EX3 Investigating Time to Next Treatment As a Surrogate Endpoint for Overall Survival in Previously Untreated Intermediate- to Poor-Risk Advanced Renal Cell Carcinoma Patients: An Insight from the Phase III CheckMate-214

On the 15 November 2018, the Committee for Medicinal Products for Human Use adopted an extension to an existing indication for the use of nivolumab (Opdivo) in combination with ipilimumab (Yervoy) for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma (RCC). The approval was based on results from the Pivotal CA209214 study, a randomised, open-label, phase III study, comparing nivolumab +ipilimumab with sunitinib in subjects≥18 years of age with previously untreated advanced RCC (not amenable for surgery or radiotherapy) or metastatic RCC, with a clear-cell component. A total of 1096 patients were randomised in the trial, of which 847 patients had intermediate/poor-risk RCC and received either nivolumab (n=425) in combination with ipilimumab administered every 3 weeks for 4 doses followed by nivolumab monotherapy 3 mg/kg every 2 weeks or sunitinib (n=422) administered orally for 4 weeks followed by 2 weeks off, every cycle. A statistically significant difference in overall survival (OS) was observed in the nivolumab + ipilimumab group compared with the sunitinib group in intermediate/poor-risk subjects (HR 0.63 (99.8% CI 0.44 to 0.89); stratified log-rank 2-sided p-value<0.0001). The median OS was not reached for the nivolumab + ipilimumab group and was 25.95 months for the sunitinib group. The OS rates were 89.5% and 86.2% at 6 months, and 80.1% and 72.1% at 12 months in the nivolumab +ipilimumab and the sunitinib groups, respectively. K-M curves separated after approximately 3 months, favouring nivolumab + ipilimumab. This was not mirrored in the favourable-risk patients where no statistically significant difference was observed between nivolumab + ipilimumab and sunitinib in favourable-risk patients (HR 1.45 (descriptive 99.8% CI 0.51 to 4.12), p =0.2715).

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Serum Lactate Dehydrogenase Predicts for Overall Survival Benefit in Patients With Metastatic Renal Cell Carcinoma Treated With Inhibition of Mammalian Target of Rapamycin

Journal of Clinical Oncology ◽

10.1200/jco.2011.40.9631 ◽

2012 ◽

Vol 30 (27) ◽

pp. 3402-3407 ◽

Cited By ~ 95

Author(s):

Andrew J. Armstrong ◽

Daniel J. George ◽

Susan Halabi

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Lactate Dehydrogenase ◽

Cell Carcinoma ◽

Renal Cell ◽

Survival Benefit ◽

Mammalian Target Of Rapamycin ◽

Phase Iii ◽

Target Of Rapamycin ◽

Poor Risk

Purpose Lactate dehydrogenase (LDH) is an enzyme involved in anaerobic glycolysis and regulated by the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (mTOR)–containing complex 1 (PI3K/Akt/TORC1) pathway as well as tumor hypoxia/necrosis. High serum LDH levels are associated with poor prognosis in patients with cancer, including renal cell carcinoma (RCC). We tested whether serum LDH is prognostic and has predictive value in patients with metastatic RCC receiving an mTOR inhibitor. Patients and Methods We evaluated pretreatment and post-treatment serum LDH in 404 poor-risk patients with RCC treated with the TORC1 inhibitor temsirolimus or interferon alfa in an international phase III randomized trial. The proportional hazards model was used to test for the prognostic and predictive association of LDH in predicting overall survival (OS). Results Mean baseline serum normalized LDH was 1.23 times the upper limit of normal (ULN; range, 0.05 to 28.5 × ULN). The multivariable hazard ratio for death was 2.81 (95% CI, 2.01 to 3.94; P < .001) for patients with LDH more than 1 × ULN versus patients with LDH ≤ 1 × ULN. The LDH-treatment interaction term was statistically significant for OS (P = .016). Among 140 patients with LDH above the ULN, OS was significantly improved with temsirolimus (6.9 v 4.2 months; P < .002). Among 264 patients with normal LDH, OS was not significantly improved with temsirolimus as compared with interferon therapy (11.7 v 10.4 months; P = .514). Conclusion Serum LDH is a prognostic and a predictive biomarker for the survival benefit conferred by TORC1 inhibition in poor-risk RCC. Further investigation of the predictive role of LDH as a measure of benefit with PI3K/TORC1 pathway inhibition in other RCC risk groups and other tumor types is warranted.

