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Background: PARP inhibitors have recently been approved for the treatment of mCRPC. In this Phase 2 study, we explore the safety profile of TALA in men with mCRPC with the aim of ...understanding how patients (pts) with adverse events (AEs) were managed during the trial. Methods: TALAPRO-1 (NCT03148795) is a single-arm, open-label, phase 2 study of TALA in pts with progressive mCRPC, measurable soft tissue disease, and DDRm likely to sensitize to PARPi ( ATM, ATR, BRCA1/2, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, RAD51C), who received ≥1 taxane-based chemotherapy and progressed on ≥1 novel hormonal therapy (enzalutamide/abiraterone). The primary objective was confirmed objective response by central independent review; the assessment of safety included AEs, incidence of dose modifications and of permanent treatment discontinuation due to AEs, and clinical laboratory tests. Results: In the TALA-treated population (1 mg/daily; n=127), 95.3% (121/127) experienced all-causality AEs. The most common (≥15%) hematologic AEs were anemia (any grade, 48.8%; G3, 30.7% no G4 events), thrombocytopenia (all grade, 18.9%; G3/4, 8.7%), and neutropenia (all grade, 16.5%, G3, 7.9% no G4). Median time from first dose of TALA to onset of first episode of G≥3 anemia, neutropenia, and thrombocytopenia was 56, 48, and 17 days, respectively. G3 anemia lasted a median of 7 days, G3 neutropenia lasted a median of 12 days, G3 and G4 thrombocytopenia lasted a median of 8 and 11 days, respectively. Hematologic AEs typically occurred during the first 4–5 months of TALA treatment and were managed by dose modifications and supportive care. 34.6% of pts received a blood transfusion product, and most transfusions occurred when hemoglobin was between 7.0–10.0 g/dL. Overlapping G3/4 hematologic AEs were infrequent on TALA (anemia + neutropenia 4.7%; anemia + thrombocytopenia 5.5%; neutropenia + thrombocytopenia 1.6%). In pts who had anemia, 12.6% also had fatigue; in those with thrombocytopenia, 4.7% had a subsequent bleeding event; in those with neutropenia, 1.6% had an overlapping infection. The most common non-hematologic AEs (≥15%) were nausea (any grade, 33.1%; G3/4, 2.4%), decreased appetite (any grade, 28.3%; G3/4, 3.1%), and asthenia/fatigue (any grade, 23.6%/19.7%; G3/4, 3.9%/1.6%). In the treated population, dose reduction of TALA due to all-causality AE occurred in 33 pts (26.0%). Treatment discontinuation due to all-causality AEs was low and occurred in 15 pts (11.8%); the most frequent (≥2 pts) AEs leading to discontinuation of TALA were back pain and platelet count decrease (each, 1.6% 2/127 pts). There were no treatment-related deaths. Conclusions: A manageable safety profile and durable antitumor effects were observed with TALA in men with heavily pretreated mCRPC in this phase 2 study. Clinical trial information: NCT03148795.
Renal cell carcinoma (RCC) is the seventh most common neoplasm in high-income countries. New clinical pathways have been developed to deal with this tumor, which includes costly drugs that pose an ...economic threat to the sustainability of healthcare services. This study provides an estimate of the direct costs of care for patients with RCC by stage of disease (early vs. advanced) at diagnosis, and disease management phase along the pathway recommended by local and international guidelines.
Considering the clinical pathway for RCC adopted in the Veneto region (north-east Italy) and the latest guidelines, we developed a very detailed “whole-disease” model that covers the probabilities of all potentially necessary diagnostic and therapeutic actions involved in the management of RCC. Based on the cost of each procedure according to the Veneto Regional Authority's official reimbursement tariffs, we estimated the total and average per-patient costs by stage of disease (early or advanced) and phase of its management.
In the first year after diagnosis, the mean expected cost of a patient with RCC is €12,991 if it is localized or locally-advanced and reaches €40,586 if it is advanced. For early disease, the main cost is incurred by surgery, whereas medical therapy (first and second line) and supportive care become increasingly important for metastatic disease.
