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For the past few years, platform trials have experienced a significant increase, recently amplified by the COVID-19 pandemic. The implementation of a platform trial is particularly useful in certain pathologies, particularly when there is a significant number of drug candidates to be assessed, a rapid evolution of the standard of care or in situations of urgent need for evaluation, during which the pooling of protocols and infrastructure optimizes the number of patients to be enrolled, the costs, and the deadlines for carrying out the investigation. However, the specificity of platform trials raises methodological, ethical, and regulatory issues, which have been the subject of the round table and which are presented in this article. The round table was also an opportunity to discuss the complexity of sponsorship and data management related to the multiplicity of partners, funding, and governance of these trials, and the level of acceptability of their findings by the competent authorities.

In the current era of immune checkpoint inhibitors (ICIs), the role and optimal timing of a nephrectomy in patients with metastatic renal cell carcinoma (mRCC) remain unknown.To assess the oncological outcomes of patients who responded to ICI-based treatments and were subsequently treated with a delayed nephrectomy.This national retrospective evaluation included 30 patients with mRCC who underwent a nephrectomy after a complete response (CR) or a major partial response (80%) to ICI treatment at metastatic sites.Partial or radical nephrectomy after a favorable response to ICI treatment.Disease-free survival (DFS), progression-free survival (PFS), overall survival (OS), and potential discontinuation of systemic treatment were assessed.ICI-based treatments included ipilimumab-nivolumab (40%), ICI + tyrosine kinase inhibitor (10%), and nivolumab (50%). A delayed nephrectomy was performed after a median ICI treatment duration of 10 mo. In 19 cases (63.3%), surgeons faced difficulties due to adhesions or inflammatory changes. A complete pathological response was observed in 16.7% of patients. After a median follow-up of 19.5 mo after nephrectomy, 76.7% of patients achieved DFS. At 1 yr, 66.7% of patients were free from systemic treatment. The PFS and OS rates were, respectively, 96.7% and 100% at 1 yr, and 78.3% and 86.1% at 2 yr. Patients with a CR at metastatic sites had a better prognosis than those with a major partial response, in terms of DFS (p = 0.022) and PFS (p = 0.014).Despite potentially challenging surgery, a delayed nephrectomy for patients who responded to ICI treatment provided promising oncological outcomes, and the majority of patients could discontinue systemic treatment.In this study, we evaluated the clinical outcome in patients who responded well to immunotherapy, and subsequently underwent kidney ablation surgery. Three-quarters of patients experienced no recurrence, and in most cases, medical treatment could be discontinued.

For the last few decades, many efforts have been made in developing cell culture methods in order to overcome the biological limitations of the conventional two-dimensional culture. This paradigm shift is driven by a large amount of new hydrogel-based systems for three-dimensional culture, among other systems, since they are known to mimic some living tissue properties. One class of hydrogel precursors has received interest in the field of biomaterials, low-molecular-weight gelators (LMWGs). In comparison to polymer gels, LMWG gels are formed by weak interactions upon an external trigger between the molecular subunits, giving them the ability to reverse the gelation, thus showing potential for many applications of practical interest. This study presents the use of the nucleoside derivative subclass of LMWGs, which are glyco-nucleo-bola-amphiphiles, as a proof of concept of a 3D cell culture scaffold. Physicochemical characterization was performed in order to reach the optimal features to fulfill the requirements of the cell culture microenvironment, in terms of the mechanical properties, architecture, molecular diffusion, porosity, and experimental practicality. The retained conditions were tested by culturing glioblastoma cells for over a month. The cell viability, proliferation, and spatial organization showed during the experiments demonstrate the proof of concept of nucleoside-derived LMWGs as a soft 3D cell culture scaffold. One of the hydrogels tested permits cell proliferation and spheroidal organization over the entire culture time. These systems offer many advantages as they consume very few matters within the optimal range of viscoelasticity for cell culture, and the thermoreversibility of these hydrogels permits their use with few instruments. The LMWG-based scaffold for the 3D cell culture presented in this study unlocked the ability to grow spheroids from patient cells to reach personalized therapies by dramatically reducing the variability of the lattice used.

Inserting complex biomolecules such as oligonucleotides during the synthesis of polymers remains an important challenge in the development of functionalized materials. In order to engineer such a biofunctionalized interface, a single-step method for the covalent immobilization of oligonucleotides (ONs) based on novel electropolymerizable lipid thiophene-oligonucleotide (L-ThON) conjugates was employed. Here, we report a new thiophene phosphoramidite building block for the synthesis of modified L-ThONs. The biofunctionalized material was obtained by direct electropolymerization of L-ThONs in the presence of 2,2'-bithiophene (BTh) to obtain a copolymer film on indium tin oxide electrodes.

