PCN421 STABILITY OF LIFETIME OVERALL SURVIVAL ESTIMATES OF NIVOLUMAB+IPILIMUMAB IN FIRST-LINE ADVANCED/METASTATIC INTERMEDIATE- OR POOR-RISK RENAL CELL CARCINOMA

523 Background: The objective of this study was to assess the prognostic impact of early tumor shrinkage induced by first-line tyrosine kinase inhibitors (TKIs) on overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC). Methods: This study included a total of 185 consecutive Japanese patients with mRCC, consisting of 120 and 65 who were treated with sunitinib and sorafenib, respectively, for at least 3 months as first-line therapy. Prognostic outcomes in these 185 patients were retrospectively assessed focusing on the significance of tumor shrinkage at 12 weeks after the introduction of TKIs as a predictive factor of OS. Results: As the best responses to TKIs, 3, 40, 105 and 37 were judged to show a complete response, partial response, stable disease and progressive disease, respectively. The median progression-free survival (PFS) and OS in the 185 patients was 7.3 and 33.6 months, respectively. At 12 weeks after the introduction of TKIs, 9 patients reached a tumor shrinkage from -100 to -50%, 42 patients from -49 to -25%, 59 patients from -24 to 0%, and the remaining 70 patients had a gain of tumor size or new metastatic lesions. The median OS stratified according to tumor shrinkage at 12 weeks after the introduction of TKIs as shown above was 59.2, 39.1, 27.8 and 19.1 months, respectively. Univariate analysis identified the Memorial Sloan-Kettering Cancer Center (MSKCC) classification, Heng risk classification, C-reactive protein (CRP) level, lymph node metastasis, bone metastasis, liver metastasis, number of metastatic organs, histological subtype, sarcomatoid feature, PS and tumor shrinkage as significant predictors of OS. Of these significant factors, only the MSKCC classification, CRP level, liver metastasis and tumor shrinkage were shown to be independently associated with OS by multivariate analysis. Conclusions: These findings suggest that tumor shrinkage at 12 weeks after the introduction of TKIs was shown to have a significant impact on the OS in mRCC patients; therefore, early tumor shrinkage could be used as a reliable surrogate endpoint of OS in patients with mRCC receiving TKI as first-line agent.

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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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Comparison of quality-adjusted survival in patients with advanced renal cell carcinoma receiving first-line treatment with temsirolimus (TEMSR) or interferon-α (IFN) or the combination of IFN+TEMSR

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.5049 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 5049-5049 ◽

Cited By ~ 7

Author(s):

S. Parasuraman ◽

G. Hudes ◽

D. Levy ◽

A. Strahs ◽

L. Moore ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Cell Carcinoma ◽

Renal Cell ◽

Health State ◽

Line Treatment ◽

First Line ◽

Significant Difference ◽

Grade 3 ◽

First Line Treatment

5049 Background: In a phase 3, randomized, 3-arm study of TEMSR or IFN or the combination of TEMSR + IFN in the first-line treatment of patients with advanced renal cell carcinoma (RCC) and poor-prognostic features, TEMSR improved overall survival (p=0.0069) and progression-free survival (p=0.0001) vs. IFN (Hudes et al. J Clin Oncol. 2006;24:LBA4). Quality-adjusted survival was a pre-defined endpoint and is reported. Methods: Quality-adjusted time without symptoms and toxicity (QTWiST) was estimated by partitioning overall survival into 3 distinct health states: time with serious toxicity, time with progression, and time without symptoms and toxicity (TWiST). Survival was value-weighted when patients completed quality of life questionnaires (EQ-5D) at weeks 12 and 32, when a grade 3 or 4 adverse event (AE) was reported, upon relapse or progression, or upon withdrawal from the study. Treatment group comparisons used restricted means analyses estimated from censored survival data. Restricted means were computed for duration of each health state by truncating data at median follow-up (17.9 months). Variance and covariance were estimated using bootstrap methods. Results: All 626 randomized patients in the study were included in computation of health state durations. EQ-5D questionnaires were obtained from 260/300 (87%) upon progression and 230/570 (40%) after a grade 3/4 AE. Patients receiving TEMSR alone had 38% greater TWiST than those receiving IFN alone (TEMSR=6.5 months vs. IFN=4.7 months, p=0.00048). There was no significant difference in TWiST between the combination arm and IFN alone (IFN+TEMSR=5.4 months vs. IFN=4.7 months, p=0.1288). Patients receiving TEMSR alone had 23% greater Q-TWiST than those receiving IFN alone (TEMSR=7.0 months vs. IFN=5.7 months; p=0.0015). There was no significant difference in Q-TWiST for the combination arm compared with IFN alone (IFN+TEMSR=6.1 months vs. IFN=5.7 months, p=0.3469). Conclusions: Patients with advanced RCC receiving TEMSR alone had significantly greater quality-adjusted survival than those receiving IFN alone. No significant financial relationships to disclose.

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