•Efficacy of combinations vs sunitinib remain debated in patients with favorable risk.•Favorable risk mRCC patients receiving TKIs as first-line therapy were enrolled.•One metastatic site correlated ...with longer OS in mRCC patients with good prognosis.•In patients with 1 metastatic site hepatic involvement resulted in worse PFS and OS.•The metastatic site should be considered in the therapeutic choice.
Although in metastatic renal cell carcinoma (mRCC) patients with intermediate and poor risk the benefit of combination strategies versus tyrosine kinase inhibitor (TKI) has been ascertained, in those with favorable risk data are ambiguous. Herein, we investigated the impact of number and type of metastatic site in patients with favorable risk to contribute to the best therapeutic choice.
Multicenter data regarding patients with favorable risk mRCC carcinoma receiving first-line TKIs, sunitinib or pazopanib, were retrospectively collected. We divided our population into 2 groups based on the number of metastatic sites and analyzed its impact on tumor response and efficacy outcome. The Kaplan-Meier method was used to estimate efficacy outcomes and the log-rank test to examine differences between subgroups.
A total of 107 patients with a median age of 69 years were included in the final analysis. Patients with 1 metastatic site, compared with patients with > 1 site, had a significantly longer overall survival (OS) (not reached vs. 66 months) and a trend, although not statistically significant, of better progression-free survival (PFS) (31 vs. 17 months). In patients with 1 metastatic site, liver involvement was correlated with worse PFS and OS at the univariate analysis (P = .01) and was confirmed as independent poor prognostic factor for PFS at multivariate analysis.
In conclusion, we reported a longer OS in favorable risk mRCC patients receiving TKI with only 1 metastatic site. Nevertheless, in patients with a single metastatic site, hepatic involvement correlated with worse PFS compared to other metastatic sites.
In this retrospective study, among 107 mRCC patients with favorable risk receiving TKIs, those with 1 metastatic site had significantly longer overall survival and a trend of better progression-free survival compared to patients with > 1 site. Liver involvement was identified as independent poor prognostic factor for PFS. The site of metastases should be considered when choosing therapies for these patients.
Abstract only
349
Background: 25-30% of renal cell carcinoma presents with metastases (mRCC) at diagnosis. The activity of immune checkpoint inhibitor (ICI)-combinations on the primary tumor (PT) is ...debated. Patients and Methods: mRCC patients (pts) with PT who received first-line nivolumab plus ipilimumab (N/I) or pembrolizumab plus axitinib (P/A) were included. We investigated the early primary tumor response (EPTR) at the first radiological assessment. Results: 73 pts were included. The median early reduction of the PT longest diameter was 12.4% with P/A versus 6.2% with N/I (p = 0.42). We evaluated if the type of EPTR could affect the metastases response. Among pts with PT stable disease (SD), 8.3% had metastatic disease progression (PD) with P/A and 34.8% with N/I. Early PT partial response (PR) was associated with no metastatic PD with both N/I and P/A. The 2 pts with PT PD had also metastatic PD to P/A. Of the 3 PT with PD to N/I, 1 had metastatic SD and 2 PD. In the overall population, of the 94.1% without PT progression (PR+SD), 47.5% had metastatic PR, 35.6% SD, 16.9% PD. Conclusions: ICIs-combinations achieved an early PT PR in about 10-20%, without any complete responses. Only a small percentage of PT had an early PD, mainly associated with metastatic PD. However, among those PT without an early progression, metastatic PR can be achieved in approximately 50% of cases.Table: see text
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.
...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.
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.
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.
Meet-URO12 was a randomized phase 2 trial testing the poly-ADP ribose-polymerase (PARP) inhibitor niraparib as maintenance treatment in patients with advanced urothelial cancer after platinum-based ...chemotherapy. We did not demonstrate a significant improvement in progression-free survival. The conduction of a phase 3 trial with single agent niraparib in this population is not supported by these results.
Platinum-based chemotherapy (PBCT) is the standard first-line treatment for advanced urothelial carcinoma (UC). Potential cross-sensitivity can be hypothesized between platinum drugs and poly-ADP ribose-polymerase (PARP) inhibitors.
To compare maintenance treatment with the PARP inhibitor niraparib plus best supportive care (BSC) versus BSC alone in patients with advanced UC without disease progression after first-line PBCT.
Meet-URO12 is a randomized, multicenter, open-label phase 2 trial. Patients with advanced UC, without disease progression after four to six cycles of PBCT, with Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, were enrolled between August 2019 and March 2021. Randomization was stratified by ECOG performance status (0/1) and response to PBCT (objective response/stable disease).