Purpose:Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC.Patients and Methods:Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics.Results:Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3–22.9); n = 65; HR, 0.45 (95% CI, 0.3–0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33–0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged.Conclusions:NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population.See related commentary by Hwang et al., p. 5

Overall survival (A) and progression-free survival (B) by baseline tumor PD-L1 expression (PD-L1 {greater than or equal to}1% and PD-L1

ORR in patients with sRCC and I/P-risk disease, per IRRC, by central or local pathology review.

Background The taxanes docetaxel and cabazitaxel prolong overall survival for men with metastatic castration-resistant prostate cancer (mCRPC), with cabazitaxel approved in the postdocetaxel setting only. Recent data suggest they have similar efficacy but a different safety profile in the first-line mCRPC setting. Objective To assess patient preference between docetaxel and cabazitaxel among men who received one or more doses of each taxane and did not experience progression after the first taxane. Design, setting, and participants Chemotherapy-naive patients with mCRPC were randomized 1:1 to receive docetaxel (75 mg/m2 every 3 wk × 4 cycles) followed by cabazitaxel (25 mg/m2 every 3 wk × 4 cycles) or the reverse sequence. Randomization was stratified by prior abiraterone or enzalutamide use. Outcome measurements and statistical analysis The primary endpoint was patient preference, assessed via a dedicated questionnaire after the second taxane. Secondary endpoints included reasons for patient preference, prostate-specific antigen response, radiological progression-free survival, and overall survival. This clinical trial is registered at ClinicalTrials.gov as NCT02044354. Results and limitations Of 195 men randomized, 152 met the prespecified modified intent-to-treat criteria for analysis. Overall, 66 patients (43%) preferred cabazitaxel, 40 (27%) preferred docetaxel, and 46 (30%) had no preference (p = 0.004, adjusted for treatment period effect). More patients preferred treatment period 1 (43%, 95% confidence interval [CI] 36–52%) versus period 2 (27%, 95% CI 20–34%). Patient preference for cabazitaxel was mainly related to less fatigue (72%), better quality of life (64%), and other adverse events (hair loss, pain, nail disorders, edema). Adverse events were consistent with the known safety profile of each drug. Conclusions A significantly higher proportion of chemotherapy-naive men with mCRPC who received both taxanes preferred cabazitaxel over docetaxel. Less fatigue and better quality of life were the two main reasons driving patient choice. Patient summary Men with metastatic castration-resistant prostate cancer preferred cabazitaxel over docetaxel for chemotherapy, mainly because of less fatigue and better quality of life.

Contains fulltext : 290894.pdf (Publisher’s version ) (Open Access) BACKGROUND: Talazoparib has shown antitumor activity with a manageable safety profile in men with metastatic castration-resistant prostate cancer (mCRPC) and DNA damage response (DDR)/homologous recombination repair (HRR) alterations. OBJECTIVE: To evaluate patient-reported health-related quality of life (HRQoL) and pain in patients who received talazoparib in the TALAPRO-1 study, with a special interest in patients harboring breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations. DESIGN, SETTING, AND PARTICIPANTS: TALAPRO-1 is a single-arm, phase 2 study in men with mCRPC DDR alterations either directly or indirectly involved in HRR, who previously received one to two taxane-based chemotherapy regimens for advanced prostate cancer and whose mCRPC progressed on one or more novel hormonal agents. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Men completed the European Quality-of-life Five-dimension Five-level scale (EQ-5D-5L), EQ-5D visual analog scale (VAS), and Brief Pain Inventory-Short Form at predefined time points during the study. The patient-reported outcome (PRO) population included men who completed a baseline and one or more postbaseline assessments before study end. Longitudinal mixed-effect models assuming an unstructured covariance matrix were used to estimate the mean (95% confidence interval [CI]) change from baseline for pain and general health status measurements among all patients and patients with BRCA1/2 mutations. RESULTS AND LIMITATIONS: In the 97 men in the PRO population treated with talazoparib (BRCA1/2, n = 56), the mean (95% CI) EQ-5D-5L Index improved (all patients, 0.05 [0.01, 0.08]; BRCA1/2 subset, 0.07 [0.03, 0.10]), as did the EQ-5D VAS scores (all patients, 5.42 [2.65, 8.18]; BRCA1/2 subset, 4.74 [1.07, 8.41]). Improvements in the estimated overall change from baseline (95% CI) in the mean worst pain were observed in all patients (-1.08 [-1.52, -0.65]) and the BRCA1/2 subset (-1.15 [-1.67, -0.62]). The probability of not having had experienced deterioration of worst pain by month 12 was 84% for all patients and 83% for the BRCA1/2 subset. CONCLUSIONS: In heavily pretreated men with mCRPC and DDR/HRR alterations, talazoparib was associated with improved HRQoL in all patients and the BRCA1/2 subset. In both patient groups, worst pain improved from baseline and the probability of not experiencing a deterioration in worst pain with talazoparib was high. PATIENT SUMMARY: We show that talazoparib was associated at least with no change or improvements in health-related quality of life (HRQoL) and pain burden in men with metastatic castration-resistant prostate cancer and DNA damage response/homologous recombination repair gene alterations in the TALAPRO-1 study. These findings in patient-reported HRQoL and pain complement the antitumor activity and tolerability profile of talazoparib. 01 april 2023

