Daniel Yick Chin Heng

Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: clinical characteristics, risk factors, and subsequent therapy

BACKGROUND A subset of patients treated with initial anti-vascular endothelial growth factor (VEGF) therapy exhibit progressive disease (PD) as the best response per RECIST criteria. METHODS Data from patients with metastatic renal cell carcinoma (mRCC) treated with anti-VEGF therapy were collected through the International mRCC Database Consortium from 12 centers. RESULTS One thousand and fifty-six assessable patients received initial VEGF inhibitors and 272 (26%) of these patients had PD as best response. Initial treatment included sunitinib (n = 203), sorafenib (n = 51), or bevacizumab (n = 18). Six percent of patients were at favorable risk, 55% at intermediate risk, and 39% at poor risk. On multivariable analysis, predictors of PD were Karnofsky performance status < 80% [odds ratio (OR) = 2.3, P < 0.0001], diagnosis to treatment < 1 year (OR = 2.1, P < 0.0001), neutrophilia (OR = 1.9, P = 0.0021), thrombocytosis (OR = 1.7, P = 0.0068), and anemia (OR = 1.6, P = 0.0058). Median progression-free survival (PFS) in patients with PD versus without PD was 2.4 versus 11 months (P < 0.0001) and overall survival (OS) was 6.8 versus 29 months (P < 0.0001), respectively. One hundred and eight (40%) VEGF-refractory patients proceeded to receive further systemic therapies. Response rate, PFS, and OS for subsequent therapy were 9%, 2.5 months, and 7.4 months, respectively, with no statistical differences between patients who received VEGF versus mammalian target of rapamycin (mTOR) inhibitors. CONCLUSIONS Primary anti-VEGF-refractory mRCC patients have a dismal prognosis. Second-line anti-mTOR and anti-VEGF agents produce similar outcomes.

First-, second-, third-line therapy for mRCC: benchmarks for trial design from the IMDC.

Background:Limited data exist on outcomes for metastatic renal cell carcinoma (mRCC) patients treated with multiple lines of therapy. Benchmarks for survival are required for patient counselling and clinical trial design.Methods:Outcomes of mRCC patients from the International mRCC Database Consortium database treated with 1, 2, or 3+ lines of targeted therapy (TT) were compared by proportional hazards regression. Overall survival (OS) and progression-free survival (PFS) were calculated using different population inclusion criteria.Results:In total, 2705 patients were treated with TT of which 57% received only first-line TT, 27% received two lines of TT, and 16% received 3+ lines of TT. Overall survival of patients who received 1, 2, or 3+ lines of TT were 14.9, 21.0, and 39.2 months, respectively, from first-line TT (P<0.0001). On multivariable analysis, 2 lines and 3+ lines of therapy were each associated with better OS (HR=0.738 and 0.626, P<0.0001). Survival outcomes for the subgroups were as follows: for all patients, OS 20.9 months and PFS 7.2 months; for those similar to eligible patients in the first-line ADAPT trial, OS 14.7 months and PFS 5.6 months; for those similar to patients in first-line TIVO-1 trial, OS 24.8 months and PFS 8.2 months; for those similar to patients in second-line INTORSECT trial, OS 13.0 months and PFS 3.9 months; and for those similar to patients in the third-line GOLD trial, OS 18.0 months and PFS 4.4 months.Conclusions:Patients who are able to receive more lines of TT live longer. Survival benchmarks provide context and perspective when interpreting and designing clinical trials.

A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel

A prognostic index model was developed, composed of six readily available and assessable factors and categorizing patients with metastatic castration-resistant prostate cancer treated with abiraterone–prednisone into distinct prognostic risk groups. This model could be useful for determining patient prognosis for follow-up, monitoring and patient stratification for clinical trials.

