Cisplatin-based combination chemotherapy remains the standard of care for locally advanced or metastatic urothelial cancer (la/mUC); however, toxicity is substantial, responses are rarely durable, ...and many patients with la/mUC are ineligible. Each enfortumab vedotin and pembrolizumab have shown a survival benefit versus chemotherapy in UC, are not restricted by cisplatin eligibility, and warrant investigation as a first-line (1L) combination therapy in patients ineligible for cisplatin.
In this ongoing phase Ib/II, multicenter, open-label study, 1L cisplatin-ineligible patients with la/mUC received enfortumab vedotin 1.25 mg/kg once daily on days 1 and 8 and pembrolizumab 200 mg (day 1) intravenously once daily in 3-week cycles. The primary end point was safety. Key secondary end points included confirmed objective response rate, duration of response (DOR), and overall survival (OS).
Forty-five patients received enfortumab vedotin plus pembrolizumab. The most common treatment-related adverse events (TRAEs) were peripheral sensory neuropathy (55.6%), fatigue (51.1%), and alopecia (48.9%). Twenty-nine patients (64.4%) had grade 3 or higher TRAEs; the most common were increased lipase (17.8%), maculopapular rash (11.1%), and fatigue (11.1%). One death (2.2%) was classified as a TRAE. The confirmed objective response rate after a median of nine cycles was 73.3% with a complete response rate of 15.6%. The median DOR and median OS were 25.6 months and 26.1 months, respectively.
Enfortumab vedotin plus pembrolizumab showed a manageable safety profile. Most patients experienced tumor shrinkage. The median DOR and median OS exceeding 2 years in a cisplatin-ineligible patient population make this a promising combination currently under investigation in a phase III study (ClinicalTrials.gov identifier: NCT04223856).
Stereotactic ablative body radiotherapy (SABR) is associated with good oncological outcomes and a favourable toxicity profile in patients with localised renal cell carcinoma (RCC). Intriguing ...multimodality approaches, which include SABR in the operable setting, are emerging. In the context of metastatic RCC, SABR alone or in combination with systemic treatment has shown promising clinical outcomes with minimal toxicity. Other investigational applications of SABR, including cytoreduction and neoadjuvant SABR, for primary RCC, oligometastatic RCC in deferring systemic therapy, and oligoprogressive RCC concurrent with systemic therapy are evolving and should be tested in clinical trials.
Stereotactic ablative body radiotherapy (SABR) is an emerging treatment modality for primary and metastatic renal cell carcinoma (RCC).
To review and summarise the evidence on the use of SABR in RCC in a narrative review.
We performed an online search of the PubMed database from January 2000 through December 2021. Studies of SABR/stereotactic radiosurgery (SRS) targeting primary, extracranial, or intracranial metastatic RCC were included.
Two meta-analyses (including 54 studies), and 13 prospective and 20 retrospective studies were included in this review. In aggregate, SABR for 589 primary RCCs in 575 patients resulted in a local control rate of above 90% with grade 3–4 toxicity of 0–9%. Similarly, the local control rate ranged between 90% and 97% with SRS in 1225 patients with intracranial metastatic RCC. SABR was able to delay systemic therapy for at least 1 yr in 70–90% of oligometastatic RCC patients with grade 3–4 toxicity of <10%. As per the early data, the combination of SABR with systemic therapy for metastatic RCC, such as targeted therapy or immunotherapy, appears safe, feasible, and tolerable.
We outlined data supporting SABR in the key clinical scenarios of primary and metastatic, including oligometastatic, RCC in lieu of systemic therapy, in combination with systemic therapy, and palliation of brain and spinal metastases.
Stereotactic ablative body radiotherapy (SABR) is a relatively new treatment option in kidney cancer. Here, we review the published literature on the experience of using SABR in kidney cancer. The accumulated evidence demonstrates that SABR can be used safely and effectively to treat selected cases of primary or secondary kidney cancer.
In recent decades, variability in the incidence and mortality of kidney cancer (KC) has been reported. This study aimed to compare trends in incidence, mortality, and disability-adjusted life years ...(DALY) of KC between the European Union (EU) 15 + countries and 6 World Health Organization (WHO) regions. The data of KC Age-standardized incidence rates (ASIRs), age-standardized mortality rates (ASMRs), and age-standardized DALYs were extracted from the Global Burden of Disease database. Joinpoint regression was employed to examine trends. From 1990 to 2019, the ASIR increased in most countries except for Luxembourg (males), the USA (females) and Austria and Sweden (both sexes). ASIR increased across all 6 WHO regions for both sexes except for females in Americas. The ASMR increased in 10/19 countries for males and 9/19 for females as well across most WHO regions. The mortality-to-incidence ratio (MIR) decreased in all countries and WHO regions. Trends in DALYs were variable across countries and WHO regions. While the incidence and mortality from KC rose in most EU15 + countries and WHO regions from 1990 to 2019, the universal drop in MIR suggests an overall improvement in KC outcomes. This is likely multifactorial, including earlier detection of KC and improved treatments.
