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. Keywords: Metastatic renal cell carcinoma, Immunotherapy, Immune checkpoint inhibitor, Clinical practice, Real-world, IMDC score, Meet-URO score, Prospective, Retrospective
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Introduction
Immunotherapy with nivolumab (a monoclonal antibody that targets the programmed cell death protein 1, PD1) has become the standard treatment for patients with metastatic renal cell ...carcinoma (mRCC) after progression to single-agent tyrosine kinase inhibitors. However, the optimal duration of immunotherapy in this setting has not yet been established.
Patients and methods
We retrospectively reviewed all patients treated with nivolumab at our institution from January 2014 to December 2021 and identified those who discontinued treatment for reasons other than disease progression (PD). We then associated progression-free survival (PFS) and overall survival following treatment cessation with baseline clinical data.
Results
Fourteen patients were found to have discontinued treatment. Four patients (28.6%) ceased treatment due to G3/G4 toxicities, whereas the remaining ten (71.4%) opted to discontinue treatment in agreement with their referring clinicians. The median duration of the initial treatment with nivolumab was 21.7 months (7.5-37.3); during treatment, two patients (14.3%) achieved stable disease as the best response, and the remaining twelve (85.7%) a partial response. At a median follow-up time of 24.2 months after treatment discontinuation, 7 patients (50%) were still progression-free. The median PFS from the date of discontinuation was 19.8 months (15.2 - not reached); a radiological objective response according to RECIST and treatment duration of more than 12 months were associated with a longer PFS. Three patients were re-treated with Nivolumab after disease progression, all of whom achieved subsequent radiological stability.
Conclusion
In our experience, the majority of patients who discontinued treatment in the absence of PD were still progression-free more than 18 months after discontinuation. Patients whose initial treatment duration was less than 12 months or who did not achieve a radiological objective response had a greater risk of progression. Immunotherapy rechallenge is safe and seems capable of achieving disease control.
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Background: The oral tyrosine kinase inhibitor Cabozantinib (CABO) is frequently used to treat patients with metastatic RCC. Polypharmacy is common in elderly pts, thus several drug-drug ...interactions (DDIs) with cabozantinib may ensue. Methods: ZEBRA /MEET-URO 9 was a prospective, real world trial enrolling pts ≥ 70 years with mRRC treated with CABO at 13 Italian Oncology Centers. All concomitants drugs administered to pts were collected and categorized according to active principles and indication. DDIs were identified through a dedicated software (Lexicomp), scientific databases (Sider4.1) and published articles. Results: we enrolled 104 pts, median age 75.8 years (range 70.2-87.4 yrs). Overall, 91.4% of the cohort was treated at a reduced dose either upfront or due to side effects. Pts took a median of 6 concomitant drugs (IQR: 4-9), for a total of 131 active principles. Software analysis identified 4 DDIs (warfarin, apixaban, diltiazem and furosemide); whereas scientific reports allowed us to identify 15 additional DDIs involving metoprolol, nebivolol, olmesartan, amiloride, simvastatin, rosuvastatin, polyenoic omega-3 fatty acids, loperamide, metoclopramide, metformin, dutasteride, dexamethasone, prednisone, cetirizine and doxazosin. Seventy pts with potential DDIs experienced a trend for higher rate of grade 3-4 adverse events compared to other pts, although difference was not statistically significant (48.7% v 23.5 %, p=0.485). The table summarizes the main DDIs and suggestions to avoid or mitigate their effects Conclusions: the risk of DDIs was not negligible in our cohort of elderly mRCC pts treated with CABO, although the frequent dose reductions of CABO probably confounded their impact on toxicities. Unremitting attention to concomitant medications in the elderly is thus warranted. Table: see text
TPS485
Background: Nowadays, different systemic treatments are available for the first-line setting of metastatic renal cell carcinoma (mRCC). Immuno-combinations are the standard first-line therapy ...in all mRCC patients regardless the 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 these reasons, the regimen choice represents an important issue in clinical practice and the optimal treatment sequence remains unclear. Methods: The Meet-URO 33 (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 1
st
of January 2021 will also be included. The study includes 84 Italian centers and a study amendment will be submitted to include about 10 European centers. The Meet-URO 33 study aims to provide a large-scale real-world database on mRCC patients and the primary objective is to identify potential prognostic and predictive factors that could help guide the treatment choice. Secondary objectives include the comparison between treatment strategies in first-line and subsequent lines according to response and survival outcomes and toxicity profile; the assessment of the correlation between the clinical and tumor characteristics and the choice of the first line of treatment; the assessment of the prognostic performance of the Meet-URO score compared with the IMDC score. Moreover, given the registry nature of the study, further studies will be planned subsequently, both on the entire cohort (e.g. genomic analyses and artificial intelligence) and particular subgroups (e.g. poor-risk category, elderly, non-clear cell histology) to answer as many clinical questions as possible. The descriptive statistics will be used to summarize the clinical characteristics of patients and the distribution of prognostic factors. All time-to-event endpoints (PFS, OS) will be analyzed using the Kaplan-Meier method, the restricted mean survival time (RMST) and the Cox proportional hazard regression model. The binary endpoints (ORR, DCR) will be analyzed through relative frequencies and logistic regression. For all the comparisons between treatments, all causal inference techniques such as propensity scores and marginal structural models will be used. All the steps for a correct target trial emulation strategy will be followed to avoid potential biases deriving from the observational nature of the study. In particular, in comparing the different treatments, the principles of emulating a clinical trial will be applied, developing appropriate ad hoc protocols for each planned comparison. Clinical trial information: CESC IOV 2023-78 .
