LITESPARK-011: belzutifan plus lenvatinib vs cabozantinib in advanced renal cell carcinoma after anti-PD-1/PD-L1 therapy

Renal cell carcinoma; Immune checkpoint inhibitor; MetastaticCarcinoma de células renales; Inhibidor del punto de control inmunitario; MetastásicoCarcinoma de cèl·lules renals; Inhibidor del punt de control immunitari; MetastàticThe first-in-class, small molecule HIF-2α inhibitor, belzutifan, has demonstrated promising antitumor activity in previously treated patients with clear cell renal cell carcinoma (RCC). HIF-2α also regulates VEGF expression and is involved in resistance to anti-VEGF therapy. This study describes the rationale and design for a randomized, phase III study evaluating efficacy and safety of belzutifan plus the tyrosine kinase inhibitor (TKI) lenvatinib versus the TKI cabozantinib in patients with advanced RCC progressing after anti-PD-1/PD-L1 therapy in the first- or second-line setting or as adjuvant therapy. Considering the unmet need for effective and tolerable treatment of advanced RCC following immune checkpoint inhibitors, belzutifan plus lenvatinib may have a positive benefit/risk profile

Gut microbial species and metabolic pathways associated with response to treatment with immune checkpoint inhibitors in metastatic melanoma

In patients with metastatic cancer, gut microbiome composition differs between responder and non-responders to immune checkpoint inhibitors. However, there is little consensus on the microbiome taxa associated with response or lack of response. Additionally, recognized confounders of gut microbiome composition have generally not been taken into account. In this study, metagenomic shotgun sequencing was performed on freshly frozen pre-treatment stool samples from 25 patients (12 responders and 13 non-responders) with unresectable metastatic melanoma treated with immune checkpoint inhibitors. We observed no significant differences in alpha-diversity and bacterial prevalence between responders and non-responders (P > 0.05). In a zero-inflated multivariate analysis, correcting for important confounders such as age, BMI and use of antibiotics, 68 taxa showed differential abundance between responders and non-responders (false-discovery rate <0.05). Cox-regression analysis showed longer overall survival for carriers of Streptococcus parasanguinis [hazard ratio (HR): 6.9] and longer progression-free survival for carriers of Bacteroides massiliensis (HR: 3.79). In contrast, carriership of Peptostreptococcaceae (unclassified species) was associated with shorter overall survival (HR 0.18) and progression-free survival (HR 0.11). Finally, 17 microbial pathways differentially abundant between responder and non-responders were observed. These results underline the association between gut microbiome composition and response to immune checkpoint inhibitor therapy in a cohort of patients with cutaneous melanoma

Surgical Treatment of Renal Cell Cancer Liver Metastases: A Population-Based Study

Background: To evaluate outcomes of surgical treatment in patients with hepatic metastases from renal-cell carcinoma in the Netherlands, and to identify prognostic factors for survival after resection. Renal-cell carcinoma has an incidence of 2,000 new patients in the Netherlands each year (12.5/100,000 inhabitants). According to literature, half of these patients ultimately develop distant metastases with 20% involvement of the liver. Resection of renal-cell carcinoma liver metastases (RCCLM) is performed in only a minority of patients. Hence, little is known about outcome of resectable RCCLM. Methods: Patients were retrieved from local databases of theNetherlands Task Force for Liver Surgery (14 centers) and from the Dutch collective pathology database. Survival and prognostic factors were determined by Kaplan-Meier analysis and log rank test. Results: Thirty-three patients were identified who underwent resection (n = 29) or local ablation (n = 4) of RCCLM in the Netherlands between 1990 and 2008. These patients comprise 0.5% to 1% of the total population of patients diagnosed with RCCLM in that period. There was no operative mortality. The overall survival at 1, 3, and 5 years was 79, 47, and 43%, respectively. Metachronous metastases (n = 23, P = 0.03) and radical resection (n = 19, P < 0.001) were statistically significant prognosticators of ov

Outcomes based on prior therapy in the phase 3 METEOR trial of cabozantinib versus everolimus in advanced renal cell carcinoma

Altres ajuts: We thank the patients, their families, the investigators and site staff, and the study teams who participated in the METEOR trial. This study was funded by Exelixis, Inc. Patients treated at Memorial Sloan Kettering Cancer Center were supported in part by Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748). Editorial support was provided by Fishawack Communications (Conshohocken, PA, USA) and funded by Exelixis.In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS) versus everolimus in patients with advanced renal cell carcinoma (RCC), after prior antiangiogenic therapy. Outcomes were evaluated for subgroups defined by prior therapy with sunitinib or pazopanib as the only prior VEGFR inhibitor, or prior anti-PD-1/PD-L1 therapy. For the prior sunitinib subgroup (N = 267), median PFS for cabozantinib versus everolimus was 9.1 versus 3.7 months (HR 0.43, 95% CI 0.32-0.59), ORR was 16% versus 3%, and median OS was 21.4 versus 16.5 months (HR 0.66, 95% CI 0.47-0.93). For the prior pazopanib subgroup (N = 171), median PFS for cabozantinib versus everolimus was 7.4 versus 5.1 months (HR 0.67, 95% CI 0.45-0.99), ORR was 19% versus 4%, and median OS was 22.0 versus 17.5 months (HR 0.66, 95% CI 0.42-1.04). For prior anti-PD-1/PD-L1 therapy (N = 32), median PFS was not reached for cabozantinib versus 4.1 months for everolimus (HR 0.22, 95% CI 0.07-0.65), ORR was 22% versus 0%, and median OS was not reached versus 16.3 months (HR 0.56, 95% CI 0.21-1.52). Cabozantinib was associated with improved clinical outcomes versus everolimus in patients with advanced RCC, irrespective of prior therapy, including checkpoint inhibitor therapy