It is crucially important to examine the direct costs of care for RCC, and to predict the burden on healthcare services of new oncological therapies and treatments, as the findings could be useful for policy-makers planning the allocation of resources.
This study estimated the direct costs of managing renal cell carcinoma, the seventh most common neoplasm in high-income countries, through the development of a whole disease model based on clinical pathways, pondering the probabilities of all diagnostic-therapeutic procedures and linking the reimbursement tariff to each procedure. The results of this work could provide useful insights for policy-makers planning healthcare resources allocation.
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Background: Nivolumab is approved in the second or further line of treatment for patients with metastatic renal cell carcinoma (mRCC); cabozantinib is approved in a similar setting ...of patients. Unfortunately, no evidence is currently available regarding the best treatment option after disease progression to both nivolumab and cabozantinib. The aim of this study is to compare the treatment choices after progression to nivolumab and cabozantinib including patients followed in best supportive care (BSC) or active therapy. Methods: In this retrospective observational study, we selected 42 patients from 8 Italian cancer centers. Enrolled patients had progressed to both nivolumab and cabozantinib and subsequently referred to active treatment or BSC. Primary endpoint of the study was the OS of patients on active treatment versus BSC. Secondary endpoints were ORR, PFS and OS of patients on active treatment who received sorafenib versus everolimus. Results: The median age was 65 years, 76.2% were male. The majority of patients had undergone nephrectomy (78.6%), had clear cell histology (83%) and were at intermediate-poor risk at the diagnosis (85.7%). The most frequent site of metastatic disease in the general population and in patients referred to BSC was the lung (73.8% and 88.9%, respectively). For patients referred to active treatment, the most frequent site of metastasis was bone (70.8%). Sunitinib (71.4%), nivolumab (64.3%), and cabozantinib (54.7%) were the most commonly used drugs in the I, II and III lines of treatment, respectively. After progression to both nivolumab and cabozantinib 42.9% of patients were referred to BSC, while 57.1% received active treatment (28.6% everolimus, 16.7% sorafenib, 4.8% sunitinib, 4.8% IL2-HD, 2.4% lenvatinib + everolimus). Median OS was 13 (95% CI: 4-NR) and 3 months (95% CI: 2-4) in patients on active treatment versus BSC ( p=0.001). Patients treated with sorafenib had better disease control when compared with those treated with everolimus (SD 71.4% versus 16.7%, PD 14.3% versus 58.3%; p=0.03), but no significant advantage in terms of PFS (5 versus 3 months, 95% CI: 2-6 versus 2-5; p= 0.5) and OS (NR versus 13 months, 95% CI: 3-NR versus 2-NR; p=0.2) was observed. Conclusions: After treatment with both nivolumab and cabozantinib, when possible, the choice of an active treatment seems to produce an OS advantage when compared with BSC. However, although sorafenib seems to demonstrate better results, we cannot indicate which is the drug of choice, as no significant advantage was shown in terms of OS or PFS from the comparison between sorafenib and everolimus. The limitations of this study are given by the size of the sample examined and its retrospective nature. Further studies are needed to confirm whether active treatment choice is associated with improved OS.
