Association of baseline neutrophil-to-eosinophil ratio with response to nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma

Abstract Background The identification of biomarkers to select patients with metastatic renal cell carcinoma (mRCC) most likely to respond to combination immunotherapy (IO) is needed. We sought to investigate an association of the baseline neutrophil-to-eosinophil ratio (NER) with outcomes to nivolumab plus ipilimumab for patients with mRCC. Methods We performed a retrospective review of patients with clear cell mRCC treated with nivolumab plus ipilimumab from Vanderbilt-Ingram Cancer Center and Duke Cancer Institute. Patients with prior receipt of immunotherapy and those without available baseline complete blood count with differential were excluded. Patients were divided into groups by the median baseline NER and analyzed for overall survival (OS), progression free survival (PFS), and objective response rate (ORR). Patients were also divided by median baseline neutrophil-to-lymphocyte ratio (NLR) and analyzed for clinical outcome. Further analyses of patients above/below the median NER and NLR were performed in subgroups of IMDC intermediate/poor risk, IMDC favorable risk, and treatment naïve patients. Results A total of 110 patients were included: median age was 61 years and 75% were treatment naïve. The median NER (mNER) at baseline was 26.4. The ORR was 40% for patients with <mNER compared to 21.8% among patients with >mNER (OR 2.39, p = 0.04). The median PFS for patients with <mNER was significantly longer at 8.6 months (mo) compared to 3.2 mo for patients with >mNER (HR 0.50, p < 0.01). Median OS was not reached (NR) for patients with <mNER compared with 27.3 mo for patients with >mNER (HR 0.31, p < 0.01). The median NLR (mNLR) was 3.42. While patients with <mNLR showed improvement in OS (HR 0.42, p = 0.02), PFS and ORR did not differ compared with patients in the >mNLR group. Conclusions A lower baseline NER was associated with improved clinical outcomes (PFS, OS, and ORR) in patients with mRCC treated with nivolumab plus ipilimumab, and prospective validation of the baseline NER as a predictive biomarker for response to immunotherapy-based combinations in mRCC is warranted.

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Association of the neutrophil to eosinophil ratio with response to immunotherapy-based combinations in metastatic renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.341 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 341-341

Author(s):

Matthew D Tucker ◽

Katy Beckermann ◽

Kristin Kathleen Ancell ◽

Kerry Schaffer ◽

Renee McAlister ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Clinical Outcomes ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Objective Response ◽

Progression Free Survival ◽

Rank Test ◽

Cancer Center ◽

Exact Test

341 Background: Neutrophilia is known to be associated with worse prognosis in metastatic renal cell carcinoma (mRCC); however, less is known about the role of eosinophils in the response to immunotherapy (IO). We investigated the association of the baseline neutrophil to eosinophil ratio (NER) with outcomes to IO-based combination treatment in mRCC. Methods: Patients with mRCC treated with ipilimumab plus nivolumab, pembrolizumab plus axitinib, or avelumab plus axitinib at the Vanderbilt-Ingram Cancer Center were retrospectively identified. Patients on >10mg prednisone and patients with prior IO were excluded. Baseline NER (at time of first IO) and association with progression free survival (PFS), overall survival (OS), and objective response rate (ORR) were investigated. Data cutoff was 9/1/2020. Analysis for PFS and OS was performed using the log-rank test and Mantel-Haenszel method, and analysis of the odds ratio for ORR was performed using Fischer’s exact test. Results: Sixty-one patients were identified: 89% clear cell histology, 74% prior nephrectomy, 69% IMDC intermediate risk, and 72% treatment-naïve. Patients with baseline NER < median (N=31) had improved clinical outcomes compared to patients with baseline NER > median (N=30) (Table). Improvement in PFS by NER was maintained when stratified by anti-PD-1/CTLA-4 and anti-PD(L)-1/VEGF (p= 0.0062 and p= 0.049); however, differences in OS and ORR were no longer significant. The median baseline NER among patients with partial response (PR) was significantly lower at 22.7 (95% CI 18.9-31.1) vs. 51.6 (95% CI 39.5-93.1) among those with progressive disease (PD) (p= 0.0054). For comparison, the median neutrophil to lymphocyte ratio was not significantly different between PR (2.60) and PD (3.84, p= 0.056). Conclusions: Patients with a low baseline NER treated with IO-based combinations had improved clinical outcomes compared to patients with a high baseline NER. Additional investigation of this parameter in larger cohorts is warranted. [Table: see text]