Background : Cisplatin-based combination chemotherapy before surgery is the standard of care for muscle-invasive bladder cancer. However, the optimal chemotherapy modalities have not been precisely defined to date. Patients and Methods : In the VESPER trial, patients received after randomization either gemcitabine and cisplatin (GC, 4 cycles) or methotrexate, vinblastine, doxorubicin and cisplatin (dose dense [dd]-MVAC, 6 cycles). Creatinine clearance (CrCl) was calculated before each cycle according to the Cockroft and Gault formula. Definition criteria for local control after neoadjuvant chemotherapy included pathological complete response (ypT0N0), pathological downstaging ( Results : A total of 2,128 cycles of chemotherapy were delivered, including 2,120 (99.6%) with cisplatin. Full doses of cisplatin were given in 1866 (88%) cycles. Twenty-three (4.7%) patients had to stop chemotherapy (12 GC, 11 dd-MVAC) because of renal failure. No difference in CrCl median values was observed between the two regimens during the first four cycles. A mild decrease occurred thereafter in patients treated with two additional cycles of dd-MVAC. A minimum total dose of 270 mg/m2 for cisplatin was mandatory to optimize pathological complete responses. Conclusion : At least 4 cycles of cisplatin-based chemotherapy should be delivered before cystectomy. Increasing the number of cycles beyond 4 cycles does not lead to a clinically significant deterioration in renal function but without obvious gain on local control. MicroAbstractCGC : A deep analysis of data from a randomized trial of perioperative chemotherapy in muscle-invasive bladder cancer shows that a minimum number of 4 cycles is required to optimize the chances of pathological complete response at cystectomy. Increasing the number beyond 4 cycles does not lead to a clinically significant deterioration in renal function without any obvious gain on pathological complete response.

Background Cabazitaxel was shown to improve overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) after abiraterone/enzalutamine and docetaxel failure, though benefit by the presence of DNA damage repair (DDR) defects is unknown. With the advent of poly(adenosine diphosphate–ribose) polymerase inhibitors (PARPi) in partially overlapping indications with cabazitaxel, we aimed to determine cabazitaxel activity in men with mCRPC according to their DDR status. Methods This is a retrospective multicenter study that enrolled patients with mCRPC treated with cabazitaxel who had undergone DDR tumour tissue profiling. Patients with at least one deleterious germline or somatic alterations were considered DDR positive (DDR+). Each DDR + patient has been matched with a DDR negative (DDR-) from the same institution who underwent the same test. An exploratory cohort of patients found to be DDR + by liquid biopsy was also included. Prostate specific antigen (PSA) decline≥50% (PSA50), PSA progression-free survival (PFS, PSA-PFS), radiographic PFS (rPFS), clinical PFS or radiographic PFS (c/rPFS) and OS were evaluated. Results Among 190 men (95 DDR+, 95 DDR-) with tissue sequencing, PSA50 was achieved with cabazitaxel in 29/92 (32%) and 33/92 (36%) in patients with DDR+ and DDR- (P = 0.64). The median rPFS was 5.33 months [95%CI 4.34–7.04] versus 5.75 months [95%CI 4.67–7.27] (P = 0.55). The median OS was 15.4 months [95%CI 12.16–26.6] and 11.5 months [95%CI 9.76–14.4] (P = 0.036), respectively. No PSA50 responses on cabazitaxel were observed in BRCA1/2 patients previously treated with PARPi (n = 10). Similar outcomes with cabazitaxel were observed in the liquid biopsy cohort (n = 63 DDR+). Conclusions Our study suggests that cabazitaxel is active in patients with mCRPC regardless of their DDR status, although its activity in men pretreated with a PARPi may be lower.