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Background: Targeted therapies (TT) improved survival in mRCC but treatment-related toxicities may worsen quality of life and lead to treatment discontinuation. AS is a feasible ...strategy in pts with indolent disease but effects on tumor burden (TB) and prognosis have not been investigated. Methods: In this retrospective study we included pts who received AS at our centre. The TB, defined as the number of sites of disease, was collected with the IMDC class, just before and after AS. The time on surveillance (ToS) was defined as the time from the start of AS to the beginning of therapy or last follow-up. The OSs were collected from the start of AS or TT. Results: 48 pts started AS from January 2007 to April 2016. After a median follow up of 37.3 months, 79.2% are still alive. At baseline the main sites of metastases were: lung (56%), nodes (25%), pancreas (14%), adrenal gland (8%), CNS (8%), and bone (6%). TB was one site in 65 %, two in 31%, and >2 sites in 4%. The IMDC prognostic class was favorable in 68,8%, intermediate in 25%, and poor in 6.3% of pts. After a median ToS of 16.7 months (95% CI 9.6-23.7), 34 patients (70.8%) started a TT, only 1/24 patient had progression as the best response. Significant difference in ToS were found where pts with good (19.9 mos) or intermediate (17.7 mos) class were compared to the poor group (5.2 months) (p<0.04). At the beginning of TT, the main sites of metastases were: lung (71%), nodes (44%), bone (15%), adrenal gland (15%), pancreas (15%), and CNS (9%). The TB was one site in 35%, two in 47%, and >2 sites in 18%; and 14 pts had new sites of disease. The IMDC class changed in four patients from good to intermediate. The median OSs was not reached from the start of surveillance and was 64.4 months from the start of TT. Conclusions: AS is an option for management of mRCC pts with good and intermediate prognosis. AS allows to delay the start of TT avoiding toxicity and worsening quality of life. Despite the fact pts in AS have increased TB and rarely a worsening of prognostic class, the survival remains longer and the effectiveness of subsequent therapy seems not to be affected.
In Europe, about 4% of prostate cancer (PC) patients have metastatic disease at the time of diagnosis (1). A prognostic stratification of these patients still lacks. Recently, CHAARTED and LATITUDE ...trials demonstrated improved outcomes with the addition of docetaxel and abiraterone acetate to androgen deprivation therapy (ADT) in metastatic hormone sensitive PC (mHSPC) with high-volume (HV) and high-risk (HR) disease, respectively (2,3). The aim of the present study was to evaluate how many patients with HR disease according to the LATITUDE trial can also be considered as HV based on the CHAARTED study, and vice versa, in the subset of de novo metastatic PC. A retrospective analysis was performed on patients with de novo metastatic PC referring to our Institution between January 2007 and September 2017. Clinical and pathological features were recorded (Table I). Patients were divided according to the CHAARTED and LATITUDE prognostic groups in three categories: 1) HV/HR, 2) low-volume (LV)/ low-risk (LR), and 3) HV or HR (HV/LR and LV/HR). The PASW software (Predictive Analytics SoftWare; v 21; IBM SPSS) was used for the statistical analysis. Survivals were estimated by the KaplanMeier method. Comparisons of survival across groups using the log-rank test Cox proportional-hazard models, stratified according to the baseline characteristics, were used to estimate hazard ratios for overall survival. We identified 126 de novo metastatic PC patients, with a median age of 72.0 years interquartile range (IQR)=64.6-78.4, 73.8% of Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1 (n=93), and the remaining 26.2% of ECOG PS ≥2 (n=33). Tumours were mainly of high Gleason Score (GS ≥ 8 in 69.8% of cases). The most frequent metastatic sites were: bone (88.9%), lymph node (68.3%), lung (16.7%), and liver (5.6%). The median value of prostate-specific antigen (PSA) at the time of diagnosis was 89.0 ng/ml. Data available allowed to stratify all patients (n=126) according to the CHAARTED classification (LV n=30; HV n=96), while 106 out of 126 patients were evaluated for the LATITUDE score (LR n=33; HR n=73). Therefore, the final study population included 106 patients analysed for both prognostic risk groups: 69 patients (65.1%) were HV/HR, 23 patients (21.7%) were LV/LR, and 14 patients (13.2%) fulfilled the criteria of only one of the two classification systems (HV or HR: 10 patients HV/LR and 4 patients LV/HR) (Table II). After a median