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The clinical significance of routine risk categorization in metastatic renal cell carcinoma and its impact on treatment decision-making: a systematic review

Future Oncology ◽

10.2217/fon-2020-0500 ◽

2020 ◽

Vol 16 (34) ◽

pp. 2879-2896

Author(s):

Shouki Bazarbashi ◽

Abdullah Alsharm ◽

Faisal Azam ◽

Hazem El Ashry ◽

Jamal Zekri

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Objective Response ◽

Treatment Decision ◽

Progression Free Survival ◽

Risk Groups ◽

Cancer Center ◽

Eligibility Criteria

Aim: To analyze responses to first-line metastatic renal cell carcinoma (mRCC) treatment stratified by risk criteria. Patients & methods: Clinical trials and observational studies of patients aged ≥18 years, published January 2005–May 2019, were identified via Ovid from MEDLINE, EMBASE, the Cochrane Central Trials Register and the Cochrane Database of Systematic Reviews. Data extracted included progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). Results: 47/1269 articles met eligibility criteria. Most studies stratified patients by International Metastatic RCC Database Consortium (n = 19) or Memorial Sloan Kettering Cancer Center (n = 21). PFS, OS and ORR varied according to risk group. Conclusion: Pembrolizumab + axitinib, ipilimumab + nivolumab and avelumab + axitinib were most effective across all risk groups. Favorable-risk patients benefit from sunitinib treatment.

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Efficacy and Safety of Nivolumab and Ipilimumab for Advanced or Metastatic Renal Cell Carcinoma: A Multicenter Retrospective Cohort Study

Current Oncology ◽

10.3390/curroncol28020133 ◽

2021 ◽

Vol 28 (2) ◽

pp. 1402-1411

Author(s):

Koji Iinuma ◽

Koji Kameyama ◽

Kei Kawada ◽

Shota Fujimoto ◽

Kimiaki Takagi ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Objective Response ◽

Predictive Biomarkers ◽

Progression Free Survival ◽

Predictive Marker ◽

Efficacy And Safety ◽

Lymphocyte Ratio

We conducted a multicenter, retrospective study to evaluate the efficacy and safety of combination nivolumab plus ipilimumab (NIVO+IPI) in 35 patients with advanced or metastatic renal cell carcinoma (mRCC). In this study, we focused on patients who received NIVO+IPI and were stratified into intermediate- or poor-risk disease according to the International Metastatic Renal Cell Carcinoma Database Consortium model at five institutions in Japan. The primary endpoint was overall survival (OS). Secondary endpoints were disease control rate (DCR), best overall response (BOR), objective response rate (ORR), and progression-free survival (PFS). In addition, we evaluated the role of inflammatory cell ratios, namely neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), as predictive biomarkers in patients with mRCC. The median follow-up period was 1 year, and the 1-year OS rate was 95.8%. The ORR and DCR were 34.3% and 80.0%, respectively. According to BOR, four patients (11.4%) achieved complete response. According to NLR stratification, the 1-year PFS rates were 82.6% and 23.7% when the NLR was ≤4.6 and >4.6, respectively (p = 0.04). Based on PLR stratification, the 1-year PFS rates were 81.7% and 34.3% when the PLR was ≤188.1 and >188.1, respectively (p = 0.033). Although 71.4% of the patients experienced treatment-related adverse events (TRAEs) with NIVO+IPI, only four patients discontinued NIVO+IPI due to grade 3/4 TRAEs. Patients treated with NIVO+IPI as a first-line therapy for advanced or mRCC achieved relatively better oncological outcomes. Therefore, NIVO+IPI may have potential advantages and may lead to a treatment effect compared to those receiving targeted therapies. In addition, PLR >188.1 may be a useful predictive marker for mRCC patients who received NIVO+IPI.