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Correlation of response with overall survival (OS) for nivolumab vs everolimus in advanced renal cell carcinoma (aRCC): Results from the phase III CheckMate 025 study.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.15_suppl.4552 ◽

2016 ◽

Vol 34 (15_suppl) ◽

pp. 4552-4552 ◽

Cited By ~ 4

Author(s):

Robert J. Motzer ◽

Padmanee Sharma ◽

Bernard J. Escudier ◽

David F. McDermott ◽

Saby George ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Cell Carcinoma ◽

Renal Cell ◽

Phase Iii ◽

Advanced Renal Cell Carcinoma

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A phase III study (COSMIC-313) of cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal cell carcinoma of intermediate or poor-risk.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.tps5102 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. TPS5102-TPS5102

Author(s):

Toni K. Choueiri ◽

Laurence Albiges ◽

Thomas Powles ◽

Christian Scheffold ◽

Fong Wang ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Renal Cell ◽

Prognostic Score ◽

Phase Iii ◽

Advanced Renal Cell Carcinoma ◽

Phase 3 ◽

Poor Risk ◽

Recist 1.1 ◽

Flat Dose

TPS5102 Background: Cabozantinib (C) inhibits tyrosine kinases involved in tumor growth, angiogenesis, and immune regulation, including MET, VEGFR, and TAM kinases (Tyro3, AXL, MER), and may promote an immune-permissive tumor environment, resulting in enhanced response to immune checkpoint inhibitors. C has shown preliminary clinical activity and tolerability in combination with the PD-1 inhibitor nivolumab (N) and as part of a triplet combination with N and the CTLA-4 inhibitor ipilimumab (I) in patients (pts) with advanced renal cell carcinoma (aRCC) (Nadal et al. ASCO 2018). C is approved for pts with aRCC, and N+I is approved as a combination therapy in pts with previously untreated aRCC of intermediate or poor risk. We present the study design of a phase 3 trial of C+N+I vs N+I in previously untreated pts with aRCC of IMDC intermediate or poor risk (NCT03937219). Methods: This randomized, double-blind, controlled phase 3 study evaluates the efficacy and safety of C+N+I vs N+I in previously untreated pts with IMDC intermediate or poor risk aRCC. Eligible pts are randomized 1:1 to receive C+N+I or N+I in combination with placebo, stratified by IMDC prognostic score and geographic region. Pts receive C (40 mg oral QD) + N (3 mg/kg IV Q3W) x 4 doses + I (1 mg/kg IV Q3W) x 4 doses, followed by C (40 mg oral QD) + N (480 mg IV flat dose Q4W). Control pts receive C-matched placebo and the same treatment regimen for N+I as the experimental arm. N will be administered for a maximum of 2 years. Eligibility criteria include histologically confirmed metastatic or aRCC with a clear cell component, intermediate or poor risk RCC per IMDC criteria, measurable disease per RECIST 1.1, KPS ≥70%, adequate organ and marrow function and age ≥18 years. Exclusion criteria include prior systemic therapy for aRCC and uncontrolled significant illnesses. The primary endpoint is PFS per RECIST 1.1 by BICR; the secondary endpoint is OS. Additional endpoints include ORR, safety, correlation of biomarkers with outcomes, and pharmacokinetics of C in combination with N+I. The first patient was enrolled in June 2019 and enrollment is ongoing. Clinical trial information: NCT03937219 .

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Temsirolimus in the treatment of advanced renal cell carcinoma

Oncology Reviews ◽

10.4081/oncol.2007.142 ◽

2011 ◽

pp. 73-80

Author(s):

Bernard J. Escudier

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Cell Carcinoma ◽

Renal Cell ◽

Antitumour Activity ◽

Dose Range ◽

Progression Free Survival ◽

Phase Iii ◽

Advanced Renal Cell Carcinoma ◽

Prognostic Features

Temsirolimus is a novel inhibitor of mammalian target of rapamycin (mTOR), which is a central regulator of the response of tumour cells to growth and survival signals. When heavily pretreated patients with advanced solid tumours received intravenous (IV) temsirolimus over a broad dose range, antitumour activity was observed in various tumour types, including advanced renal cell carcinoma (RCC). A study of singleagent temsirolimus in patients with cytokine-refractory metastatic RCC subsequently demonstrated antitumour activity and encouraging progression- free survival and overall survival. Temsirolimus was generally well tolerated over the 3 dose levels tested (25 mg, 75 mg or 250 mg weekly as a 30-minute IV infusion). The most frequent grade 3 or 4 treatment-related adverse events reported (n=110) were hyperglycemia (17%), hypophosphatemia (13%), anemia (9%), and hypertriglyceridemia (6%). Results from a randomized phase III study that enrolled previously untreated patients with advanced RCC and poor-prognostic features have recently demonstrated a significant increase in overall survival (p=0.0089) for patients who received temsirolimus 25 mg IV, 30-minute infusion once weekly compared with those who received interferon-alpha up to 18 million units subcutaneously thrice weekly. On the basis of improved survival, temsirolimus can be considered a first-line treatment for patients with advanced RCC.

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