follow-up of 35.6 months 69 deaths occurred. The median overall survival (mOS) of the entire population was 32.6 months (95% CI=24.8-40.3). In accordance with the CHAARTED classification, HV patients had a mOS of 28.2 months (95% CI=21.0-5.4) compared with 60.9 months (95% CI=27.1-94.7) of LV patients, with a statistically significant difference (p=0.008). Similarly, mOS significantly differed between the two prognostic groups based on LATITUDE criteria, with mOS of 28.2 months in HR patients (95% CI=22.8-33.6) compared to 40.6 months (95% CI=24.7-56.4) in LR patients (p=0.022). Concerning the three categories previously identified, a statistically significant difference in OS was observed between HR/HV group and LR/LV population (p=0.005), with a mOS of 26.3 months (95% CI=20.0-32.7) and 72.6 months (95% CI=25.5-119.6), respectively. Analogously, mOS was significantly longer in LV/LR patients compared to HV or HR (mOS of HV/LR and LV/HR was 35.1 months; 95% CI=31.4- 38.8) patients (p=0.003). No difference in OS was observed when HV/HR patients were compared with HV or HR patients (p=0.7). To date, chemotherapy with docetaxel or hormonal therapy with abiraterone acetate represent two possible therapeutic options for mHSPC (2,3). However, a direct comparison between these two strategies still lacks. Therefore, patient stratification is important in guiding clinicians to an adequate treatment selection. The present analysis showed the absence of a complete concordance between CHAARTED and LATITUDE prognostic stratification systems in the cohort of de novo metastatic PC patients. In particular, 13.2% of patients met only one of the two prognostic classifications (HV/LR and LV/HR). We can speculate that patients with HV/LR could be treated with chemotherapy plus ADT, while LV/HR patients could receive abiraterone acetate plus ADT. When the concordance between CHAARTED and LATITUDE systems was observed (in about 86.8% of cases), two opposite clinical disease patterns could be delineated: patients with very good prognosis (LV/LR group) and patients with poor prognosis (HV/HR group). The prognosis of patients belonging to only one of the two risk classifications did not differ from the HV/HR group prognosis. Significantly better outcome was observed in LV/LR group, which could benefit from ADT alone. Conversely, the prognostic stratification systems of the LATITUDE and CHAARTED trials did not help to better delineate the subgroup of HV/HR and HV or HR (HV/LR and LV/HR) disease, which represent the majority of de novo metastatic PC. Further clinical and or molecular prognostic factors supporting the choice of a specific therapy for HV/HR disease are warranted.
•Active surveillance (AS) is an option for selected patients with metastatic renal cell carcinoma.•No evidences are available about changes of international metastatic renal cell carcinoma database ...consortium (IMDC) prognostic factors and tumor burden during AS.•Active surveillance rarely deteriorates IMDC risk class.•Changes in the tumor burden were related to post overall survival.
Despite important results achieved for metastatic renal cell carcinoma, some patients could benefit from local treatments or an initial active surveillance (AS) period for recurrent disease. We aim to analyze: changes in the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk class, the number of metastases and the disease burden from the start of AS to the beginning of systemic therapy; and if these changes influenced patient outcomes.
Patients who started AS at our institution from January 2007 to April 2016 were included. The Kaplan-Meier method was used to estimate total overall survival (tOS) and progression-free survival. Changes in IMDC class, number of metastatic sites, and tumor burden (TB) were evaluated and related to patient survival. Among the patients who started active treatment, progression-free survival and post surveillance OS (psOS) were evaluated.
52 patients were included in the analysis. Median time on AS and tOS were 18.3 and 80.1 months respectively. Baseline factors were not related to the time on AS apart from the IMDC classification (HR = 2.15; 95% CI: 1.19–3.87; P = 0.011). The increase in the number of metastatic sites during AS was correlated with poor tOS (HR = 2.86; 95% CI: 1.29–6.34; P = 0.010). The increase of the TB was a negative prognosis factor for tOS (HR = 1.16; 95% CI: 1.02–1.31; P = 0.024) and psOS (HR = 1.21; 95% CI: 1.07–1.40; P = 0.004). Both IMDC class and change in the TB at the start of therapy were related to psOS. The retrospective nature and the lack of an external review of the imaging are its main limitations.