1050OPHASE I STUDY OF NIVOLUMAB IN COMBINATION WITH IPILIMUMAB IN METASTATIC RENAL CELL CARCINOMA (MRCC)

ABSTRACT Aim: Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has shown durable responses and encouraging overall survival (OS) data in mRCC. IPI, a fully human monoclonal antibody to CTLA-4, improved OS in melanoma and has antitumor activity in mRCC. The combination of these agents showed encouraging antitumor activity and an acceptable safety profile in advanced melanoma. We report preliminary results of this combination in mRCC. Methods: Patients (pts) with mRCC were randomized to nivolumab 3 mg/kg + IPI 1 mg/kg (arm N3 + I1) or nivolumab 1 mg/kg + IPI 3 mg/kg (N1 + I3) IV every 3 wk for 4 doses then nivolumab 3 mg/kg IV every 2 wk until progression/toxicity (protocol-defined post-progression treatment allowed). The primary objective was to assess safety; secondary objective was to assess efficacy (RECIST 1.1). Results: 21 and 23 pts were randomized to the N3 + I1 and N1 + I3 arms, respectively. Most pts (n = 35; 80%) had prior systemic therapy (N3 + I1: 17; N1 + I3: 18). Treatment-related adverse events (AEs) were seen in 39 pts (89%); 8 pts (18%; N3 + I1: 2; N1 + I3: 6) discontinued due to related AEs. Grade 3-4-related AEs occurred in 20 pts (46%; N3 + I1: 6; N1 + I3: 14), most commonly ↑ lipase (21%, n = 9), ↑ ALT (14%, n = 6), diarrhea (9%, n = 4), and ↑ AST (7%, n = 3). No grade 3-4 pneumonitis was seen. Objective response rate (ORR) was 43% (N3 + I1) and 48% (N1 + I3); median duration of response (DOR) was 31.1 wk (7 ongoing) in N3 + I1 and not reached (9 ongoing) in N1 + I3 (Table). Responses occurred by first tumor assessment (wk 6) in 44% of pts in the N3 + I1 arm and 55% of pts in the N1 + I3 arm. Stable disease (SD) as best overall response was seen in 5 (24%) (N3 + I1) and 8 (35%) (N1 + I3) pts. Arm N3 + I1 n = 21 Arm N1 + I3 n = 23 ORR, n (%) 9 (43) 11 (48) SD, n (%) 5 (24) 8 (35) DOR, range (wk) 4.1+ - 42.1+ 12.1+ - 35.1 + Median progression-free survival, wk (95% CI) 36.6 (6.0, ) 38.3 (18.3, ) CI, confidence interval Conclusions: Nivolumab + IPI showed acceptable safety and encouraging antitumor activity in mRCC, with most responses ongoing. Studies are ongoing to explore this combination in a Phase III trial. Disclosure: H. Hammers: Has received Honoraria from Ono Pharma USA; E.R. Plimack: Has received grants and/or personal fees from: BMS, GSK, Dendreon, Astellas, Pfizer, Amgen, Acceleron, MedImmune, Merck, Lilly, AZ; M. Ernstoff: I have received funding for research from Bristol Myers Squibb, and hold stocks in BMS; B.I. Rini: I have consulted for the following companies: Pfizer, BMS, Merck, GSK; received funding for research from: Pfizer, BMS, Immatics, GSK, Roche, Acceleron; D.F. McDermott: I have received honoraria from and worked as a consultant/ in an advisory capacity to Bristol-Myers Squibb; M. Voss: Dr. Voss reports grants from BMS, outside the submitted work; P. Sharma: I have served as a consultant for: MedImmune, GSK, BMS, Jounce, Janssen, Pfizer, and Helsinn Therapeutics. I also own stock in Jounce; D. Heng: I have worked as a consultant for the following: BMS, Bayer, Pfizer, Novartis; Y. Shen: I am an employee of Bristol-Myers Squibb, and immediate family member employed at BM.; J. Kurland: I am an employee of and have stock or other ownership interest in BMS; P. Gagnier: I am an employee of and have stock or other ownership interest in BMS; A. Amin: I have worked as a consultant/ in an advisory capacity to: Bristol Myers Squibb. I have received Honoraria from: Bristol Myers Squibb. All other authors have declared no conflicts of interest.