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Background: The development of Prostate Cancer Units (PCUs) determined a paradigm shift in the treatment of this disease based on multidisciplinary management and shared clinical pathways among ...several specialists, but activities of PCUs are rarely reported. The Multi-Institutional PCU of Padova was decreed on Nov 2020 and involves Istituto Oncologico Veneto (IOV IRCCS), Azienda Ospedaliera-University of Padova (AOPD UNIPD) and Casa di Cura of Abano Terme. Padova PCU achieved the ISO 9001 certification on Dec 2020 and performance indicators were identified. Methods: We assessed clinical indicators of coordination, process and outcome of our PCU from 1
st
Jan 2021 to 30 Jun 2022. Data were extracted from the Electronic Medical Record ONCOSYS and from HEALTHMEETING, the software dedicated to register clinical information of patients, shared therapeutic decisions and participation of specialists to the PCU meetings. Results: A total of 739 consecutive pts were managed by the PCU in 18 months, generating a total of 1002 case discussions in 76 meetings, for a mean of 12,8 case discussions per week. Three Urology units performed 500 prostatectomies per year. Presence of at least one specialist for each core team specialty (either in presence of teleconference) was almost 100% with the exception of the pathologists, who were consulted mainly on demand. Waiting time for case discussion was always less than 2 weeks. Pts were presented by urologist, oncologist, radiation oncologist or other specialist in 46,3, 39,8, 10,5 and 3,4% of cases, respectively. They had localized/locally advanced, biochemically recurrent, metastatic castration-sensitive or castration-resistant disease in 43.3, 8, 28.2 and 20.5% of cases, respectively. Decision by the PCU was eventually carried out in 75,5% of cases, was changed due to pt’s preference of other reasons in 6.5%, or was still pending or not assessable in 18% of cases. Median time to completion of pathology report of prostatic biopsies was 8 days, median time from surgery to adjuvant radiotherapy was 5 months. Clinical trials with investigational drugs were proposed to 17% of pts with metastatic disease. Several process and outcome indicators (e.g., rate of active surveillance, rate of combined systemic therapy in men with metastatic castration sensitive cancer, survival of patients with metastatic castration resistant disease, etc.) could not be verified yet because they could not be extracted as aggregate data from institutional software and administrative databases. Conclusions: The volumes of Padova PCU and participation rate of core team specialists fulfill international requirements. Institutional software should be implemented in order to allow for aggregate data collection for the assessment of pre-defined performance indicators of PCU instead of reviewing the clinical chart of each prostate cancer pt.