During AS, patients rarely experience a deterioration of their IMDC prognostic class, and the change in the TB, more than the increase in the number of metastatic sites, may help physicians to make decisions about the early termination of AS and the start of systemic therapy.
The aim of our study was to collect data about of the outcome of metastatic renal cell carcinoma patients who progressed after immune checkpoint inhibitors in order to enhance data about efficacy and ...safety of treatment beyond immune-oncology (IO).
A total of 162 eligible patients, progressing to IO, were enrolled from 16 Italian referral centers adhering to the Meet-Uro association. Baseline characteristics, outcome data and toxicities were retrospectively collected. Descriptive analysis was made using median values and ranges. Kaplan-Meier method and Mantel-Haenszel log-rank test were performed to compare differences between groups.
A total of 111 patients (68.5%) were treated after IO progression. In all, 51 patients (31.5%) did not receive further treatment for clinical deterioration. Median IO progression free survival (PFS) was 4 months (95% confidence interval CI: 3.1-4.8). IO-PFS tends to be longer in patients reporting adverse events (AE) of any grade (5.03 95% CI: 3.8-6.1 vs. 2.99 95% CI: 2.4-3.5 months P=0.004). Subsequent therapies included cabozantinib (n=79, 48%), everolimus (n=11, 6.7%), and others (n=21, 12.9%).Median PFS post-IO was 6.5 months (95% CI: 5.1-7.8). Cabozantinib showed longer PFS compared with everolimus (7.6 mo 95% CI: 5.2-10.1 vs. 3.2 mo 95% CI: 1.8-4.5) (hazard ratio: 0.2; 95% CI: 0.1026-0.7968) and other drugs (4.3 mo 95% CI: 1.3-7.4) (hazard ratio: 0.6; 95% CI: 0.35-1.23). All grade AE were reported in 83 patients (74%) and G3 to G4 AE in 39 patients (35%). Target therapies post-IO showed median overall survival of 14.7 months (95% CI: 0.3-21.4).
In our real world experience after progression to IO, vascular endotelial groth factor-tyrosine kinase inhibitors, given to patients, proved to be active and safe choices. Cabozantinib was associated with a better outcome in terms of median PFS.
BACKGROUNDImmune checkpoint inhibitor (ICI)-based combinations have become the first-line standard of care in metastatic renal cell carcinoma (mRCC), but their activity on the primary tumor is still ...one of the most debated issues. PATIENTS AND METHODSThe aim of our analysis was to evaluate the primary tumor's response to first-line therapy with cabozantinib or nivolumab+ipilimumab, and its correlation with metastatic response and with patient outcomes. RESULTSSixty-seven mRCC patients met the criteria for inclusion in the final analysis (30 treated with cabozantinib and 37 with nivolumab+ipilimumab). In the overall population, the primary tumor control rate (PTCR) was 90.9%; no complete responses (CR) were achieved. A significant correlation was found between the baseline size of the primary tumor's longest diameter and its response according to RECIST v1.1 criteria at the time of the second radiological assessment (rs = -0.351; P = .049). Moreover, a significant correlation between the type of primary tumor response and the response of the metastases was observed in the overall population (rs = 0.50; two-sided P < 0.001). There was also a significant correlation between primary tumor response and 1-year survival rate (P = .002), even when adjusted for the IMDC prognostic group and type of therapy (HR = 8.70; 95%CI, 2.52-30.05; P = .001). CONCLUSIONExtension of the primary tumor did not affect patient survival, while its response was significantly related to the response on metastatic disease and survival. No significant differences in terms of primary tumor shrinkage were identified between treatment with nivolumab+ipilimumab or cabozantinib in this cohort.