Introduction Cabazitaxel multiple rechallenges may be a treatment option in heavily pretreated patients with metastatic castration‐resistant prostate cancer (mCRPC) who had a good initial response to cabazitaxel and who are still fit to receive it. Our objective was to assess the efficacy and toxicity of multiple rechallenges. Patients and methods We retrospectively identified 22 mCRPC patients previously treated with docetaxel and/or androgen receptor‐targeted agents who received multiple cabazitaxel rechallenges in 9 French centers. Cabazitaxel was initiated at a dose of 25 mg/m2 q3week. A reduced dose (20 mg/m2 q3w) or an alternative schedule (mainly 16 mg/m2 q2w) was increasingly used for subsequent rechallenges. Progression‐free survival, prostate‐specific antigen (PSA) response, best clinical response, and grade ≥3 toxicities were collected. Overall survival was calculated from various time points. Results Twenty‐two patients with an initial response to cabazitaxel were rechallenged at least twice. The median number of cabazitaxel cycles was 7 at first cabazitaxel treatment, 6 at first rechallenge, and 5 at subsequent rechallenges. Median progression‐free survival at first rechallenge was 9.6 months and 5.6 months at second rechallenge. Median overall survival was 50.9 months from the first cabazitaxel dose, 114.9 months from first life‐extending therapy initiation in mCRPC, and 105 months from mCRPC diagnosis. There was no cumulative grade ≥3 neuropathy or nail disorder and one case of febrile neutropenia. Conclusion Cabazitaxel multiple rechallenges may be a treatment option without cumulative toxicity in heavily pretreated patients having a good response to first cabazitaxel use and still fit to receive it. Novelty & Impact Statements Patients with metastatic castration‐resistant prostate cancer can be treated with Cabazitaxel after docetaxel and androgen receptor‐targeted agent. This chemotherapy can be used multiple times with efficacy and manageable toxicity., We assessed the efficacy and toxicity of multiple rechallenges with cabazitaxel for 22 patients with metastatic castration‐resistant prostate cancer (mCRPC). Median overall survival was 50.9 months from the first cabazitaxel dose, 114.9 months from first life‐extending therapy initiation in mCRPC, and 105 months from mCRPC diagnosis. Cabazitaxel rechallenge may be an effective option in heavily pretreated mCRPC patients with a good initial response to cabazitaxel and still fit to receive it, without cumulative grade ≥3 toxicity.

This study looked at whether epidermal growth factor receptor inhibition by the monoclonal antibody panitumumab could increase the efficacy of standard chemotherapy in advanced urothelial cancer. Results were disappointing, with higher toxicity and no improvement in efficacy in the combination arm. Background: Epidermal growth factor receptor (EGFR) overexpression is frequent and associated with poor outcome in urothelial carcinoma. EGFR inhibition could improve the antitumor activity of chemotherapy. Patients and Methods: Patients with advanced, treatment-naive, histologically confirmed advanced urothelial carcinoma and no HRAS or KRAS mutation in the primary tumor received dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) without or with the anti-EGFR monoclonal antibody panitumumab (Pmab). A randomized (1:2) phase II design was used with progression-free survival (PFS) as the primary endpoint. Results: Ninety-seven eligible patients were randomized; 96 patients were evaluable for toxicity and 87 for efficacy. The median PFS were 6.8 months (95% confidence interval [CI], 6.3-9.2) for dd-MVAC and 5.7 months (95% CI, 4.6-6.4 months) for dd-MVAC+Pmab. For both immunohistochemical and molecular definition of basal/squamous-like (BASQ) tumors, no difference was observed in objective response rates or PFS between the two arms in BASQ and non-BASQ tumors. Conclusion: dd-MVAC+Pmab was associated with more serious adverse events and no improvement in efficacy outcomes.

Supramolecular chemistry has garnered important interest in recent years toward improving therapeutic efficacy via drug delivery approaches. Although self-assemblies have been deeply investigated, the design of novel drugs leveraging supramolecular chemistry is less known. In this contribution, we show that a Low Molecular Weight Gel (LMWG) can elicit cancer cell apoptosis. This biological effect results from the unique supramolecular properties of a bolaamphiphile-based gelator, which allow for strong interaction with the lipid membrane. This novel supramolecular-drug paradigm opens up new possibilities for therapeutic applications targeting membrane lipids.