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Background: Cabozantinib (CABO) is an oral tyrosine kinase inhibitor registered for the treatment of metastatic renal cell carcinoma (mRCC) for the first or subsequent lines. Tolerability in real ...world elderly patients is poorly documented. G8 is a short test for vulnerability gaining increased interest as a screening tool for trials in geriatric oncology. Methods: ZEBRA/MEET-URO 9 was a prospective multicenter study of safety and activity of CABO administered to pts ≥70 years with mRCC, either in the first or subsequent lines of treatment, until progression or unacceptable toxicity. All pts underwent G8 score at baseline, with a cut-off for vulnerability of 14 or below. Data on tolerability and activity were collected prospectively after signature of informed consent. Results: A total of 104 pts started CABO at 13 Italian Centers, 38,5% as first line. Median age was 75.8 yrs (range 70.2-87.4 yrs, 26 pts ≥80 yrs), 73.1% males. IMDC score was good 19.2%, intermediate 53.9%, poor 26.9%. Primary tumor had been removed in 82.7% of pts, histology was clear cell 78.8%, papillary 8.7%, chromophobe 5.8%, unclassified 6.7%. G8 score was ≤14 in 65.4% of pts. Up-front dose reduction of CABO was more frequent in pts with low G8 score (79.4 vs 41.7%, p=0.003), but eventually the majority of pts (91.4%) underwent dose reductions of CABO. After a median treatment of 6.4 months (0.5-26.1 months), 38.4% of pts developed G3-4 toxicities, 22.1% interrupted treatment due to adverse events, 2.8% (3 pts) died due to cardiovascular or thromboembolic events. Median PFS was 7.6 months (95% CI=5.8-12.6 months) in first line, 10.0 months (5.8-15.6) in second or further lines, median OS was 20.1 months (11.1-not reached) and 15.6 months (12.5-not reached), respectively. G8 score ≤14 did not correlate with rate of temporary interruptions >7 days, hospitalization, incidence of G3-5 toxicities, as well as with PFS. Pts with G8 score ≤14 had a trend for reduced OS, but difference was not statistically significant both in the first and further lines of treatment. Conclusions: Screening G8 test was positive in more than a half of pts, underlying the need for detailed geriatric assessment and increased clinical monitoring of such patients. A G8 score ≤14 correlated with up-front dose reduction of CABO but not with G3-5 toxicities probably due to the high rates of dose reductions in the whole cohort. Correlation between low G8 score and OS could not be demonstrated in this population.
•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.
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•Penile squamous cell (PSCC) carcinoma is a rare tumor with an aggressive behavior.•Meet-URO 23/I-RARE database is a multicentric registry on rare genitourinary tumors.•This retrospective study ...evaluates clinical outcomes and prognostic factors in PSCC.•Patients with an ORR to I line platinum-based chemotherapy have a better survival.•Poor ECOG PS, lymph node metastases and higher age are poor prognostic factors.
This retrospective study explores clinical outcomes and prognostic factors in penile squamous cell carcinoma. We included 128 patients with localized or metastatic penile carcinoma included into the Meet-URO 23/I-RARE Italian registry. Different survival outcomes were found according to clinical factors, such as ECOG PS, median age, type of response to first-line therapy. Relevant prognostic factors were ECOG PS 2-4 at diagnosis, lymph node metastases, age >77 years, and regimens with platinum plus taxane.
Penile squamous cell carcinoma (PSCC) is a rare tumor with an aggressive behavior. The Meet-URO 23/I-RARE registry includes rare genitourinary malignancies. We extracted patients with PSCC to conduct a retrospective study aimed at assessing clinical outcomes and prognostic factors.
Primary endpoints were overall survival and progression-free survival. Prognostic factors for OS and PFS were analyzed using univariate and multivariate analysis.
From the Meet-URO 23/I-RARE database, we extracted 128 patients with diagnosis of PSCC. About 48% of patients underwent first-line of therapy.
In the overall population, median OS from diagnosis was 34.6 months. Significant differences in median OS were observed according to ECOG PS at diagnosis (57.3 months vs. 8.3 months; P < .001), and median age (≤77y 88.8 months vs. >77y 26 months; P = .013). At multivariate analysis, ECOG PS 2-4 at diagnosis (HR 3.04) and lymph node metastases (HR 2.49) were independently associated with a higher risk of death.
Among patients undergoing first-line therapy (n = 61), median OS was 12.3 months, and a statistically significant difference was found according to type of response to first-line (DCR 24.4 months vs. PD 7.1 months; P < .001). Multivariate analysis showed that only age >77 years was associated with a worse OS (HR 2.16). A statistically significant difference in PFS was found according to platinum plus 5-fluorouracil versus platinum plus taxane (4.9 vs. 3.4 months; P = .036) and regimens with 2 versus 3 drugs (3.4 vs. 8.6 months; P = .019). At the multivariate analysis only regimens with platinum plus taxane were associated with worse PFS (HR 2.83).
In our registry study, PSCC is confirmed to be an aggressive disease. Poor ECOG PS, presence of lymph node metastases, and higher age at diagnosis appear to be associated with worse survival outcomes.
