Exploratory analysis of the platelet-to-lymphocyte ratio prognostic value in the adjuvant renal cell cancer setting.

Aim: To examine the prognostic value of the platelet-to-lymphocyte ratio (PLR) in the adjuvant renal cell carcinoma setting. Materials & methods: Patients received adjuvant sunitinib (50 mg/day; 4 weeks on/2 weeks off) or placebo. The primary end point was disease-free survival (DFS). Results: In 609 patients, DFS was similar for baseline PLR <140 versus ≥140 overall (median: 6.4 vs 5.9 years; hazard ratio: 0.9; 95% CI: 0.7-1.2). A ≥25% decrease in PLR at week 4 overall was associated with longer DFS versus no change (hazard ratio: 0.8; 95% CI: 0.6-1.0). Conclusion: Baseline PLR was not prognostic for DFS with adjuvant sunitinib treatment in patients with renal cell carcinoma. Clinical Trials Registration: NCT00375674 (ClinicalTrials.gov).

Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.

BACKGROUND: Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy. METHODS: In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety. RESULTS: The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects. CONCLUSIONS: Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674 .).

Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial.

BACKGROUND: Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. METHODS: In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. FINDINGS: Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0-84·4) patients achieved an objective response (complete or partial response). INTERPRETATION: The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331). FUNDING: Pfizer Inc.

Phase I study of sunitinib plus S-1 and cisplatin in Japanese patients with advanced or metastatic gastric cancer.

BACKGROUND: This phase I, dose-finding study evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of sunitinib plus S-1/cisplatin in Japanese patients with advanced/metastatic gastric cancer. PATIENTS AND METHODS: Patients received oral sunitinib on a continuous daily dosing (CDD) or 2-weeks-on/2-weeks-off schedule (Schedule 2/2; 25 mg/day or 37.5 mg/day), plus S-1 (80-120 mg/day)/cisplatin 60 mg/m(2). RESULTS: Twenty-seven patients received treatment, including 26 patients treated per protocol (sunitinib 25 mg/day CDD schedule, n = 4; sunitinib 25 mg/day Schedule 2/2, n = 16 [dose-limiting toxicity (DLT) cohort, n = 6 plus expansion cohort, n = 10]; sunitinib 37.5 mg/day Schedule 2/2, n = 6). One patient erroneously self-administered sunitinib 12.5 mg/day and was excluded from the analyses. The MTD was sunitinib 25 mg/day on Schedule 2/2. DLTs were reported for: 2/4 patients given sunitinib 25 mg/day on the CDD schedule; 1/6 patients administered sunitinib 25 mg/day on Schedule 2/2 (grade [G] 3 neutropenic infection, G4 thrombocytopenia, and S-1 dose interruption ≥5 days), and 3/6 patients given sunitinib 37.5 mg/day on Schedule 2/2. Results below are for the overall MTD cohort (n = 16). The most frequently reported G3/4 adverse events were neutropenia (93.8 %) and leukopenia (75.0 %). The objective response rate was 37.5 %; six additional patients experienced no disease progression for ≥24 weeks. Median progression-free survival was 12.5 months. No pharmacokinetic drug-drug interactions were observed between sunitinib/S-1/cisplatin and S-1/cisplatin. CONCLUSIONS: The MTD of sunitinib was 25 mg/day on Schedule 2/2 combined with cisplatin/S-1 in patients with advanced/metastatic gastric cancer. This regimen had a manageable safety profile and preliminary antitumor activity.

Radiographic progression by Prostate Cancer Working Group (PCWG)-2 criteria as an intermediate endpoint for drug development in metastatic castration-resistant prostate cancer.

OBJECTIVE: To investigate the association of radiographic progression defined by Prostate Cancer Working Group (PCWG)-2 guidelines and overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Two trials that used PCWG-2 guidelines to define progression were analysed: a randomized phase II trial (n = 221) comparing first-line docetaxel-prednisone plus AT-101 or placebo, and a phase III trial (n = 873) comparing prednisone plus sunitinib or placebo after docetaxel-based chemotherapy. Cox proportional hazards regression models were used to estimate the association of radiographic progression with OS. Landmark analyses compared progressing patients with those who had not progressed. Sub-analyses compared patients removed from trial for progression vs other reasons. RESULTS: An increased risk of death was seen for radiographic progression at landmark times from 6 to 12 months with docetaxel-based therapy (hazard ratio [HR] >1.7 at all time-points). An increased risk of death was also seen with post-docetaxel prednisone alone or with sunitinib for progression at landmark times from 2 to 8 months (HR >2.7 at all time-points). Kendall's τ was 0.50 (P < 0.001) in the setting of docetaxel-based therapy and 0.34 (P < 0.001) in the post-docetaxel setting for association between radiographic progression and death amongst patients with both events. Removal from study due to radiographic progression was associated with a significantly lower OS compared with removal for other reasons in both trials. Limitations of a retrospective analysis apply and there was no central radiology review. CONCLUSIONS: Radiographic progression by PCWG-2 criteria was significantly associated with OS in patients with mCRPC receiving first-line docetaxel-based chemotherapy or post-docetaxel therapy. With external validation as a surrogate endpoint in trials showing survival benefits, the use of radiographic progression-free survival may expedite drug development in mCRPC, which has been hampered by the lack of intermediate endpoints.