We describe a large series of patients with solid tumors in an early COVID‐19 cluster in the eastern part of France. From February to May 2020, this multicenter retrospective study enrolled 212 patients with cancer under treatment or on follow‐up for any type of malignant solid tumor and positive for SARS‐CoV‐2. The mortality rate was 30%. Patients with gastrointestinal cancers were identified as a subset of more vulnerable patients; immunotherapy and radiotherapy within 3 months from COVID‐19 diagnosis were risk factors for death. The reported data support the essential need to be proactive and weigh the risks of morbidity from COVID‐19 against the magnitude of benefits of intended cancer therapies during this pandemic. Implications for Practice This article supports the essential need to be proactive (treatment delay or modification) in oncology in the setting of pandemic. This study identified patients with gastrointestinal cancers as a more vulnerable subset of patients with cancer and found that immunotherapy and radiotherapy within 3 months from COVID‐19 diagnosis to be risk factors for death. The reported data indicate the necessity of weighing the risks of morbidity from COVID‐19 against the magnitude of benefits of intended cancer therapies in any future wave of COVID‐19., In the light of a local experience in an area of France, this article describes disease characteristics, management, and outcomes in patients with cancer and confirmed or highly suspected COVID‐19.

In this study, we designed aptamer-based self-assemblies for the delivery of quinine. Two different architectures were designed by hybridizing quinine binding aptamers and aptamers targeting Plasmodium falciparum lactate dehydrogenase (PfLDH): nanotrains and nanoflowers. Nanotrains consisted in controlled assembly of quinine binding aptamers through base-pairing linkers. Nanoflowers were larger assemblies obtained by Rolling Cycle Amplification of a quinine binding aptamer template. Self-assembly was confirmed by PAGE, AFM and cryoSEM. The nanotrains preserved their affinity for quinine and exhibited a higher drug selectivity than nanoflowers. Both demonstrated serum stability, hemocompatibility, low cytotoxicity or caspase activity but nanotrains were better tolerated than nanoflowers in the presence of quinine. Flanked with locomotive aptamers, the nanotrains maintained their targeting ability to the protein PfLDH as analyzed by EMSA and SPR experiments. To summarize, nanoflowers were large assemblies with high drug loading ability, but their gelating and aggregating properties prevent from precise characterization and impaired the cell viability in the presence of quinine. On the other hand, nanotrains were assembled in a selective way. They retain their affinity and specificity for the drug quinine, and their safety profile as well as their targeting ability hold promise for their use as drug delivery systems.

The impact of single-agent antibodies against programmed death-ligand 1 (PD-L1) as maintenance therapy is unknown in patients with metastatic breast cancer. The SAFIR02-BREAST IMMUNO substudy included patients with human epidermal growth factor receptor type 2 (Her2)-negative metastatic breast cancer whose disease did not progress after six to eight cycles of chemotherapy. Patients (n = 199) were randomized to either durvalumab (10 mg kg−1 every 2 weeks) or maintenance chemotherapy. In the overall population, durvalumab did not improve progression-free survival (adjusted hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.00–1.96; P = 0.047) or overall survival (OS; adjusted HR: 0.84, 95% CI: 0.54–1.29; P = 0.423). In an exploratory subgroup analysis, durvalumab improved OS in patients with triple-negative breast cancer (TNBC; n = 82; HR: 0.54, 95% CI: 0.30–0.97, P = 0.0377). Exploratory analysis showed that the HR of death was 0.37 (95% CI: 0.12–1.13) for patients with PD-L1+ TNBC (n = 32) and 0.49 (95% CI: 0.18–1.34) for those with PD-L1− TNBC (n = 29). In patients with TNBC, exploratory analyses showed that the HR for durvalumab efficacy (OS) was 0.18 (95% CI: 0.05–0.71; log-rank test, P = 0.0059) in patients with CD274 gain/amplification (n = 23) and 1.12 (95% CI: 0.42–2.99; log-rank test, P = 0.8139) in patients with CD274 normal/loss (n = 32). Tumor infiltration by lymphocytes (CD8, FoxP3 and CD103 expressions) and homologous recombination deficiency did not predict sensitivity to durvalumab in exploratory analyses. This latter finding should be interpreted with caution since only one patient presented a germline BRCA mutation. The present study provides a rationale to evaluate single-agent durvalumab in maintenance therapy in patients with TNBC. Exploratory analyses identified CD274 amplification as a potential biomarker of sensitivity. Maintenance chemotherapy was more effective than durvalumab in patients with hormone receptor-positive and Her2-negative disease. Exploratory analyses from the phase 2 randomized SAFIR02-IMMUNO trial identify biomarkers associated with improved outcomes to durvalumab as compared to maintenance chemotherapy in patients with triple-negative breast cancer.