Incidence and risk of treatment-related mortality in cancer patients treated with the mammalian target of rapamycin inhibitors

BACKGROUND Inhibition of the mammalian target of rapamycin (mTOR) is an established treatment for multiple malignancies. We carried out an up-to-date meta-analysis to determine the risk of fatal adverse events (FAEs) in cancer patients treated with mTOR inhibitors. PATIENTS AND METHODS PubMed, conferences and clinicaltrials.gov databases were searched for articles reported from January 1966 to June 2012. Eligible studies were limited to approved mTOR inhibitors (everolimus and temsirolimus) and reported on patients with cancer, randomized design and adequate safety profiles. Data extraction was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. RESULTS In all, 3193 patients from eight randomized, controlled trials (RCTs) were included, 2236 from everolimus trials and 957 from temsirolimus trials. The relative risk (RR) of FAEs related to mTOR inhibitors use was 2.20 (95% CI, 1.25-3.90; P = 0.006) compared with control patients. On subgroup analysis, no difference in the rate of FAEs was found between everolimus and temsirolimus or between tumor types [renal cell carcinoma (RCC) versus non-RCC]. No evidence of publication bias was observed. CONCLUSION The use of mTOR inhibitors is associated with a small but higher risk of FAEs compared to control patients. In the appropriate clinical scenario, the use of these drugs remains justified in their approved indications.

Conditional Survival of Patients With Metastatic Testicular Germ Cell Tumors Treated With First-Line Curative Therapy

PURPOSE The International Germ Cell Cancer Collaborative Group (IGCCCG) criteria prognosticate survival outcomes in metastatic testicular germ cell tumor (MT-GCT), but how the initial risk changes over time for those who survived since curative treatment is unknown. PATIENTS AND METHODS We assessed patients eligible for first-line therapy for MT-GCT at five tertiary cancer centers from 1990 to 2012 for 2-year conditional overall survival (COS) and conditional disease-free survival (CDFS), defined as the probability of surviving, or surviving and being disease free, respectively, for an additional 2 years at a given time point since the initial diagnosis. RESULTS For all patients (N = 942), 2-year COS increased from 92% (95% CI, 91% to 94%) at 0 months to 98% (95% CI, 97% to 99%), and 2-year CDFS increased from 83% (95% CI, 81% to 86%) at baseline to 98% (95% CI, 97% to 99%) at 24 months after diagnosis. Two-year COS improved by 2% (97% at 0 months, 99% at 24 months) in the IGCCCG favorable-risk group, by 5% (94% at 0 months, 99% at 24 months) in the intermediate-risk group, and by 22% (71% at 0 months to 93% at 24 months) in the poor-risk group. Two-year CDFS improved significantly at 12 months for each risk group (favorable, 91% baseline v 95% at 12 months; intermediate, 84% v 95%; poor, 55% v 85%). Baseline IGCCCG risk stratification was not associated with long-term COS or CDFS for patients who survived to greater than 2 years post therapy. No significant differences in COS and CDFS were noted between seminoma and nonseminoma; patients ≥ 40 years old had inferior 2-year COS from 0 to 12 months, but no differences were noted at 18 months. CONCLUSION Our data suggest that the concept of conditional survival applies to patients with MT-GCT treated with curative therapy. Patients with MT-GCT who survived and remained disease free more than 2 years after the diagnosis had an excellent chance of staying alive and disease free in additional subsequent years, regardless of the initial IGCCCG risk stratification.