Abstract Background The skeleton and liver are frequently involved sites of metastasis in patients with metastatic renal cell carcinoma (RCC). Objective To analyze outcomes based on the presence of ...bone metastases (BMs) and/or liver metastases (LMs) in patients with RCC treated with targeted therapy. Design, setting, and participants We conducted a review from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) of 2027 patients with metastatic RCC. Outcome measurements and statistical analysis We analyzed the impact of the site of metastasis on overall survival (OS) and time-to-treatment failure. Statistical analyses were performed using multivariable Cox regression. Results and limitations The presence of BMs was 34% overall, and when stratified by IMDC risk groups was 27%, 33%, and 43% in the favorable-, intermediate-, and poor-risk groups, respectively ( p < 0.001). The presence of LMs was 19% overall and higher in the poor-risk patients (23%) compared with the favorable- or intermediate-risk groups (17%) ( p = 0.003). When patients were classified into four groups based on the presence of BMs and/or LMs, the hazard ratio, adjusted for IMDC risk factors, was 1.4 (95% confidence interval CI, 1.22–1.62) for BMs, 1.42 (95% CI, 1.17–1.73) for LMs, and 1.82 (95% CI, 1.47–2.26) for both BMs and LMs compared with other metastatic sites ( p < 0.0001). The prediction model performance for OS was significantly improved when BMs and LMs were added to the IMDC prognostic model (likelihood ratio test p < 0.0001). Data in this analysis were collected retrospectively. Conclusions The presence of BMs and LMs in patients treated with targeted agents has a negative impact on survival. Patients with BMs and/or LMs may benefit from earlier inclusion on clinical trials of novel agents or combination-based therapies.
COSMIC-021 is evaluating cabozantinib plus atezolizumab in patients with solid tumors. We report results from patients with advanced clear cell (cc) and non-clear cell (ncc) renal cell carcinoma ...(RCC).
This phase Ib study (NCT03170960) enrolled patients age ≥ 18 years with advanced RCC. A dose-escalation stage was followed by expansion cohorts. For cohort expansion, prior systemic therapy was not permitted for ccRCC but allowed for nccRCC. Patients received oral cabozantinib 40 mg once a day (ccRCC and nccRCC) or 60 mg once a day (ccRCC only) plus atezolizumab (1,200 mg intravenously, once every 3 weeks). The primary end point was investigator-assessed objective response rate (ORR) per RECIST v1.1; the secondary end point was safety.
A total of 102 patients were enrolled. Median follow-up was 25.8, 15.3, and 13.3 months for the 40-mg ccRCC, 60-mg ccRCC, and nccRCC groups, respectively. ORR was 53% (80% CI, 41 to 65) in the 40-mg ccRCC group (n = 34) and 58% (80% CI, 46 to 70) in the 60-mg ccRCC group (n = 36), 3% and 11%, respectively, with complete response; median progression-free survival (exploratory end point) was 19.5 and 15.1 months, respectively. In nccRCC (n = 32), ORR was 31% (80% CI, 20 to 44), all partial responses; median progression-free survival was 9.5 months. Grade 3 or 4 treatment-related adverse events (TRAEs) were reported by 71% of patients in the 40-mg ccRCC group, 67% in the 60-mg ccRCC group, and 38% in the nccRCC group; TRAEs leading to discontinuation of both agents occurred in 15%, 6%, and 3% of patients, respectively. There were no grade 5 TRAEs.
The novel combination of cabozantinib plus atezolizumab demonstrated encouraging clinical activity and acceptable tolerability in patients with advanced ccRCC and nccRCC. Disease control was observed across dose levels and histologic subtypes.
In this phase II response-adaptive trial, we investigated the rational application of immune checkpoint blockade in renal cell carcinoma (RCC; ClinicalTrials.gov identifier: NCT03203473).
We enrolled ...patients with metastatic RCC with no prior checkpoint inhibitor exposure. All patients received nivolumab alone with subsequent arm allocation based on response. Patients with a confirmed partial response (PR) or complete response (CR) within 6 months discontinued nivolumab and were observed (arm A). Patients with stable disease or progressive disease (PD) after no more than 6 months of nivolumab received two doses of ipilimumab (arm B). The primary endpoints were the proportion of patients with PR/CR at 1 year after nivolumab discontinuation (arm A) and proportion of nivolumab nonresponders who converted to PR/CR after ipilimumab (arm B).
Overall, 83 patients initiated treatment, of whom 96% had clear-cell histology, 51% were treatment naïve, and 67% had intermediate/poor-risk disease. Median follow-up was 19.5 months. Within 6 months, induction nivolumab resulted in a confirmed PR in 12% of patients (n = 10). Fourteen patients were not allocated to a study arm (seven because of toxicity, seven because of PD). Twelve patients (14%) were allocated to arm A and discontinued nivolumab, of whom five (42%; 90% CI, 18% to 68%) remained off nivolumab at ≥ 1 year. Of 57 patients (69%) allocated to arm B, two patients converted to a confirmed PR (4%; 90% CI, 1% to 11%), and no CRs were observed.
In this study, nivolumab followed by two doses of ipilimumab resulted in no CRs and a low PR/CR conversion. The number of patients evaluated for nivolumab discontinuation was too small to assess the value of this approach. Currently, our data do not support a response-adaptive strategy for checkpoint blockade in advanced RCC.
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