Background Treatment with tivozanib, a highly selective and potent vascular endothelial growth factor receptor tyrosine kinase inhibitor, has demonstrated single-agent efficacy in advanced renal cell carcinoma (RCC) along with minimal off-target toxicities and a favorable adverse event (AE) profile. We report final results from TiNivo, a phase Ib/II study of tivozanib combined with nivolumab. Patients and methods In phase Ib, patients with metastatic RCC received tivozanib 1.0 mg once daily (QD) for 21 days followed by 7 days off treatment (n = 3) or tivozanib 1.5 mg QD (n = 3) plus nivolumab 240 mg every 2 weeks. The maximum tolerated dose was determined to be tivozanib 1.5 mg, and 22 additional patients were enrolled at the maximum tolerated dose for phase II. Primary end points included safety and tolerability, with secondary end points of objective response rate, disease control rate, and progression-free survival. Results In total, 25 patients were treated with tivozanib 1.5 mg QD [12 (48%) treatment-naive; 13 (52%) previously treated]. Treatment-related grade 3/4 AEs were reported in 20 patients (80%); 4 patients (17%) experienced AEs that led to dose reduction, and 8 (32%) discontinued due to AEs. The objective response rate was 56% (including one complete response) and disease control rate was 96%, with a median time to best response of 7.9 weeks. Twenty patients (80%) had tumor shrinkage. With a median follow-up of 19.0 months (range, 12.6–22.8), median progression-free survival was 18.9 months (95% confidence interval 16.4–not reached) in all patients and was similar in treatment-naive and previously treated patients. Conclusions Tivozanib plus nivolumab combination therapy showed a generally tolerable AE profile and promising antitumor efficacy. These results support further development of tivozanib combined with nivolumab as a treatment option in patients with treatment-naive or previously treated metastatic RCC. Clinical Trial number NCT03136627.

Purpose: Patients with advanced renal cell carcinoma with sarcomatoid features (sRCC) have poor prognoses and suboptimal outcomes with targeted therapy. This post hoc analysis of the phase III CheckMate 214 trial analyzed the efficacy of nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in patients with sRCC. Patients and Methods: Patients with sRCC were identified via independent central pathology review of archival tumor tissue or histologic classification per local pathology report. Patients were randomized 1:1 to receive nivolumab (3 mg/kg) plus ipilimumab (1 mg/kg) every 3 weeks (four doses) then nivolumab 3 mg/kg every 2 weeks, or sunitinib 50 mg orally every day (4 weeks; 6-week cycles). Outcomes in patients with sRCC were not prespecified. Endpoints in patients with sRCC and International Metastatic Renal Cell Carcinoma Database Consortium intermediate/poor-risk disease included overall survival (OS), progression-free survival (PFS) per independent radiology review, and objective response rate (ORR) per RECIST v1.1. Safety outcomes used descriptive statistics. Results: Of 1,096 randomized patients in CheckMate 214, 139 patients with sRCC and intermediate/poor-risk disease and six with favorable-risk disease were identified. With 42 months' minimum follow-up in patients with sRCC and intermediate/poor-risk disease, median OS [95% confidence interval (CI)] favored NIVO+IPI [not reached (NR) (25.2-not estimable [NE]); n = 74] versus sunitinib [14.2 months (9.3–22.9); n = 65; HR, 0.45 (95% CI, 0.3–0.7; P = 0.0004)]; PFS benefits with NIVO+IPI were similarly observed [median 26.5 vs. 5.1 months; HR, 0.54 (95% CI, 0.33–0.86; P = 0.0093)]. Confirmed ORR was 60.8% with NIVO+IPI versus 23.1% with sunitinib, with complete response rates of 18.9% versus 3.1%, respectively. No new safety signals emerged. Conclusions: NIVO+IPI showed unprecedented long-term survival, response, and complete response benefits versus sunitinib in previously untreated patients with sRCC and intermediate/poor-risk disease, supporting the use of first-line NIVO+IPI for this population. See related commentary by Hwang et al., p. 5