Patients were randomized (2:1) to experimental arm A (niraparib 300 or 200 mg daily according to body weight and baseline platelets, plus BSC) or control arm B (BSC alone).
The primary endpoint was progression-free survival (PFS). The analysis was performed on an intention-to-treat basis. The secondary endpoints reported in this primary analysis are progression-free rate at 6 mo and safety (adverse event rate).
Fifty-eight patients were randomized (39 in arm A and 19 in arm B). The median age was 69 yr, ECOG performance status was 0 in 66% and 1 in 34%; and the best response with chemotherapy was objective response in 55% and stable disease in 45%. The median PFS was 2.1 mo in arm A and 2.4 mo in arm B (hazard ratio 0.92; 95% confidence interval 0.49–1.75, p = 0.81). The 6-mo progression-free rates were 28.2% and 26.3%, respectively. The most common adverse events with niraparib were anemia (50%, grade G3 11%), thrombocytopenia (37%, G3–4 16%), neutropenia (21%, G3 5%), fatigue (32%, G3 16%), constipation (32%, G3 3%), mucositis (13%, G3 3%), and nausea (13%, G3 3%). The main limitation of the study is the small sample size: in March 2021, approval of maintenance avelumab for the same setting rendered randomization of patients in the control arm to BSC alone unethical, and accrual was stopped prematurely.
Addition of maintenance niraparib to BSC after first-line PBCT did not demonstrate a significant improvement in PFS in patients with UC. These results do not support the conduction of a phase 3 trial with single agent niraparib in this population.
In this trial, we tested the efficacy of niraparib as maintenance treatment in patients affected by advanced urothelial cancer after the completion of first-line chemotherapy. We could not demonstrate a significant improvement in progression-free survival with maintenance niraparib.
Tivozanib is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR-1), VEGFR-2, and VEGFR-3, recently approved in Europe for the first-line ...treatment of metastatic renal cell carcinoma (mRCC).
Retrospective analysis of safety and activity of tivozanib administered at 1.34 mg daily (3 weeks on, 1 week off) within a compassionate-use program to patients with mRCC with no prior systemic treatment in Italy.
From August 2018 to April 2019, 64 patients have started tivozanib in 9 oncology units. The median age was 67.5 years (range 40-85), 62.5% males. According to International Metastatic Renal Cell Carcinoma Database Consortium criteria, 27.1% of patients were good prognosis, 57.6% intermediate, and 15.3% poor. Primary tumor had been removed in 71.9% of patients. Histology was clear cell 89%, papillary 4.7%, and unclassified 6.3%. The response rate was 34.4%, stable disease 40.6%, and progression 15.6%. Grade 3-4 toxicities were 7.8% hypertension, 4.7% anemia, 3.1% mucositis, 3.1% asthenia, 1.6% diarrhea, 1.6% anorexia, 1.6% worsening of renal function, and 3.1% cardiac events. Dose reduction to 0.89 mg was applied to 17.2% of patients, and the discontinuation rate due to toxicity was 5.8%. Median progression-free survival was 12.4 months, with 68.7% of patients alive at 12 months. The developing of hypertension predicted increased progression-free survival at multivariate analysis (HR, 0.128; 95% CI, 0.03-0.59; p = 0.008).
Tivozanib showed good activity and favorable safety profile in a real-world cohort of unselected patients with mRCC. Predictive biomarkers of response to antiangiogenic therapy are urgently needed in order to identify RCC patients who could still receive a monotherapy with VEGFR inhibitors in the first line.