1052PDNIVOLUMAB (N) (ANTI-PD-1; BMS-936558, ONO-4538) IN COMBINATION WITH SUNITINIB (S) OR PAZOPANIB (P) IN PATIENTS (PTS) WITH METASTATIC RENAL CELL CARCINOMA (MRCC)

ABSTRACT Aim: Antiangiogenic agents S and P are standard of care in mRCC, but effects are not durable. N, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, has clinical activity in mRCC. VEGF TKIs have been shown to suppress Tregs and MDSCs making the immune environment more conducive for T cell-mediated antitumor activity. Combining VEGF TKIs with positive immune modulation may result in greater and more durable therapeutic benefit. We report preliminary results of a phase I trial of N in combination with S or P in mRCC. Methods: mRCC pts received N in combination with S (50 mg, 4 wk on/2 wk off; arm S) or P (800 mg daily; arm P) until progression/unacceptable toxicity. Starting dose of N was 2 mg/kg IV every 3 wk (N2), with planned escalation to 5 mg/kg IV every 3 wk (N5). Based on tolerability, arm S N5 was expanded to treatment-naive pts. Primary objectives were safety/tolerability and determination of maximum tolerated dose (MTD) for the combinations; secondary objective was antitumor activity. Results: 7 pts each were treated on arms S N2 and N5. No dose-limiting toxicities (DLTs) were observed and MTD was not reached; thus N5 was expanded by 19 pts (total n = 33). Arm P had 20 pts at N2; 4 DLTs (elevated ALT/AST [n = 3], fatigue [n = 1]) were observed, leading to closure of the arm. Grade 3-4-related adverse events (AEs) were observed in 27/33 pts (82%) in arm S and 14/20 pts (70%) in arm P. Most common related grade 3-4 AEs were elevated ALT and hypertension (18% each), hyponatremia and lymphocyte count decreased (15% each) in arm S, and elevated ALT and AST, and diarrhea (20% each) and fatigue (15%) in arm P. Grade 3 pneumonitis occurred in 1 pt (arm S, N5). Grade 3-4-related AEs led to discontinuation in 10/33 pts (30%; 2 N2, 8 N5) in arm S and 4/20 pts (20%) in arm P. Objective response rate was 52% (17/33) in arm S and 45% (9/20) in arm P. Responses occurred by first assessment (6 wk) in 41% (arm S) and 56% (arm P) of pts. Duration of response (wk) was 18.1-80+ in arm S and 12.1-90.1+ in arm P. Progression-free survival rate at 24 wk was 79% for arm S and 55% for arm P. Conclusions: N plus S showed encouraging antitumor activity and a manageable safety profile in pts with mRCC. Arm P was closed due to DLTs. Disclosure: A. Amin: I have worked as a consultant/ in an advisory capacity to: Bristol Myers Squibb I have received Honoraria from: Bristol Myers Squibb; E.R. Plimack: I have received grants and/or personal fees from: BMS, GSK, Dendreon, Astellas, Pfizer, Amgen, Acceleron, MedImmune, Merck, Lilly, AZ; M. Ernstoff: I have received funding for research from Bristol Myers Squibb, and hold stocks in BMS; B.I. Rini: I have consulted for the following companies: Pfizer, BMS, Merck, GSK; received funding for research from: Pfizer, BMS, Immatics, GSK, Roche, Acceleron; D.F. McDermott: I have received honoraria from and worked as a consultant/ in an advisory capacity to Bristol-Myers Squibb; M. Voss: Dr. Voss reports grants from BMS, outside the submitted work; P. Sharma: I have served as a consultant for: MedImmune, GSK, BMS, Jounce, Janssen, Pfizer, and Helsinn Therapeutics. I also own stock in Jounce; D. Heng: Has worked as a consultant for the following: BMS, Bayer, Pfizer, Novartis; Y. Shen: I am an employee of Bristol-Myers Squibb, and immediate family member employed at BMS; J. Kurland: I am an employee of and have stock or other ownership interest in BMS; P. Gagnier: I am an employee of and have stock or other ownership interest in BMS; H. Hammers: Has received Honoraria from Ono Pharma USA. All other authors have declared no conflicts of interest.

A population-based overview of sequences of targeted therapy in metastatic renal cell carcinoma (mRCC).