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Cytoreductive Nephrectomy and Overall Survival of Patients with Metastatic Renal Cell Carcinoma Treated with Targeted Therapy—Data from the National Renis Registry

Cancers ◽

10.3390/cancers12102911 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2911

Author(s):

Alexandr Poprach ◽

Milos Holanek ◽

Renata Chloupkova ◽

Radek Lakomy ◽

Michal Stanik ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Overall Survival ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Locally Advanced ◽

Treatment Algorithm ◽

Progression Free Survival ◽

Cancer Center ◽

Cytoreductive Nephrectomy

The role of cytoreductive nephrectomy (CN) in treatment of locally advanced or metastatic renal cell carcinoma (mRCC) in the era of targeted therapies (TT) is still not clearly defined. The study population consisted of 730 patients with synchronous mRCC. The RenIS (Renal carcinoma Information System) registry was used as the data source. The CN/TT cohort included patients having CN within 3 months from the mRCC diagnosis and subsequently being treated with TT, while the TT cohort included patients receiving TT upfront. Median progression-free survival from the first intervention was 6.7 months in the TT arm and 9.3 months in the CN/TT patients (p < 0.001). Median overall survival was 14.2 and 27.2 months, respectively (p < 0.001). Liver metastasis, high-grade tumor, absence of CN, non-clear cell histology, and MSKCC (Memorial Sloan-Kettering Cancer Center) poor prognosis status were associated with adverse treatment outcomes. According to the results of this retrospective study, patients who underwent CN and subsequently were treated with TT had better outcomes compared to patients treated with upfront TT. The results of the study support the use of CN in the treatment algorithm for mRCC.

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Effect of third- and fourth-line systemic therapies for metastatic renal cell carcinoma

Scientific Reports ◽

10.1038/s41598-019-51305-7 ◽

2019 ◽

Vol 9 (1) ◽

Author(s):

Sei Naito ◽

Osamu Ichiyanagi ◽

Tomoyuki Kato ◽

Hidenori Kanno ◽

Takafumi Narisawa ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Systemic Therapy ◽

Renal Cell ◽

Objective Response ◽

Progression Free Survival ◽

University Hospital ◽

Line Therapy ◽

Third Line

Abstract Data on the outcomes of third- or fourth-line therapy for metastatic renal cell carcinoma (mRCC) are limited. The aim of our study was to evaluate the efficacy of therapy beyond the second line. We retrospectively analysed data of mRCC patients who underwent systemic therapy at Yamagata University Hospital. The best objective response (BOR), response rate (RR), and progression-free survival (PFS) were assessed for each line of treatment. To investigate the correlation between overall survival (OS) and the number of treatment lines during a patient’s lifetime, the median OS was assessed using univariate and multivariate analyses. In the first-, second-, and third-line therapies, approximately 20% of patients had long PFS of >15 months. In targeted treatments beyond the third line, only one treatment suppressed disease progression for >10 months. Among patients who died during the follow-up period, those treated with triple and quadruple lines had similar OS (42.5 months vs. 48.4 months, respectively). Multivariate analysis showed that patients with triple or more lines of therapy had better OS; however, quadruple or more lines of therapy was not an independent prognostic factor. We concluded that third-line systemic therapy could improve OS; however, fourth-line therapy could not.

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A Phase II Study of Intermittent Sunitinib in Previously Untreated Patients With Metastatic Renal Cell Carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2016.71.1184 ◽

2017 ◽

Vol 35 (16) ◽

pp. 1764-1769 ◽

Cited By ~ 27

Author(s):

Moshe C. Ornstein ◽

Laura S. Wood ◽

Paul Elson ◽

Kimberly D. Allman ◽

Jennifer Beach ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Objective Response ◽

