Lenvatinib with or Without Everolimus in Patients with Metastatic Renal Cell Carcinoma After Immune Checkpoint Inhibitors and Vascular Endothelial Growth Factor Receptor-Tyrosine Kinase Inhibitor Therapies.
Lenvatinib (Len) plus everolimus (Eve) is an approved therapy for metastatic renal cell carcinoma (mRCC) after first-line vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs), but limited data exist on the efficacy of Len ± Eve after progression on immune checkpoint inhibitors (ICIs) and VEGFR-TKIs.
We retrospectively reviewed the records of patients with mRCC at our institution who were treated with Len ± Eve after ICI and VEGFR-TKI. A blinded radiologist assessed objective response as defined by RECIST version 1.1. Descriptive statistics and the Kaplan-Meier method were used.
Fifty-five patients were included in the analysis. Of these patients, 81.8% had clear-cell histology (ccRCC), and 76.4% had International Metastatic RCC Database Consortium intermediate-risk disease. Median number of prior therapies was four (range, 2-10); all patients had prior ICIs and VEGFR-TKIs, and 80% were previously treated with ICI and at least two VEGFR-TKIs, including cabozantinib. One patient (1.8%) achieved a complete response, and 11 patients (20.0%) achieved a partial response, for an overall response rate (ORR) of 21.8%; 35 patients (63.6%) achieved stable disease. In all patients, median progression-free survival (PFS) was 6.2 months (95% confidence interval [CI], 4.8-9.4) and median overall survival (OS) was 12.1 months (95% CI, 8.8-16.0). In patients with ccRCC, ORR was 24.4%, PFS was 7.1 months (95% CI, 5.0-10.5), and OS was 11.7 months (95% CI, 7.9-16.1). 50.9% of patients required dose reductions and 7.3% discontinued treatment because of toxicity.
Len ± Eve demonstrated meaningful clinical activity and tolerability in heavily pretreated patients with mRCC after disease progression with prior ICIs and VEGFR-TKIs.
As the therapeutic landscape for patients with metastatic renal cell carcinoma continues to evolve, this single-center, retrospective review highlights the real-world efficacy of lenvatinib with or without everolimus in heavily pretreated patients. This article supports the use of lenvatinib with or without everolimus as a viable salvage strategy for patients whose disease progresses after treatment with immune checkpoint inhibitors and vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapies, including cabozantinib.
Wiele AJ
，Bathala TK
，Hahn AW
，Xiao L
，Duran M
，Ross JA
，Jonasch E
，Shah AY
，Campbell MT
，Msaouel P
，Tannir NM
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Randomized phase II dose comparison LITESPARK-013 study of belzutifan in patients with advanced clear cell renal cell carcinoma.
Belzutifan is a first-in-class hypoxia-inducible factor subunit 2α (HIF-2α) inhibitor approved at a dose of 120 mg once daily for certain adults with VHL disease and adults with advanced renal cell carcinoma (RCC) following therapy with a programmed cell death protein 1 (PD-1) [or programmed death ligand 1 (PD-L1)] inhibitor and a vascular endothelial growth factor tyrosine kinase inhibitor. However, whether the belzutifan dose could be optimized is unclear.
The phase II LITESPARK-013 study (NCT04489771) enrolled patients with advanced clear cell RCC whose disease progressed after one to three prior systemic therapies, including an anti-PD-(L)1 regimen. Patients were randomly assigned 1 : 1 to receive belzutifan 120 or 200 mg once daily. The primary endpoint was the objective response rate (ORR) per RECIST version 1.1. The secondary endpoints were duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety.
Overall, 154 patients were enrolled (120 mg: n = 76; 200 mg: n = 78). The median follow-up was 20.1 months (range 14.8-28.4). The ORR was 23.7% versus 23.1% for the 120 mg and 200 mg groups, respectively [P = 0.5312; -0.5%, 95% confidence interval (CI) -14.0% to 12.9%]. The median DOR was not reached for the 120 mg arm and was 16.1 months (2.1+ to 23.5+) for the 200 mg arm. No between-group differences were observed for PFS [hazard ratio (HR) 0.94, 95% CI 0.63-1.40] or OS (medians not reached; HR 1.11, 95% CI 0.65-1.90). Grade 3 or 4 treatment-related adverse events were observed in 35 patients (46.1%) in the 120 mg group and 36 patients (46.2%) in the 200 mg group.
The efficacy of belzutifan was similar between the 120 mg dose and the 200 mg dose for previously treated clear cell RCC. Safety at both doses was consistent with the known safety profile of belzutifan. These results further support 120 mg once daily as the preferred dose for belzutifan.
Agarwal N
，Brugarolas J
，Ghatalia P
，George S
，Haanen JB
，Gurney H
，Ravilla R
，Van der Veldt A
，Beuselinck B
，Pokataev I
，Suelmann BBM
，Tuthill MH
，Vaena D
，Zagouri F
，Wu J
，Perini RF
，Liu Y
，Merchan J
，Atkins MB
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Real-world Outcome of Patients with Advanced Renal Cell Carcinoma and Intermediate- or Poor-risk International Metastatic Renal Cell Carcinoma Database Consortium Criteria Treated by Immune-oncology Combinations: Differential Effectiveness by Risk Group?
Renal c carcinoma (RCC) is one of the most common urinary cancers worldwide, with a predicted increase in incidence in the coming years. Immunotherapy, as a single agent, in doublets, or in combination with anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), has rapidly become a cornerstone of the RCC therapeutic scenario, but no head-to-head comparisons have been made. In this setting, real-world evidence emerges as a cornerstone to guide clinical decisions.
The objective of this retrospective study was to assess the outcome of patients treated with first-line immune combinations or immune oncology (IO)-TKIs for advanced RCC.