Разработка и валидация номограммы, позволяющей прогнозировать выживаемость без прогрессирования при терапии пазопанибом по поводу распространенного рака почки

Цель исследования – разработка и валидация номограммы, позволяющей прогнозировать 12-месячную выживаемость без прогрессирования (ВБП) у пациентов, получающих пазопаниб в качестве первой линии терапии распространенного рака почки.Материалы и методы. Проведено статистическое моделирование данных 557 пациентов, получавших пазопаниб, в исследовании III фазы COMPARZ. Известные прогностические факторы были внесены в мультивариантную модель по Cox. Рассмотренные параметры включали уровень нейтрофилов, содержание альбумина и щелочной фосфатазы в сыворотке, время между постановкой диагноза и началом лечения, а также наличие костных метастазов. Для валидации были использованы данные по группе участников плацебоконтролируемого исследования III фазы, получавших пазопаниб.Результаты. Данная модель включала 10 прогностических факторов, представленных в виде номограммы, позволяющей прогнозировать 12-месячную ВБП. Сопоставления, проведенные с целью калибровки разработанной модели, позволяют предполагать достаточное соответствие расчетных вероятностей ВБП ее фактическим показателям. Индекс конкордантности для 12-месячной ВБП составил 0,625. Отмечена достоверная взаимосвязь (p &lt; 0,05) между ВБП и наличием костных метастазов, интервалом времени между постановкой диагноза и началом лечения, а также уровнями альбумина и щелочной фосфатазы. Прогностическая роль последних 2 параметров оказалась весьма существенной.Выводы. Номограмма позволяет с достаточной точностью прогнозировать ВБП у пациентов с распространенным раком почки, получающих пазопаниб, в зависимости от исходных клинических характеристик.Цель исследования – разработка и валидация номограммы, позволяющей прогнозировать 12-месячную выживаемость без прогрессирования (ВБП) у пациентов, получающих пазопаниб в качестве первой линии терапии распространенного рака почки.Материалы и методы. Проведено статистическое моделирование данных 557 пациентов, получавших пазопаниб, в исследовании III фазы COMPARZ. Известные прогностические факторы были внесены в мультивариантную модель по Cox. Рассмотренные параметры включали уровень нейтрофилов, содержание альбумина и щелочной фосфатазы в сыворотке, время между постановкой диагноза и началом лечения, а также наличие костных метастазов. Для валидации были использованы данные по группе участников плацебоконтролируемого исследования III фазы, получавших пазопаниб.Результаты. Данная модель включала 10 прогностических факторов, представленных в виде номограммы, позволяющей прогнозировать 12-месячную ВБП. Сопоставления, проведенные с целью калибровки разработанной модели, позволяют предполагать достаточное соответствие расчетных вероятностей ВБП ее фактическим показателям. Индекс конкордантности для 12-месячной ВБП составил 0,625. Отмечена достоверная взаимосвязь (p &lt; 0,05) между ВБП и наличием костных метастазов, интервалом времени между постановкой диагноза и началом лечения, а также уровнями альбумина и щелочной фосфатазы. Прогностическая роль последних 2 параметров оказалась весьма существенной.Выводы. Номограмма позволяет с достаточной точностью прогнозировать ВБП у пациентов с распространенным раком почки, получающих пазопаниб, в зависимости от исходных клинических характеристик

Angiogenesis inhibitor therapies for advanced renal cell carcinoma: Toxicity and treatment patterns in clinical practice from a global medical chart review

The aim of this study was to assess the treatment patterns and safety of sunitinib, sorafenib and bevacizumab in real-world clinical settings in US, Europe and Asia. Medical records were abstracted at 18 community oncology clinics in the US and at 21 tertiary oncology centers in US, Europe and Asia for 883 patients ≥18 years who had histologically/cytologically confirmed diagnosis of advanced RCC and received sunitinib (n=631), sorafenib (n=207) or bevacizumab (n=45) as first‑line treatment. No prior treatment was permitted. Data were collected on all adverse events (AEs) and treatment modifications, including discontinuation, interruption and dose reduction. Treatment duration was estimated using Kaplan-Meier analysis. Demographics were similar across treatment groups and regions. Median treatment duration ranged from 6.1 to 10.7 months, 5.1 to 8.5 months and 7.5 to 9.8 months for sunitinib, sorafenib and bevacizumab patients, respectively. Grade 3/4 AEs were experienced by 26.0, 28.0 and 15.6% of sunitinib, sorafenib and bevacizumab patients, respectively. Treatment discontinuations occurred in 62.4 (Asia) to 63.1% (US) sunitinib, 68.8 (Asia) to 90.0% (Europe) sorafenib, and 66.7 (Asia) to 81.8% (US) bevacizumab patients. Globally, treatment modifications due to AEs occurred in 55.1, 54.2 and 50.0% sunitinib, sorafenib and bevacizumab patients, respectively. This study in a large, global cohort of advanced RCC patients found that angiogenesis inhibitors are associated with high rates of AEs and treatment modifications. Findings suggest an unmet need for more tolerable agents for RCC treatment