Evaluation Criteria ◽

Progression Free Survival ◽

Initial Therapy ◽

Primary Objective ◽

Intermittent Therapy

Purpose Sunitinib is a standard initial therapy in metastatic renal cell carcinoma (mRCC), but chronic dosing requires balancing toxicity with clinical benefit. The feasibility and clinical outcome with intermittent sunitinib dosing in patients with mRCC was explored. Patients and Methods Patients with treatment-naïve, clear cell mRCC were treated with four cycles of sunitinib (50 mg once per day, 4 weeks of receiving treatment followed by 2 weeks of no treatment). Patients with a ≥ 10% reduction in tumor burden (TB) after four cycles had sunitinib held, with restaging scans performed every two cycles. Sunitinib was reinitiated for two cycles in those patients with an increase in TB by ≥ 10%, and again held with ≥ 10% TB reduction. This intermittent sunitinib dosing continued until Response Evaluation Criteria in Solid Tumors-defined disease progression while receiving sunitinib, or unacceptable toxicity occurred. The primary objective was feasibility, defined as the proportion of eligible patients who underwent intermittent therapy. Results Of 37 patients enrolled, 20 were eligible for intermittent therapy and all patients (100%) entered the intermittent phase. Patients were not eligible for intermittent sunitinib because of progressive disease (n = 13), toxicity (n = 1), or consent withdrawal (n = 3) before the end of cycle 4. The objective response rate was 46% after the first four cycles of therapy. The median increase in TB during the periods off sunitinib was 1.6 cm (range, −2.9 to 3.4 cm) compared with the TB immediately before stopping sunitinib. Most patients exhibited a stable sawtooth pattern of TB reduction while receiving sunitinib and TB increase while not receiving sunitinib. Median progression-free survival to date is 22.4 months (95% CI, 5.4 to 37.6 months) and median overall survival is 34.8 months (95% CI, 14.8 months to not applicable). Conclusion Periodic extended sunitinib treatment breaks are feasible and clinical efficacy does not seem to be compromised.

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Phase III Trial of Bevacizumab Plus Interferon Alfa Versus Interferon Alfa Monotherapy in Patients With Metastatic Renal Cell Carcinoma: Final Results of CALGB 90206

Journal of Clinical Oncology ◽

10.1200/jco.2009.26.5561 ◽

2010 ◽

Vol 28 (13) ◽

pp. 2137-2143 ◽

Cited By ~ 568

Author(s):

Brian I. Rini ◽

Susan Halabi ◽

Jonathan E. Rosenberg ◽

Walter M. Stadler ◽

Daniel A. Vaena ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Objective Response ◽

Progression Free Survival ◽

Interferon Alfa ◽

Phase Iii ◽

Phase Iii Trial ◽

Grade 3

Purpose Bevacizumab is an antibody that binds vascular endothelial growth factor and has activity in metastatic renal cell carcinoma (RCC). Interferon alfa (IFN-α) is the historic standard initial treatment for RCC. A prospective, randomized, phase III trial of bevacizumab plus IFN-α versus IFN-α monotherapy was conducted. Patients and Methods Patients with previously untreated, metastatic clear cell RCC were randomly assigned to receive either bevacizumab (10 mg/kg intravenously every 2 weeks) plus IFN-α (9 million units subcutaneously three times weekly) or the same dose and schedule of IFN-α monotherapy in a multicenter phase III trial. The primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), objective response rate, and safety. Results Seven hundred thirty-two patients were enrolled. The median OS time was 18.3 months (95% CI, 16.5 to 22.5 months) for bevacizumab plus IFN-α and 17.4 months (95% CI, 14.4 to 20.0 months) for IFN-α monotherapy (unstratified log-rank P = .097). Adjusting on stratification factors, the hazard ratio was 0.86 (95% CI, 0.73 to 1.01; stratified log-rank P = .069) favoring bevacizumab plus IFN-α. There was significantly more grade 3 to 4 hypertension (HTN), anorexia, fatigue, and proteinuria for bevacizumab plus IFN-α. Patients who developed HTN on bevacizumab plus IFN-α had a significantly improved PFS and OS versus patients without HTN. Conclusion OS favored the bevacizumab plus IFN-α arm but did not meet the predefined criteria for significance. HTN may be a biomarker of outcome with bevacizumab plus IFN-α.