International audience; Background: Real-world data on cabozantinib in metastatic renal cell carcinoma (mRCC) is limited. This study (CABOREAL) reports treatment patterns and outcomes for patients treated with cabozantinib through the French Early Access Program.Patients and methods: This multicentre (n = 26), observational, retrospective study enrolled patients with mRCC who had received ≥1 dose of cabozantinib. Overall survival (OS) was estimated using the Kaplan-Meier method; subgroups were compared using the log-rank test. A multiple Cox regression model assessed predictive factors of OS after cabozantinib initiation.Results: Four hundred and ten recruited patients started treatment between September 2016 and February 2018: the Eastern Cooperative Oncology Group Performance Status ≥2, 39.3%; poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk, 31.7%; 0-1, 2 and ≥3 previous treatment lines, 25.3%, 33.4% and 41.2%, respectively; bone metastases, 55.9%; brain metastases, 16.8%. Median (min-max) follow-up was 14.4 (0-30) months. Overall, 57.0% of patients had a dose reduction, 15.6% an alternative dose schedule. The median average daily dose was 40.0 mg. Median (quartile [Q]1-Q3) treatment duration was 7.6 (0.1-29.1) months, median OS was 14.4 months, and the 12-month OS rate was 56.5% (95% confidence interval: 51.5-61.2). Most patients (54.4%) received subsequent treatment. Predictive factors associated with longer OS were body mass index ≥25 kg/m2 (p = 0.0021), prior nephrectomy (p = 0.0109), favourable or intermediate IMDC risk (p < 0.0001) and cabozantinib initiation at 60 mg/day (p = 0.0486).Conclusions: In the largest real-world study to date, cabozantinib was effective in unselected, heavily pretreated patients with mRCC. Initiation at 60 mg/day was associated with improved outcomes. CLINICALTRIALS.

International audience; Background: We previously reported a 35-gene expression classifier identifying four clear-cell renal cell carcinoma groups (ccrcc1 to ccrcc4) with different tumour microenvironments and sensitivities to sunitinib in metastatic clear-cell renal cell carcinoma. Efficacy profiles might differ with nivolumab and nivolumab-ipilimumab. We therefore aimed to evaluate treatment efficacy and tolerability of nivolumab, nivolumab-ipilimumab, and VEGFR-tyrosine kinase inhibitors (VEGFR-TKIs) in patients according to tumour molecular groups.Methods: This biomarker-driven, open-label, non-comparative, randomised, phase 2 trial included patients from 15 university hospitals or expert cancer centres in France. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 0-2, and had previously untreated metastatic clear-cell renal cell carcinoma. Patients were randomly assigned (1:1) using permuted blocks of varying sizes to receive either nivolumab or nivolumab-ipilimumab (ccrcc1 and ccrcc4 groups), or either a VEGFR-TKI or nivolumab-ipilimumab (ccrcc2 and ccrcc3 groups). Patients assigned to nivolumab-ipilimumab received intravenous nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four doses followed by intravenous nivolumab 240 mg every 2 weeks. Patients assigned to nivolumab received intravenous nivolumab 240 mg every 2 weeks. Patients assigned to VEGFR-TKIs received oral sunitinib (50 mg/day for 4 weeks every 6 weeks) or oral pazopanib (800 mg daily continuously). The primary endpoint was the objective response rate by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1. The primary endpoint and safety were assessed in the population who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02960906, and with the EU Clinical Trials Register, EudraCT 2016-003099-28, and is closed to enrolment.Findings: Between June 28, 2017, and July 18, 2019, 303 patients were screened for eligibility, 202 of whom were randomly assigned to treatment (61 to nivolumab, 101 to nivolumab-ipilimumab, 40 to a VEGFR-TKI). In the nivolumab group, two patients were excluded due to a serious adverse event before the first study dose and one patient was excluded from analyses due to incorrect diagnosis. Median follow-up was 18·0 months (IQR 17·6-18·4). In the ccrcc1 group, objective responses were seen in 12 (29%; 95% CI 16-45) of 42 patients with nivolumab and 16 (39%; 24-55) of 41 patients with nivolumab-ipilimumab (odds ratio [OR] 0·63 [95% CI 0·25-1·56]). In the ccrcc4 group, objective responses were seen in seven (44%; 95% CI 20-70) of 16 patients with nivolumab and nine (50% 26-74) of 18 patients with nivolumab-ipilimumab (OR 0·78 [95% CI 0·20-3·01]). In the ccrcc2 group, objective responses were seen in 18 (50%; 95% CI 33-67) of 36 patients with a VEGFR-TKI and 19 (51%; 34-68) of 37 patients with nivolumab-ipilimumab (OR 0·95 [95% CI 0·38-2·37]). In the ccrcc3 group, no objective responses were seen in the four patients who received a VEGFR-TKI, and in one (20%; 95% CI 1-72) of five patients who received nivolumab-ipilimumab. The most common treatment-related grade 3-4 adverse events were hepatic failure and lipase increase (two [3%] of 58 for both) with nivolumab, lipase increase and hepatobiliary disorders (six [6%] of 101 for both) with nivolumab-ipilimumab, and hypertension (six [15%] of 40) with a VEGFR-TKI. Serious treatment-related adverse events occurred in two (3%) patients in the nivolumab group, 38 (38%) in the nivolumab-ipilimumab group, and ten (25%) patients in the VEGFR-TKI group. Three deaths were treatment-related: one due to fulminant hepatitis with nivolumab-ipilimumab, one death from heart failure with sunitinib, and one due to thrombotic microangiopathy with sunitinib.Interpretation: We demonstrate the feasibility and positive effect of a prospective patient selection based on tumour molecular phenotype to choose the most efficacious treatment between nivolumab with or without ipilimumab and a VEGFR-TKI in the first-line treatment of metastatic clear-cell renal cell carcinoma.

