Background

The current study was conducted to investigate the dependence between progression-free survival (PFS) and overall survival (OS) in patients with metastatic renal cell carcinoma (mRCC) and to explore whether PFS can be used as an intermediate endpoint of OS in this patient population.

Methods

A total of 1381 patients from 2 prospective phase 3 trials (Cancer and Leukemia Group B [CALGB] 90206 and AVOREN) of interferon-alpha with or without bevacizumab were analyzed. Both trials recruited previously untreated patients with clear cell mRCC with an Eastern Cooperative Oncology Group performance status of 0 to 2; adequate bone marrow, hepatic, cardiac, and renal function; and controlled blood pressure. The CALGB study served as the training data set, and the AVOREN study served as the testing data set. The dependence between PFS and OS was investigated using the Kendall tau for bivariate time-to-event endpoints.

Results

In the training data set, the median OS times among patients who experienced progressive disease at 3 months or 6 months were 6 months and 8 months, respectively, compared with 25 months and 30 months, respectively, (P < .001) in patients who did not develop disease progress. The adjusted hazard ratios (HR) were 2.6 (P < .0001) and 2.8 (P < .0001), respectively, for patients who did and did not progress at 3 months or 6 months. The dependence between PFS and OS was 0.53. These associations were confirmed in the testing data set.

Conclusions

In patients with mRCC who were treated with interferon-alpha with or without bevacizumab, the PFS at 3 months and 6 months was found to be predictive of OS. A high dependence between PFS and OS was observed, suggesting that PFS may be used as a surrogate endpoint for OS. Although this is a novel observation for RCC, these findings require validation in patients with mRCC who are treated with other targeted agents.

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).

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.

Purpose

Nivolumab, an anti-PD-1 immune checkpoint inhibitor, improved overall survival versus everolimus in a phase 3 trial of previously treated patients with metastatic renal cell carcinoma (mRCC). We investigated immunomodulatory activity of nivolumab in a hypothesis-generating prospective mRCC trial.

Experimental design

Nivolumab was administered intravenously every 3 weeks at 0.3, 2, or 10 mg/kg to previously treated patients and 10 mg/kg to treatment-naïve patients with mRCC. Baseline and on-treatment biopsies and blood were obtained. Clinical activity, tumor-associated lymphocytes, PD-L1 expression (Dako immunohistochemistry; ≥5% vs. <5% tumor membrane staining), tumor gene expression (Affymetrix U219), serum chemokines, and safety were assessed.

Results

In 91 treated patients, median overall survival [95% confidence interval (CI)] was 16.4 months [10.1 to not reached (NR)] for nivolumab 0.3 mg/kg, NR for 2 mg/kg, 25.2 months (12.0 to NR) for 10 mg/kg, and NR for treatment-naïve patients. Median percent change from baseline in tumor-associated lymphocytes was 69% (CD3⁺), 180% (CD4⁺), and 117% (CD8⁺). Of 56 baseline biopsies, 32% had ≥5% PD-L1 expression, and there was no consistent change from baseline to on-treatment biopsies. Transcriptional changes in tumors on treatment included upregulation of IFNγ-stimulated genes (e.g., CXCL9). Median increases in chemokine levels from baseline to C2D8 were 101% (CXCL9) and 37% (CXCL10) in peripheral blood. No new safety signals were identified.

Conclusions

Immunomodulatory effects of PD-1 inhibition were demonstrated through multiple lines of evidence across nivolumab doses. Biomarker changes from baseline reflect nivolumab pharmacodynamics in the tumor microenvironment. These data may inform potential combinations. Clin Cancer Res; 22(22); 5461-71. ©2016 AACR.

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.

We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.