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Randomized Phase III Trial of Temsirolimus and Bevacizumab Versus Interferon Alfa and Bevacizumab in Metastatic Renal Cell Carcinoma: INTORACT Trial

Journal of Clinical Oncology ◽

10.1200/jco.2013.50.5305 ◽

2014 ◽

Vol 32 (8) ◽

pp. 752-759 ◽

Cited By ~ 134

Author(s):

Brian I. Rini ◽

Joaquim Bellmunt ◽

Jill Clancy ◽

Kongming Wang ◽

Andreas G. Niethammer ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Combination Therapy ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Clear Cell ◽

Objective Response ◽

Interferon Alfa ◽

Phase Iii ◽

Cancer Center

PurposeTo prospectively determine the efficacy of combination therapy with temsirolimus plus bevacizumab versus interferon alfa (IFN) plus bevacizumab in metastatic renal cell carcinoma (mRCC).Patients and MethodsIn a randomized, open-label, multicenter, phase III study, patients with previously untreated predominantly clear-cell mRCC were randomly assigned, stratified by prior nephrectomy and Memorial Sloan-Kettering Cancer Center prognostic group, to receive the combination of either temsirolimus (25 mg intravenously, weekly) or IFN (9 MIU subcutaneously thrice weekly) with bevacizumab (10 mg/kg intravenously, every 2 weeks). The primary end point was independently assessed progression-free survival (PFS).ResultsMedian PFS in patients treated with temsirolimus/bevacizumab (n = 400) versus IFN/bevacizumab (n = 391) was 9.1 and 9.3 months, respectively (hazard ratio [HR], 1.1; 95% CI, 0.9 to 1.3; P = .8). There were no significant differences in overall survival (25.8 ν 25.5 months; HR, 1.0; P = .6) or objective response rate (27.0% ν 27.4%) with temsirolimus/bevacizumab versus IFN/bevacizumab, respectively. Patients receiving temsirolimus/bevacizumab reported significantly higher overall mean scores in the Functional Assessment of Cancer Therapy–Kidney Symptom Index (FKSI) –15 and FKSI-Disease Related Symptoms subscale compared with IFN/bevacizumab (indicating improvement); however, no differences in global health outcome measures were observed. Treatment-emergent all-causality grade ≥ 3 adverse events more common (P < .001) with temsirolimus/bevacizumab were mucosal inflammation, stomatitis, hypophosphatemia, hyperglycemia, and hypercholesterolemia, whereas neutropenia was more common with IFN/bevacizumab. Incidence of pneumonitis with temsirolimus/bevacizumab was 4.8%, mostly grade 1 or 2.ConclusionTemsirolimus/bevacizumab combination therapy was not superior to IFN/bevacizumab for first-line treatment in clear-cell mRCC.

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Evaluation of parameters for treatment duration of sunitinib in metastatic renal cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e15042 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e15042-e15042

Author(s):

Ellen Kossoff ◽

Nicolas Batty ◽

Alice C. Ceacareanu ◽

Kristopher Attwood ◽

Dustyn Miller ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Treatment Duration ◽

Performance Status ◽

Progression Free Survival ◽

Cancer Center ◽

Significant Prognostic Factor ◽

Lower Baseline

e15042 Background: In metastatic renal cell carcinoma (mRCC), there is a need for predictive indicators for treatment duration (TD) of sunitinib. Our study evaluates parameters that may be associated with TD of sunitinib. Methods: From 01/2007-12/2011, consecutive mRCC patients (pts) were reviewed. Responders (R) were defined as having either complete response (CR) or partial response (PR) by Response Evaluation Criteria In Solid Tumors (RECIST) criteria, while non-responders (NR) were defined as having either stable disease (SD) or progressive disease (PD). Long term duration (LTD) was defined as therapy with sunitinib ≥ 18 months (mos). Hazard ratios (HR) and 95% confidence interval (95CI) representing the association between TD and specific parameters were computed with Cox proportional hazard model. Results: After a median follow-up of 9.8 mos (<1 - 63.8) of 128 mRCC pts, 57 (45%) received sunitinib. Responses were CR, PR, SD, PD of 3, 13, 8 and 33 pts, respectively. LTD was observed in 9 pts (21%). Hemoglobin < 12.5 g/dL (p = 0.048), prior nephrectomy (PN) (p = 0.001), prior therapies (p = 0.016), dose reduction (DR) (p = 0.001), an increased skin toxicity (p = 0.025) and low/intermediate (LI) Memorial Sloan-Kettering Cancer Center (MSKCC) risk-groups (p = 0.003) were associated with longer TD and a higher ANC (p < 0.0001) with shorter TD. In the multivariate analysis, PN was the only significant prognostic factor [HR 0.3 (95CI 0.12 -0.72) p = 0.007] that was associated with prolonged TD. Pts with LTD had a lower baseline ANC (p= 0.037), a LI MSKCC (p = 0.026), higher frequency of DR (p = 0.007), increased skin (p = 0.017) and endocrine (p = 0.015) toxicities and an increase of body mass index (BMI) from baseline (p = 0.008). When adjusted for BMI and performance status, results were maintained. Progression free survival (PFS) and overall survival (OS) of pts with LTD were not reached. However, both PFS and OS of R with TD < 18 mos, were 19.5 mos 95CI (3.4 - 27.9). Conclusions: PN, lower baseline ANC, DR, an increase of BMI from baseline, skin and endocrine toxicities were associated with prolonged TD of sunitinib in mRCC. There is a need for prospective studies to develop a predictive TD model in this setting.