Neutrophil-to-Lymphocyte Ratio as a Prognostic Factor of Disease-free Survival in Postnephrectomy High-risk Locoregional Renal Cell Carcinoma: Analysis of the S-TRAC Trial.

PURPOSE: In the S-TRAC trial, adjuvant sunitinib improved disease-free survival (DFS) compared with placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence. This post hoc exploratory analysis investigated the neutrophil-to-lymphocyte ratio (NLR) for predictive and prognostic significance in the RCC adjuvant setting. EXPERIMENTAL DESIGN: Kaplan-Meier estimates and Cox proportional analyses were performed on baseline NLR and change from baseline at week 4 to assess their association with DFS. Univariate P values were two-sided and based on an unstratified log-rank test. RESULTS: 609 of 615 patients had baseline NLR values; 574 patients had baseline and week 4 values. Sunitinib-treated patients with baseline NLR <3 had longer DFS versus placebo (7.1 vs. 4.7; HR, 0.71; P = 0.02). For baseline NLR ≥3, DFS was similar regardless of treatment (sunitinib 6.8 vs. placebo not reached; HR, 1.03; P = 0.91). A ≥25% NLR decrease at week 4 was associated with longer DFS versus no change (6.8 vs. 5.3 years; HR, 0.71; P = 0.01). A greater proportion of sunitinib-treated patients had ≥25% NLR decrease at week 4 (71.2%) versus placebo (17.4%). Patients with ≥25% NLR decrease at week 4 received a higher median cumulative sunitinib dose (10,137.5 mg) versus no change (8,168.8 mg) or ≥25% increase (6,712.5 mg). CONCLUSIONS: In the postnephrectomy high-risk RCC patient cohort, low baseline NLR may help identify those most suitable for adjuvant sunitinib. A ≥25% NLR decrease at week 4 may be an early indicator of those most likely to tolerate treatment and derive DFS benefit.

Comparison of two doses of intravenous temsirolimus in patients with relapsed/refractory mantle cell lymphoma.

Temsirolimus 175 mg once-weekly for 3 weeks, followed by 75 mg once-weekly intravenously dosed (175/75 mg) is approved in the European Union for treatment of relapsed/refractory mantle cell lymphoma (MCL). A phase IV study explored whether similar efficacy, but improved safety could be achieved with 75 mg without 175 mg loading doses (ClinicaTrials.gov: NCT01180049). Patients with relapsed/refractory MCL were randomized to once-weekly temsirolimus 175/75 mg (n = 47) or 75 mg (n = 42). Treatment continued until objective disease progression. Primary endpoint: progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AEs). Median PFS was 4.3 versus 4.5 months (hazard ratio [HR] 0.731; 80% confidence interval [CI], 0.520-1.027), and median OS 18.7 versus 11.0 months (HR 0.681; 80% CI, 0.472-0.982) with 175/75 mg versus 75 mg. There were fewer patients with serious AEs, dose reduction, or death with 175/75 mg (57.4%, 48.9%, and 48.9%) versus 75 mg (73.8%, 64.3%, and 65.1%). Temsirolimus 175/75 mg remains the preferred dosing regimen for relapsed/refractory MCL.

Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results.

BACKGROUND: Adjuvant sunitinib significantly improved disease-free survival (DFS) versus placebo in patients with locoregional renal cell carcinoma (RCC) at high risk of recurrence after nephrectomy (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.59-0.98; p=0.03). OBJECTIVE: To report the relationship between baseline factors and DFS, pattern of recurrence, and updated overall survival (OS). DESIGN, SETTING, AND PARTICIPANTS: Data for 615 patients randomized to sunitinib (n=309) or placebo (n=306) in the S-TRAC trial. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Subgroup DFS analyses by baseline risk factors were conducted using a Cox proportional hazards model. Baseline risk factors included: modified University of California Los Angeles integrated staging system criteria, age, gender, Eastern Cooperative Oncology Group performance status (ECOG PS), weight, neutrophil-to-lymphocyte ratio (NLR), and Fuhrman grade. RESULTS AND LIMITATIONS: Of 615 patients, 97 and 122 in the sunitinib and placebo arms developed metastatic disease, with the most common sites of distant recurrence being lung (40 and 49), lymph node (21 and 26), and liver (11 and 14), respectively. A benefit of adjuvant sunitinib over placebo was observed across subgroups, including: higher risk (T3, no or undetermined nodal involvement, Fuhrman grade ≥2, ECOG PS ≥1, T4 and/or nodal involvement; hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.55-0.99; p=0.04), NLR ≤3 (HR 0.72, 95% CI 0.54-0.95; p=0.02), and Fuhrman grade 3/4 (HR 0.73, 95% CI 0.55-0.98; p=0.04). All subgroup analyses were exploratory, and no adjustments for multiplicity were made. Median OS was not reached in either arm (HR 0.92, 95% CI 0.66-1.28; p=0.6); 67 and 74 patients died in the sunitinib and placebo arms, respectively. CONCLUSIONS: A benefit of adjuvant sunitinib over placebo was observed across subgroups. The results are consistent with the primary analysis, which showed a benefit for adjuvant sunitinib in patients at high risk of recurrent RCC after nephrectomy. PATIENT SUMMARY: Most subgroups of patients at high risk of recurrent renal cell carcinoma after nephrectomy experienced a clinical benefit with adjuvant sunitinib. TRIAL REGISTRATION: ClinicalTrials.gov NCT00375674.