387 Background: There are several types of targeted therapy (TT) available to treat mRCC and data on outcomes and different sequences of therapies are required. METHODS Consecutive series of patients with mRCC treated with TT were examined. Multivariable analysis was performed when significant differences on univariable analysis were seen. RESULTS 2106 patients were included with a median follow-up of 36 months. 907 (43%) and 318 (15%) patients received subsequent second-line and third-line TT, respectively. Baseline characteristics of the groups below were not different except there were more patients with non-clear cell histology in the VEGF to mTOR group compared to the VEGF to VEGF group. When adjusting for the Heng et al poor risk criteria and non-clear cell histology, the hazard ratio of death for the VEGF to mTOR group vs the VEGF to VEGF group was 0.833 (95%CI 0.669-1.037, p=0.1016). When adjusting for poor risk criteria, the hazard ratio of death for the sunitinib to everolimus vs sunitinib to temsirolimus sequences was 0.774 (0.52-1.153, p=0.2086). CONCLUSIONS The sequence of TT may not have a substantial effect on outcome but results of prospective randomized studies are awaited. [Table: see text].

Anti-VEGF therapy in mRCC: differences between Asian and non-Asian patients

Background:Several reports suggest that vascular endothelial growth factor (VEGF)-targeted therapy in metastatic renal cell carcinoma (mRCC) may be more toxic in Asian vs non-Asian populations. Comparative efficacy of these agents with respect to ethnicity is not well characterised.Methods:A multicentre, retrospective, cohort study using Asian and non-Asian centres which collected data on ethnicity, dose reductions and outcomes using the International mRCC Database Consortium.Results:This study included 1024 (464 Asian, 560 non-Asian) patients with a 29.4 months median follow-up. The percentage of dose modifications/reductions between non-Asians and Asians was similar (55% vs 61% P=0.1197). When adjusted for risk groups, there was no difference in overall or progression-free survival between non-Asians and Asians. Patients with dose reductions due to toxicity had longer treatment durations and overall survival than those who did not in both non-Asian (10.6 vs 5.0 months, P<0.0001; 22.6 vs 16.1 months, P=0.0016, respectively) and Asian populations (8.9 vs 5.4 months, P=0.0028; 28.0 vs 18.7 months, P=0.0069, respectively).Conclusions:Adjusting for risk groups, there appears to be no difference in outcome between Asian vs non-Asian patients with mRCC treated with VEGF-targeted therapy. Judicious dose reductions may allow for better outcomes in both populations due to longer treatment durations, but direct comparisons are needed.

Using the Delphi Technique to Improve Clinical Outcomes Through the Development of Quality Indicators in Renal Cell Carcinoma

PURPOSE Optimal quality of care is needed for ideal outcomes. In renal cell carcinoma (RCC), there is a lack of information defining optimal care. This is particularly important in RCC, with increased complexity of care and a need for coordination among providers. The goal of this study was to identify quality indicators (QIs) and measures of quality care across the RCC disease spectrum. MATERIALS AND METHODS A modified Delphi technique was used to select QIs that are relevant and practical to RCC care. This technique involved an expert panel of 13 urologic and medical oncologists who participated in two e-mail questionnaires and an in-person meeting to review and prioritize potential QIs. These potential QIs were identified from a systematic literature review or were suggested by panel members. RESULTS From 233 literature citations, 34 possible QIs were identified; 24 additional potential QIs were suggested. A final set of 23 QIs was established. These are distributed across the RCC disease spectrum as follows (number of QIs in parentheses): screening (n=1), diagnosis/prognosis (n=3), surgical for localized disease (n=6), surgery for advanced disease (n=3), systemic therapy (n=6), and follow-up (n=2). In addition, two QIs related to survival outcomes (overall and progression-free survival) were selected. CONCLUSION A systematic, consensus-based approach was used to determine relevant QIs in RCC care. These 23 QIs will provide a means of evaluating the quality of RCC care in an effort to improve outcomes in patients. The next step will be to establish a means of measuring each QI based on defined or yet-to-be-defined benchmarks.