We present an exploratory post hoc analysis from the phase 3 CheckMate 214 trial of first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib in a subgroup of 108 patients with advanced renal cell carcinoma (aRCC) without prior nephrectomy and with an evaluable primary tumor, a population under-represented in clinical trials. Patients with clear cell aRCC were randomized to NIVO+IPI every 3 wk for four doses followed by NIVO monotherapy, or sunitinib every day for 4 wk (6-wk cycle). Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and primary tumor shrinkage were assessed. PFS and ORR were assessed per independent radiology review committee using RECIST version 1.1. With minimum study follow-up of 4 yr for intent-to-treat patients, OS favored NIVO+IPI (n = 53) over sunitinib (n = 55; hazard ratio 0.63, 95% confidence interval 0.40–1.0) among patients without prior nephrectomy. ORR was higher (34% vs 15%; p = 0.0041) and median duration of response was longer with NIVO+IPI versus sunitinib (20.5 vs 14.1 mo); the best overall response was partial response in either arm. A ≥30% reduction in the diameter of intact target renal tumors was achieved in 35% of patients with NIVO+IPI versus 20% with sunitinib. Safety was consistent with the global study population. In conclusion, in patients with aRCC without prior nephrectomy and with an evaluable primary tumor, NIVO+IPI showed survival benefits and renal tumor reduction versus sunitinib. This trial is registered at ClinicalTrials.gov as NCT02231749. Patient summary: In an exploratory analysis of a large global trial (CheckMate 214), we observed positive outcomes (both survival and tumor response to treatment) with nivolumab plus ipilimumab over sunitinib in a subgroup of patients with advanced kidney cancer who did not undergo removal of their primary kidney tumor. This subset of patients represents a population that has not been studied in clinical trials and for whom outcomes with new immunotherapy combination regimens are not yet known. We conclude that treatment with nivolumab plus ipilimumab offers these patients a survival benefit versus sunitinib, consistent with that observed in the overall study, as well as a notable kidney tumor reduction.

The occurrence of organic pollutants into water resources, including pharmaceutics, personal care products, pesticides, and/or hormones, is a major issue for all biological species. The impacts of ...

Resume Les cancers du rein non a cellules claires representent pres de 25 % de l’ensemble des cancers du rein, et constituent un groupe de tumeurs tres heterogenes a la fois en termes de varietes histologiques, mais egalement d’anomalies biologiques oncogeniques. La presentation clinique ainsi que le pronostic des patients sont egalement tres variables. Compte tenu de la rarete de chaque entite tumorale, il n’existe que tres peu d’essais cliniques ayant porte sur une variete bien definie de cancer non a cellules claires. Ceci rend difficile l’interpretation de ces etudes, et donc l’emission de recommandations claires de prise en charge medicale pour la maladie avancee. Dans cet article, les principales caracteristiques clinico-biologiques, ainsi qu’une synthese des resultats cliniques obtenus chez des patients atteints de cancers du rein non a cellules claires, hors chirurgie, seront presentes.