Effect of celecoxib on cardiovascular events and blood pressure in two trials for the prevention of colorectal adenomas.

BACKGROUND: Cyclooxygenase-2 (COX-2) inhibitors have been shown to reduce colorectal adenomas but have been associated with increased cardiovascular risk. METHODS AND RESULTS: The Adenoma Prevention With Celecoxib (APC) trial studied celecoxib 200 mg twice daily and 400 mg twice daily and the Prevention of Spontaneous Adenomatous Polyps (PreSAP) trial used 400 mg once daily totest the efficacy and safety of celecoxib against placebo in reducing colorectal adenoma recurrence after polypectomy. An independent safety committee for both studies adjudicated and categorized serious cardiovascular events and then combined individual patient data from these long-term trials to improve the estimate of the cardiovascular risk and blood pressure changes associated with celecoxib compared with placebo. For adjudicated cardiovascular events, 77% and 54% in APC and PreSAP, respectively, had 37 months of follow-up. For APC and PreSAP combined, 83 patients experienced cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or heart failure. The hazard ratio for this prespecified composite end point was 2.6 (95% confidence interval [CI], 1.1 to 6.1) in patients taking 200 mg twice daily, 3.4 (95% CI, 1.5 to 7.9) in patients taking 400 mg twice daily in APC, and 1.3 (95% CI, 0.6 to 2.6) in patients taking 400 mg once daily in PreSAP (P for heterogeneity = 0.13 comparing the combined doses in APC with the dose in PreSAP). The overall hazard ratio for this composite end point was 1.9 (95% CI, 1.1 to 3.1). Both dose groups in APC showed significant systolic blood pressure elevations at 1 and 3 years (200 mg twice daily: 1 year, 2.0 mm Hg; 3 years,2.6 mm Hg; 400 mg twice daily: 1 year, 2.9 mm Hg; 3 years, 5.2 mm Hg); however, the 400 mg once daily group inPreSAP did not (P0.0001 between studies). CONCLUSIONS: Celecoxib at 200 or 400 mg twice daily or 400 mg once daily showed a nearly 2-fold-increased cardiovascular risk. The trend for a dose-related increase in cardiovascular events and blood pressure raises the possibility that lower doses or other dose intervals may be associated with less cardiovascular risk.

Prognostic impact of the neutrophil-to-lymphocyte ratio in men with metastatic castration-resistant prostate cancer.

BACKGROUND: We retrospectively evaluated the prognostic impact of neutrophil-lymphocyte ratio (NLR) as a marker for inflammatory and immune state in men with progressive metastatic castration resistant prostate cancer (mCRPC) following docetaxel. METHODS: The SUN-1120 phase III trial comparing prednisone combined with sunitinib (n = 584) or placebo (n = 289) for mCRPC following docetaxel-based chemotherapy was evaluated. The arms were combined for analysis, since no difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression method with forward stepwise selection, stratifying for ECOG PS, progression type (prostate specific antigen [PSA] or radiographic) and treatment group. Patients were categorized into risk groups. RESULTS: Complete data was evaluable for 784 men. The factors used in the model that remained individually significant for OS in multivariable analysis were: log-lactate dehydrogenase level (LDH) level (HR 2.86 [95% CI = 2.29, 3.56], P < .001), hemoglobin (0.80 [0.74, 0.85], P < .001), > 1 organ involved by metastatic disease (1.49 [1.21, 1.84], P < .001), log-alkaline phosphatase (1.13 [0.99, 1.28], P = .074), log-number of prior cycles of docetaxel (0.84 [0.71, 0.98], P = .031), progression on docetaxel (1.35 [1.00, 1.81], P = .049), log-PSA (1.06 [1.00, 1.12], P = .075) and log-NLR (1.55 [1.32, 1.83], P < .001). NLR increased the c-statistic of the prognostic model from 0.703 to 0.715. CONCLUSION: High NLR may be associated with an independent poor prognostic impact in post-docetaxel patients with mCRPC. These data warrant external validation.