Androgen receptor (AR) signalling remains critically important in metastatic castration-resistant prostate cancer (mCRPC) as confirmed by recent phase III trials, showing a survival advantage for ...abiraterone acetate and enzalutamide (MDV3100). The antitumour activity of abiraterone and prednisolone in patients pre-treated with enzalutamide is as yet unknown.
We investigated the antitumour activity of abiraterone and prednisolone in patients with mCRPC who had progressed following treatment with docetaxel (Taxotere) and enzalutamide. Clinical data were retrospectively analysed for prostate-specific antigen (PSA) and RECIST responses, clinical benefit and survival.
Thirty-eight patients were included in the analysis. The median age was 71 years (range 52–84); metastatic sites included bone disease in 37 patients (97%), lymph nodes in 15 patients (39%) and visceral disease in 10 patients (26%). Abiraterone was well tolerated. Three patients (8%) attained a PSA response, defined as ≥50% decline in PSA confirmed after ≥4 weeks, while seven patients (18%) had a ≥30% PSA decline. The median progression-free survival (PFS) was 2.7 months (95% CI 2.3–4.1). Of the 12 patients assessable radiologically, only 1 (8%) attained a confirmed partial response.
Abiraterone and prednisolone have modest antitumour activities in patients with mCRPC pretreated with docetaxel and enzalutamide.
•This special article provides key recommendations on the immunotherapy treatments of renal cell carcinoma.•Recommendations are based on available scientific data and the authors' collective expert ...opinion.•Authorship includes a multidisciplinary group of renal carcinoma experts.
The composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota ...diversity and composition leading to dysbiosis, which may affect effectiveness of ICI.
We examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression-free survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed.
Sixteen of 121 (13%) RCC patients and 48 of 239 (20%) NSCLC patients received ATB. The most common ATB were β-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P < 0.01), shorter PFS median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4–6.9, P < 0.01, and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1–10.8, P = 0.03). In NSCLC patients, ATB was associated with similar rates of primary PD (52% versus 43%, P = 0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0–2.2, P = 0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6–7.7, P < 0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC.
ATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.
To examine the association between hypertension (HTN), angiotensin system inhibitors (ASI) use and survival outcomes in patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib ...(SU).
We retrospectively reviewed all patients with mRCC who received SU as first-line treatment in Gustave Roussy from April 2004 to November 2013. The HTN (either pre-existing or secondary to SU), use of ASI (either before or during SU) were analysed. Overall survival (OS) and progression-free survival (PFS) of different exposures were compared with log-rank test. The associations between exposures and survival outcomes were estimated with hazard ratios (HRs) and 95% confidence interval (CI) through a multivariable Cox model adjusted for age, gender, International mRCC Database Consortium risk group and histology.
Among 213 patients with a 3.6-year median follow-up, 134 were hypertensive and 105 were ASI users with a significant association between the two exposures (P < 0.0001). Hypertensive patients have longer OS (median: 41.6 versus 16.4 months, P < 0.0001) and longer PFS (median: 12.9 versus 5.6 months, P < 0.0001) than non-hypertensive patients (n = 79). ASI users (n = 105) had more HTN_PRE compared with those (n = 108) who did not (65% versus 19%, P < 0.001). Multivariable analysis showed that hypertensive patients were significantly associated with OS (P = 0.05) and marginally with PFS (P = 0.06) while ASI intake was significantly associated with better OS HR = 0.40; 95% CI (0.24–0.66), P < 0.001 and PFS HR = 0.55 (0.35–0.86), P = 0.009. The latter remain statistically significantly associated after controlling for the number of metastases. There is no difference on outcome between patients who receive ASI before starting SU and those who received ASI during SU treatment.
Concomitant use of ASI may significantly improve OS and PFS in mRCC patients receiving SU. HTN is marginally associated with the outcome in these patients.
The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) with first-line avelumab plus axitinib versus sunitinib in advanced renal cell ...carcinoma (aRCC). We report updated efficacy data from the second interim analysis.
Treatment-naive patients with aRCC were randomized (1 : 1) to receive avelumab (10 mg/kg) intravenously every 2 weeks plus axitinib (5 mg) orally twice daily or sunitinib (50 mg) orally once daily for 4 weeks (6-week cycle). The two independent primary end points were PFS and overall survival (OS) among patients with programmed death ligand 1–positive (PD-L1+) tumors. Key secondary end points were OS and PFS in the overall population.
Of 886 patients, 442 were randomized to the avelumab plus axitinib arm and 444 to the sunitinib arm; 270 and 290 had PD-L1+ tumors, respectively. After a minimum follow-up of 13 months (data cut-off 28 January 2019), PFS was significantly longer in the avelumab plus axitinib arm than in the sunitinib arm {PD-L1+ population: hazard ratio (HR) 0.62 95% confidence interval (CI) 0.490–0.777}; one-sided P < 0.0001; median 13.8 (95% CI 10.1–20.7) versus 7.0 months (95% CI 5.7–9.6); overall population: HR 0.69 (95% CI 0.574–0.825); one-sided P < 0.0001; median 13.3 (95% CI 11.1–15.3) versus 8.0 months (95% CI 6.7–9.8). OS data were immature PD-L1+ population: HR 0.828 (95% CI 0.596–1.151); one-sided P = 0.1301; overall population: HR 0.796 (95% CI 0.616–1.027); one-sided P = 0.0392.
Among patients with previously untreated aRCC, treatment with avelumab plus axitinib continued to result in a statistically significant improvement in PFS versus sunitinib; OS data were still immature.
NCT02684006.