e16570
Background: Platinum-based chemotherapies (CTs) represent the standard first-line treatment of advanced urothelial carcinoma (aUC). However, the development of resistance and toxicities to ...these regimens is responsible for poor progression-free survival (PFS) and overall survival (OS). Maintenance treatment with the programmed death-ligand 1 (PD-L1) inhibitor avelumab after initial response to CT improved significantly OS. Despite the survival advantage, only a limited percentage of patients (pts) benefits from immunotherapy. Therefore, prognostic/predictive factors for immunotherapy are needed. Studies carried out on small cohorts of pts with melanoma, renal cell cancer or lung carcinoma proved that eosinophil count or variations could be used as prognostic factors during immunotherapy. Thus, the aim of the present study is to evaluate eosinophil levels as potential biomarker for outcome among aUC pts enrolled in the MALVA (Maintenance with AVeLumAb in advanced urothelial neoplasms in response to first-line CT: an observational retrospective and prospective study) ongoing study (Meet-URO 25). Methods: The MALVA study is an ongoing real-life multicentric retro-/prospective observational study on aUC pts receiving avelumab maintenance after response to platinum-based first-line CT. The co-primary endpoints are OS and PFS. We present here data of the first 100 enrolled aUC pts who received avelumab as maintenance therapy after response to platinum-based CT between January 2021 and January 2023. Absolute Eosinophil Counts (AEC) were registered at baseline (week 0) and at time of the first tumor assessment (week 12). This study aims to evaluate whether the AEC could be a predictive biomarker of efficacy in pts with aUC treated with avelumab. Results: One-hundred pts (median age, 72 years), 71.4% of whom were men, were enrolled (data cut off, January 2, 2023). Median follow-up time was 8.5 months. Median duration of avelumab treatment was 5.9 months. Median PFS for the entire population was 8.7 months (95% CI; 5.7 months-not reached). Predefined subgroup analyses showed PFS and OS improvement (5.1 months vs NR, p = 0.0031; 12.9 months vs NR, p = 0.056 respectively) in pts with high AEC at week 0 vs low AEC pts. Additionally, a pilot analysis was conducted for 34 pts, for whom PFS and OS were stratified by AEC at first tumor assessment (week 12). PFS was longer (6.4 months vs NR, p = 0.045) for pts with high AEC vs low AEC pts. Conclusions: In order to optimize treatment efficacy in aUC, reliable biomarkers are required. In this study, we provide data from a homogeneous cohort investigating the relevance of eosinophils in aUC pts receiving avelumab, suggesting that AEC could be an easily accessible and reproducible prognostic biomarker that warrants further studies.
Background:
First-line therapies based on immune-checkpoint inhibitors (ICIs) significantly improved survival of metastatic renal cell carcinoma (mRCC) patients. Cabozantinib was shown to target ...kinases involved in immune-escape and to prolong survival in patients pre-treated with tyrosine-kinase-inhibitors (TKIs). The impact of ICIs combinations in first line on subsequent therapies is still unclear.
Methods:
This is an open label, multicenter, single arm, phase II study designed to assess activity, safety and efficacy of cabozantinib in mRCC patients progressed after an adjuvant or first line anti-Programmed Death (PD)-1/PD-Ligand (PD-L) 1-based therapy. Primary endpoint was progression free survival (PFS), secondary endpoints were overall survival (OS), objective response rate (ORR) and safety.
Results:
31 patients were included in the analysis. After a median (m) follow-up of 11.9 months, mPFS was 8.3 months (90%CI 3.9-17.4) and mOS was 13.8 months (95%CI 7.7-29.0). ORR was 37.9% with an additional 13 patients achieving disease stability. Grade 3-4 adverse events occurred in 47% of patients, including more frequently creatine phosphokinase (CPK) serum level elevation, neutropenia, hyponatremia, diarrhea, hand-food syndrome, oral mucositis and hypertension.
Conclusions:
The BREAKPOINT trial met its primary endpoint showing that cabozantinib as second line therapy after ICIs was active in mRCC. Safety profile was manageable.
Trial registration number:
NCT03463681 - A Study of CaBozantinib in Patients With Advanced or Unresectable Renal cEll cArcinoma (BREAKPOINT) - https://clinicaltrials.gov/ct2/show/NCT03463681
Abstract only
632
Background: Tivozanib-TIVO is a potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor 1 (VEGFR1), VEGFR-2, and VEGFR-3. TIVO was recently ...approved in Europe for the first line treatment of metastatic Renal Cell Carcinoma-RCC after a randomized trial demonstrated improved PFS and different safety profile compared to sorafenib. Methods: Retrospective analysis of safety and activity of TIVO administered within a compassionate use program to pts with metastatic RCC with no prior systemic treatment. Results: From Aug 2018 to Apr 2019, 64 pts have started TIVO at 1,34 mg daily (three weeks on, 1 week off) in 9 Italian Oncology Units. Median age was 67.5 years (range 40 to 85), 61% males, median creatinine clearance 63 ml/min(range 30-97). According to IDMC criteria, 27.5 % of pts were good prognosis, 60% intermediate and 10.5 % poor. Primary tumor had been removed in 70.5% of pts. Histology was clear cell 89.5%, papillary 4.5%, unclassified 6%. Response rate was 46.5%, stable disease 37.5%, progression 16%. Grade 3-4 toxicities were 4.5% hypertension, 3% mucositis, 1.5% diarrhea and 1.5% anorexia. Dose reduction to 0.89 mg was applied to 15.5% of pts. PFS and OS data will be presented at the Meeting. Conclusions: TIVO showed good activity and favorable safety profile in a real world cohort of unselected pts with metastatic RCC. Predictive biomarkers of response to antiangiogenic therapy are urgently needed in order to identify RCC pts who should receive VEGFR inhibitors in the first line.
