8 months in the PPI/H2RA group vs. 7 months in the no PPI/H2RA group (hazard ratio (HR) 0.76 (95% confidence interval (CI) 0.42–1.35)),
p
= 0.35. Median OS was 27 months in the PPI/H2RA group vs. 23 months in the no PPI/H2RA group (HR 0.87 (95% CI 0.46–1.66)),
p
= 0.68. Mean tumor response was 17% (95% CI 8–25%) in the PPI/H2RA group vs. 11% (95% CI 0–21%) in the no PPI/H2RA group,
p
= 0.52. Median time to first dose reduction was 9 months in both subgroups (HR 1.25 (95% CI 0.65–2.39)),
p
= 0.51. Median time to second dose (< 600 mg) reduction was 17 months in the PPI/H2RA group vs. 7 months in the no PPI/H2RA group (HR 0.26 (95% CI 0.07–0.89)),
p
= 0.03.
Conclusion
In this limited patient series, no evidence of a negative impact of PPI/H2RA on clinical outcome and time to first dose reduction was observed. These results suggest that PPI/H2RA might be considered, when there is a clinical need, in patients treated with pazopanib for mRCC. However, a prospective study is warranted to confirm these results.
Purpose We identified microRNA driven mechanisms in clear cell renal cell carcinoma associated with the tumor response to the multitargeted receptor tyrosine kinase inhibitor sunitinib. Materials and ...Methods We performed screening genome-wide microRNA real-time quantitative polymerase chain reaction on 20 freshly frozen clear cell renal cell carcinoma tissue samples of patients who received sunitinib as first line targeted therapy. Nine patients with progressive disease within 6 months after initiating therapy were considered poor responders and 11 with at least 1-year progression-free survival were considered good responders. We studied microRNA-141 function in vitro by stable up-regulation of microRNA-141, quantification of target gene expression and cell viability in normoxic and hypoxic conditions. Relative expression in clinical and cell line samples was determined by real-time quantitative polymerase chain reaction. Localization of microRNA-141 and its targets was assessed by microRNA in situ hybridization and immunohistochemistry. Hypoxia induced cytotoxicity was assessed by a luminescence adenosine triphosphate detection assay. Results Compared to good responders, microRNA-141 was significantly down-regulated in tumors of poor responders to sunitinib. This seemed spatially linked to epithelial-to-mesenchymal transition in vivo. Reintroduction of microRNA-141 in vitro reversed epithelial-to-mesenchymal transition and decreased cell viability in hypoxic conditions. Conclusions In our study microRNA-141 down-regulation driven epithelial-to-mesenchymal transition in clear cell renal cell carcinoma was linked to an unfavorable response to sunitinib therapy. Reintroduction of microRNA-141 in vitro led to epithelial-to-mesenchymal transition reversal and increased sensibility to a hypoxic environment. Future experiments should be done in vivo to see whether microRNA-141 driven reversal of epithelial-to-mesenchymal transition could affect the efficacy of sunitinib treatment.
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