•Avelumab plus axitinib significantly prolonged progression-free survival versus sunitinib in advanced renal cell carcinoma.•Although overall survival data were immature, results favored the combination over sunitinib across prespecified subgroups.•Adjusting for subsequent use of PD-1/PD-L1 inhibitors in the sunitinib arm predicted a survival benefit for the combination.•Among all randomized patients, avelumab plus axitinib had a longer mean duration of response than sunitinib.•Avelumab plus axitinib prolonged progression-free survival on next-line therapy versus sunitinib.
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.
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.
In total, 25 patients were treated with tivozanib 1.5 mg QD 12 (48%) treatment-naïve; 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-naïve and previously treated patients.
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-naïve or previously treated metastatic RCC.
NCT03136627.
We established an international consortium to review and discuss relevant clinical evidence in order to develop expert consensus statements related to cancer management during the severe acute ...respiratory syndrome coronavirus 2-related disease (COVID-19) pandemic. The steering committee prepared 10 working packages addressing significant clinical questions from diagnosis to surgery. During a virtual consensus meeting of 62 global experts and one patient advocate, led by the European Society for Medical Oncology, statements were discussed, amended and voted upon. When consensus could not be reached, the panel revised statements until a consensus was reached. Overall, the expert panel agreed on 28 consensus statements that can be used to overcome many of the clinical and technical areas of uncertainty ranging from diagnosis to therapeutic planning and treatment during the COVID-19 pandemic.
Bone metastases (BMs) are associated with significant morbidity and shorter survival in renal cell carcinoma (RCC). Our purpose was to identify prognostic factors for overall survival (OS) in RCC ...patients with BMs.
Data from patients with BMs from RCC treated at Gustave Roussy between April 1992 and March 2016 were retrospectively collected. Age, sex, Eastern Cooperative Oncology Group-Performance Status, Memorial Sloan-Kettering Cancer Center (MSKCC) risk groups, histology, number and site of bone lesions, concomitant metastases (presence and sites), therapy for BMs (radical resection or palliative surgery, radiotherapy and other local and systemic treatments) and time from diagnosis to BMs were analysed. Synchronous solitary bone metastasis (SSBM) was defined as a single BM without concomitant visceral lesions at the initial diagnosis of RCC. OS was calculated from the date of BMs diagnosis to death or last follow-up using Kaplan–Maier method and modelled with Cox regression analysis.
From 1750 patients with diagnosis of RCC followed at Gustave Roussy Cancer Campus, 300 patients with BMs were identified. Median time from diagnosis to BMs was 32.4 months (range 0–324 months). In 64 patients (21%), bone was the only metastatic site, and 22 patients (7%) had an SSBM and 236 patients (79%) had concomitant metastases in other sites. Median OS was 23.2 months (95% confidence interval 19.9–26.2). SSBM patients had better OS than those with concomitant metastases (40 vs 20 months; P < 0.001). At multivariate analysis, concomitant metastases remained predictor of poor prognosis, while MSKCC risk group, radical resection and SSBM were predictors of better OS.
This study suggests that MSKCC score, numbers of BMs and radical resection are important prognostic factors for RCC patients with BMs. Additionally, in the presence of solitary BM without concomitant metastases at the initial diagnosis of RCC, bone surgery should be considered to achieve local tumour control and likely increase OS.
•Renal cell carcinoma (RCC) accounts for 3% of all cancers and commonly occurs in Western countries.•Most common metastases in RCC occurs to lung, followed by bone involvement in 20–35%, lymph nodes and liver.•Bone metastases are very destructive in RCC patients, leading to mainly osteolytic lesions that compromise bone integrity.•Skeletal involvement is associated with skeletal-related events, which may require surgical intervention and other therapy.•The presence of bone metastases in RCC has negative impact on progression free survival and overall survival of patients.
Programmed death ligand-1 (PD-L1) expression in nonclear-cell RCC (non-ccRCC) and its association with clinical outcomes are unknown.
Formalin-fixed paraffin-embedded (FFPE) specimens were obtained ...from 101 patients with non-ccRCC. PD-L1 expression was evaluated by immunohistochemistry in both tumor cell membrane and tumor-infiltrating mononuclear cells (TIMC). PD-L1 tumor positivity was defined as ≥5% tumor cell membrane staining. For PD-L1 expression in TIMC, a combined score based on the extent of infiltrate and percentage of positive cells was used. Baseline clinico-pathological characteristics and outcome data time to recurrence (TTR) and overall survival (OS) were correlated with PD-L1 staining.
Among 101 patients, 11 (10.9%) were considered PD-L1+ in tumor cells: 2/36 (5.6%) of chromophobe RCC, 5/50 (10%) of papillary RCC, 3/10 (30%) of Xp11.2 translocation RCC and 1/5 (20%) of collecting duct carcinoma. PD-L1 positivity (PD-L1+) in tumor cells was significantly associated with higher stage (P = 0.01) and grade (P = 0.03), as well as shorter OS (P < 0.001). On the other hand, PD-L1 positivity by TIMC was observed in 57 (56.4%) patients: 13/36 (36.1%) of chromophobe RCC, 30/50 (60%) of papillary RCC, 9/10 (90%) of Xp11.2 translocation RCC and 5/5 (100%) of collecting duct carcinoma. A trend toward shorter OS was observed in patients with PD-L1+ in TIMC (P = 0.08). PD-L1+ in both tumor cell membrane and TIMC cells were associated with shorter TTR (P = 0.02 and P = 0.03, respectively).
In non-ccRCC, patients with PD-L1+ tumors appear to have worse clinical outcomes, although only PD-L1 positivity in tumor cells is associated with higher tumor stage and grade.
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