•We analyzed a cohort of 72 pts treated with ICIs for advanced urothelial carcinoma.•Low fT3/fT4 was a strong, negative prognostic factors for both PFS and OS.•Patients with low fT3/fT4 had ...significantly worse disease control rates.•Prognostic role of fT3/fT4 was independent from other known prognostic factors.
A low fT3/fT4 ratio has been associated with a poorer prognosis in patients treated for different solid malignancies. However, the prognostic role of baseline thyroid function in patients with metastatic urothelial carcinoma (mUC) has not yet been established.
We analyzed 72 consecutive immunotherapy-treated patients with mUC from a single institution. We recorded clinical data, baseline blood test results, and oncological outcomes. We stratified patients into three groups according to the fT3/fT4 ratio value and analyzed differences in progression-free survival (PFS), overall survival (OS), and radiological response in the three groups. We also conducted univariate and multivariate analyses to identify prognostic factors for PFS and OS.
The median PFS in the low, intermediate, and high fT3/fT4 ratio groups was 2.2, 4.1, and 8.2 months, respectively (P < 0.01). The median OS in the low, intermediate, and high fT3/fT4 groups was 3.6, 10.3, and 19.1 months, respectively (P < .01). The low fT3/fT4 ratio maintained its prognostic role independently of other prognostic factors. Patients with a high fT3/fT4 ratio had an increased radiological response.
Thyroid hormone impairment, as measured by the fT3/fT4 ratio, is a strong prognostic factor in patients treated with immunotherapy for urothelial carcinoma.
Analysing clinical data of 72 patients treated at a single institution treated with immune-checkpoint-inhibitors (ICIs) for metastatic urothelial carcinoma (mUC), we found that free triiodothyronine/free thyroxine (fT3/fT4) ratio was a strong prognostic factors for progression free survival and overall survival. The prognostic role of fT3/fT4 ratio was independent from other established prognostic factors.
Display omitted
Abstract only
e16565
Background: Grading tissue signatures in ccRCC is a potential tool to improve patients’ selection for anti-angiogenic drugs and immunotherapies. After the molecular audit to the ...TCGA public platforms, we aimed to grade angiogenic and immune signatures in ccRCC using a new 3D next-generation gross sampling method to overcome intratumoral heterogeneity. Methods: 100 consecutive advanced ccRCCs (≥pT3a) were sampled. Paraffin-embedded blocks were obtained after mapping the position of each sample to the whole tumor, to allow the reconstruction of the entire 3D tumor mass ( fusion 3D). Multisite tumor sampling was performed to analyze the whole tumor. TCGA platforms were assessed for angiogenic and immune molecular signatures: CD31 and CD34 to evaluate the absolute count and density of vessels, while E1L3N and sp263 clones for PD-L1 expression in tumor cells (TCs). The digital analysis was performed with image processing: comparing each tissue block to whole 3D assessment, the coefficient of variation (CV) was the statistical measure of the dispersion of data points in the data series around the mean. CV < 0.2 defined the homogeneity of the assessment. Results: 656 gross photographs representative of the 3D tumoral masses were collected and 4231 paraffin blocks and tissue sections were stored. Matching gross photographs with tissue samples was performed. 6324 tissue cores were evaluated after combining standard routine sampling plus the 3D multisite sampling and tissue microarray cores. Only 18% of cores displayed homogeneous profile of angiogenesis (CV < 0.2) with two distinct patterns: homogeneous high level of angiogenesis (pattern A) (10% of cases) or homogeneous low level of angiogenesis (pattern B) (8% of cases). The heterogeneous profile of angiogenesis was more frequent than the homogeneous one and was characterized by zones with high and low density of angiogenesis (82% of cases) (pattern C). On the other hand, the homogeneity of PD-L1 expression was more frequently observed both as diffuse absence ( < 1% of TCs, grade 0) or high expression (≥50% of TCs, grade 2) compared to low PD-L1 expression (1-49% of TCs, grade 1) (60% plus 7% versus 33% of cases, respectively). After the comparison of grading angiogenic versus immune signatures, we observed that cases with low PD-L1 expression (grade 0/1) usually expressed high density of angiogenesis (pattern A). Conclusions: Grading angiogenic (pattern A, B and C) versus immune (grade 0, 1 and 2) signatures in ccRCCs can be performed using commonly available tissue vascular (CD31 or CD34) and immune (PD-L1) antibodies. We promoted a simple assay to perform fusion 3D gross sampling to reduce at minimum the bias of heterogeneity in RCCs analyses. Both angiogenic versus immune signature by using the grading systems may help treatment decision-making and response assessment in ccRCC patients.