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Background: Biomarkers to select mRCC patients most likely to benefit to immunotherapy are still needed. The retrospective multicentre Meet-URO-15 study evaluated the prognostic ...role of peripheral blood cells in mRCC patients treated with Nivolumab. Methods: Complete blood count was collected at the first four cycles of Nivolumab. The primary endpoint was median overall survival (mOS) according to baseline neutrophil-to-lymphocyte ratio. Secondary analyses included bSII defined as platelet x NLR (cutoff = 1375) and ΔSII defined as the difference between SII at 2
nd
cycle and bSII (median used as cutoff = 383). Results: From October 2015 to October 2019, 470 patients started Nivolumab as 2
nd
(67%), 3
rd
(22%) and > 3
rd
(11%) line. Median age was 66 years, 71% were male and 83% had clear cell histology. Baseline IMDC group was favorable in 25%, intermediate in 63% and poor in 12%. Lymph-nodes, visceral and bone metastases were present in 54%, 91% and 36%. mOS and progression-free survival (PFS) were 34.8 and 7.5 months. Overall response rate (ORR) and disease control rate (DCR) were 30% and 61%. SII was available in 404 patients: SII < 1375 (82%) correlated with statistically significant improvement of PFS 10.2 vs 4.1 months, HR 2.06 (1.54-2.76), p< 0.001, OS 46.2 vs 9.5 months, HR 3.16 (2.23-4.49), p< 0.001, ORR (35% vs 21%, p= 0.035) and DCR (67% vs 40%, p< 0.001). ΔSII was available in 360 patients: ΔSII < 383 (75%) correlated with statistically significant improvement of PFS 11.3 vs 4.7 months; HR 1.64 (1.23-2.18), p= 0.001 and OS NR vs 21.1 months; HR 1.76 (1.21-2.56), p= 0.003, ORR (37% vs 24%, p= 0.023) and DCR (68% vs 53%, p= 0.01). Multivariate analyses adjusted for IMDC group, line of therapy and metastatic sites, confirmed the statistically significant correlation of bSII and ΔSII with OS, PFS and DCR. Conclusions: Our study showed the statistically significant correlation of lower bSII and early ΔSII with longer OS, PFS and higher DCR in mRCC patients treated with Nivolumab.
Neutrophil-to-eosinophil ratio (NER) has been described to be associated with outcomes to immune checkpoint inhibitors (ICI) in several tumor types, but less is known about its role of in the ...response to avelumab in advanced urothelial cancer (aUC). Thus, we reported outcomes by NER of aUC patients treated with avelumab as maintenance after initial response to platinum-based chemotherapy and enrolled in the Maintenance with AVeLumAb (MALVA in advanced urothelial neoplasms in response to first-line chemotherapy: an observational retrospective study) study (Meet-URO 25).
Median NER at baseline and after 3 cycles of avelumab were calculated. Progression-free survival (PFS) and overall survival (OS) by NER were reported.
At the cutoff date (April 15, 2023), a total of 109 patients were included. The median NER was 28.05 at baseline and 24.46 after 3 cycles of avelumab, respectively. Median PFS was not reached for patients with baseline NER less than the median (<median) compared to 5.1 months for patients with baseline NER greater than the median (≥median) (P = .0005). Median OS was significantly longer for patients with baseline NER <median compared with patients with baseline NER ≥median (not reached vs. 11.7 months, respectively; P = .0016). Significantly better PFS and OS were confirmed for NER after 3 cycles of avelumab <median compared with NER ≥median at the same timepoint.
NER <median may be predictive of PFS in aUC patients treated with avelumab, and prognostic for OS regardless of treatment. Prospective studies are warranted to validate NER as a readily available and reproducible laboratory-biomarker for efficacy outcomes of avelumab in aUC.
Our retrospective analysis from MALVA Meet-URO 25 study reports progression-free survival (PFS) and overall survival (OS) by neutrophil-to-eosinophil ratio (NER) during avelumab treatment for advanced urothelial cancer (aUC). NER <median may be predictive of PFS, and prognostic for OS regardless of treatment. Prospective studies are warranted to validate NER as reproducible laboratory-biomarker for efficacy outcomes of avelumab in aUC.