Data from 930 patients, 654 intermediate risk and 276 poor risk, were collected retrospectively from 58 centers in 20 countries. Special data such as sarcomatoid differentiation, body mass index, prior nephrectomy, and metastatic localization, in addition to biochemical data such as hemoglobin, platelets, calcium, lactate dehydrogenase, neutrophils, and radiological response by investigator's criteria, were collected.
Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. The median follow-up was calculated by the inverse Kaplan-Meier method.
The median follow-up time was 18.7 mo. In the 654 intermediate-risk patients, the median OS and PFS were significantly longer in patients with the intermediate than in those with the poor International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) criteria (38.9 vs 17.3 mo, 95% confidence interval [CI] p < 0.001, and 17.3 vs 11.6 mo, 95% CI p < 0.001, respectively). In the intermediate-risk subgroup, the OS was 55.7 mo (95% CI 31.4-55.7) and 40.2 mo (95% CI 29.6-51.6) in patients treated with IO + TKI and IO + IO combinations, respectively (p = 0.047). PFS was 30.7 mo (95% CI 16.5-55.7) and 13.2 mo (95% CI 29.6-51.6) in intermediate-risk patients treated with IO + TKI and IO + IO combinations, respectively (p < 0.001). In the poor-risk subgroup, the median OS and PFS did not show a statistically significant difference between IO + IO and IO + TKI. Our study presents several limitations, mainly due to its retrospective nature.
Our results showed differences between the IO + TKI and IO + IO combinations in intermediate-risk patients. A clear association with longer PFS and OS in favor of patients who received the IO + TKI combinations compared with the IO-IO combination was observed. Instead, in the poor-risk group, we observed no significant difference in PFS or OS between patients who received different combinations.
Renal cancer is one of the most frequent genitourinary tumors. Treatment is currently based on immunotherapy combinations or immunotherapy with tyrosine kinase inhibitors, but there are no comparisons between these.In this study, we have analyzed the clinical course of 930 patients from 58 centers in 20 countries around the world. We aimed to analyze the differences between the two main treatment strategies, combination of two immunotherapies versus immunotherapy + antiangiogenic therapy, and found in real-life data that intermediate-risk patients (approximately 60% of patients with metastatic renal cancer) seem to benefit more from the combination of immunotherapy + antiangiogenic therapy than from double immunotherapy. No such differences were found in poor-risk patients. This may have important implications in daily practice decision-making for these patients.
Santoni M
，Buti S
，Myint ZW
，Maruzzo M
，Iacovelli R
，Pichler M
，Kopecky J
，Kucharz J
，Rizzo M
，Galli L
，Büttner T
，De Giorgi U
，Kanesvaran R
，Fiala O
，Grande E
，Zucali PA
，Kopp RM
，Fornarini G
，Bourlon MT
，Scagliarini S
，Molina-Cerrillo J
，Aurilio G
，Matrana MR
，Pichler R
，Cattrini C
，Büchler T
，Massari F
，Seront E
，Calabrò F
，Pinto A
，Berardi R
，Zgura A
，Mammone G
，Ansari J
，Atzori F
，Chiari R
，Bamias A
，Caffo O
，Procopio G
，Sunela K
，Bassanelli M
，Ortega C
，Grillone F
，Landmesser J
，Milella M
，Messina C
，Küronya Z
，Mosca A
，Bhuva D
，Santini D
，Vau N
，Morelli F
，Incorvaia L
，Rebuzzi SE
，Roviello G
，Soares A
，Bisonni R
，Bimbatti D
，Zabalza IO
，Rizzo A
，Mollica V
，Sorgentoni G
，Monteiro FSM
，Battelli N
，Bracarda S
，Porta C
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《European Urology Oncology》
Phase I LITESPARK-001 study of belzutifan for advanced solid tumors: Extended 41-month follow-up in the clear cell renal cell carcinoma cohort.
Accumulation of the HIF-2α transcription factor is an oncogenic event implicated in the tumorigenesis of clear cell renal cell carcinoma (ccRCC). In the phase I LITESPARK-001 study, the first-in-class HIF-2α inhibitor belzutifan demonstrated antitumor activity and an acceptable safety profile for pretreated patients with advanced ccRCC. Updated data with additional follow-up of > 40 months are presented.
LITESPARK-001 is an ongoing open-label study with a 3 + 3 dose-escalation design followed by an expansion phase. Patients with ccRCC enrolled at 7 sites received belzutifan 120 mg orally once daily until disease progression, unacceptable toxicity, or patient withdrawal. The data cutoff date was July 15, 2021. The primary end point was identifying the maximum tolerated dose and/or the recommended phase II dose. Secondary end points included objective response rate (ORR) and duration of response (DOR) per RECIST v1.1 by investigator assessment and safety.
Median follow-up was 41.2 months (range, 38.2-47.7). Patients received a median of 3 (range, 1-9) prior systemic therapies. Of 55 patients, 14 (25 %) achieved an objective response. Median DOR was not reached (range, 3.1 + to 38.0 + months). Adverse events (AEs) attributed to study treatment by investigator assessment were reported in 53 patients (96 %). 22 patients (40 %) had grade 3 treatment-related AEs; the most common were anemia (n = 13; 24 %) and hypoxia (n = 7; 13 %). No grade 4 or 5 treatment-related AEs occurred.
After a median follow-up of 41.2 months, belzutifan monotherapy demonstrated durable antitumor activity in patients with advanced ccRCC and acceptable safety.
gov. NCT02974738.
Jonasch E
，Bauer TM
，Papadopoulos KP
，Plimack ER
，Merchan JR
，McDermott DF
，Dror Michaelson M
，Appleman LJ
，Roy A
，Perini RF
，Liu Y
，Choueiri TK
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ResearchGate
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