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Tivozanib in patients treatment-naive for metastatic renal cell carcinoma: A subset analysis of the phase III TIVO-1 study.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.4513 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 4513-4513 ◽

Cited By ~ 5

Author(s):

Cora N. Sternberg ◽

Tim Eisen ◽

Piotr Tomczak ◽

Andrew Louis Strahs ◽

Brooke Esteves ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Systemic Therapy ◽

Renal Cell ◽

Progression Free Survival ◽

Common Adverse Event ◽

Phase Iii ◽

Treatment Naïve ◽

Prior Systemic Therapy

4513 Background: Tivozanib (T) is a potent, selective inhibitor of all three VEGF receptors with a long half-life of 4.5–5.1 days. Superior progression-free survival (PFS) and overall response rate (ORR) with T versus sorafenib (S) were demonstrated in a Phase III trial (TIVO-1) in patients (pts) with metastatic renal cell carcinoma (mRCC) (in ITT population, PFS: 11.9 vs 9.1 months HR=0.797, 95% CI 0.639–0.993; P=0.042; ORR: 33% vs 23%, P=0.014). Hypertension was more common with T, while lower rates of certain off-target AEs and fewer dose adjustments relative to S were reported (J Clin Oncol 2012;30[suppl]:Abstract 4501). Here we present efficacy and safety analyses for the pre-specified subset of pts who received no prior systemic therapy for mRCC. Methods: In the ITT population (N=517), pts were treatment-naïve or had received no more than 1 prior systemic therapy for metastatic disease; pts receiving prior VEGF- or mTOR-targeted therapy were excluded. Pts were randomized 1:1 to T 1.5 mg/d (once daily, 3 weeks on, 1 week off) or S 400 mg/d (twice daily, continuously). Of these, 181 pts (70%) in each treatment arm had not received prior systemic therapy for mRCC. Results: In pts who received no prior systemic therapy for mRCC, demographics were well balanced between the 2 arms. Median PFS was 12.7 for T vs 9.1 months for S (HR=0.756, 95% CI 0.580–0.985, P=0.037). ORR was 34% for T vs 24% for S (P=0.038). The most common adverse event (AE; All grades/Grade ≥3) for T was hypertension (T: 40%/25% vs S: 35%/18%), suggesting “on-target” biological activity and was manageable medically, while the most common AE for S was hand-foot syndrome (T: 11%/2% vs S: 52%/16%). Other common AEs were diarrhea (T: 22%/2% vs S: 32%/7%), fatigue (T: 19%/6% vs S: 15%/3%), and weight decrease (T: 18%/1% vs S: 17%/2%). Dose reduction (T: 12% vs S: 42%) and interruption (T: 18% vs S: 35%) rates were lower in the T arm and similar to the ITT population. Conclusions: T demonstrated significant improvement in PFS and ORR compared with S in pts who had received no prior systemic therapy for metastatic RCC. T was generally well tolerated, with low rates of treatment-related reduction/interruption in this pre-specified subgroup of pts. Clinical trial information: NCT01030783.

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