885P Are adverse events (AEs) predictive of nivolumab activity? Data from the Italian expanded access program in metastatic renal cell carcinoma (mRCC) E. Verzoni1 , G. Cartenı2 , E. Cortesi3 , F. Roila4 , M.G. Vitale5 , S. Buti6 , S. Pignata7 , F. Cognetti8 , L. Giustini9 , A. Damiani10 , D. Turci11 , C.N. Sternberg12 , C. Porta13 , F. Carrozza14 , G. Tortora15 , D. Tassinari16 , R. Passalacqua17 , A. Pazzola18 , G. Surico19 , G. Procopio20 1
Medical Oncology-Genitourinary Unit, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano - Fondazione IRCCS, Milan, Italy,2
Oncology Unit, A. Cardarelli Hospital, Naples, Italy, 3
Radiology , Oncology and Pathology, Policlinico Umberto I, Rome, Italy,4 Medical Oncology, Azienda Ospedaliera Sta Maria, Terni, Italy,5
Dipartimento di Oncologia ed Ematologia, Azienda Ospedaliero - Universitaria Policlinico di Modena, Modena, Italy, 6
Medical Oncology, Azienda Ospedaliera di Parma, Parma, Italy,7
Urology and Gynecology, Istituto Nazionale Tumori – I.R.C.C.S - Fondazione Pascale, Naples, Italy,8
Medical Oncology, Istituto Regina Elena, Rome, Italy,9
Medical Oncology, UOC Oncologia Area Vasta 4, Fermo, Italy,10
Medical Oncology, San Martino Hospital, Genoa, Italy,11 Medical Oncology, Ospedale Sta Maria delle Croci, Ravenna, Italy,12
Medical Oncology, Azienda Ospedaliera S. Camillo Forlanini, Rome, Italy,13
Medical Oncology, Ospedale San Matteo, Pavia, Italy,14
Medical Oncology, Ospedale Umberto I (AUSL Romagna), Lugo, Italy,15
Medical Oncology, AOU Integrata Verona "Borgo Roma", Verona, Italy, 16
Oncology, Ospedale Infermi, Rimini, Italy,17
Medical Oncology, Istituti Ospitalieri di Cremona, Cremona, (CR), Italy,18
Medical Oncology, Ospedale Civile SS Annunziata, Sassari, Italy,19
Medical Oncology, Ospedale Vito Fazzi, Lecce, Italy,20
Medical Oncology-Genitourinary Unit, Fondazione IRCCS - Istituto Nazionale dei Tumori, Milan, Italy Background: The Italian Renal Cell Cancer Early Access Program was an expanded access program that allowed access to nivolumab, for patients (pts) with mRCC prior to regulatory approval.
Methods: Pts with mRCC previously treated with agents targeting the vascular endo-thelial growth factor pathway were eligible to receive nivolumab 3 mg/kg once every 2 weeks. Pts included in the analysis had received 1 dose of nivolumab and were moni-tored for adverse events (AEs) using CTCAE v.4.0. Association between sex, age, BMI, metastatic sites, number and kind of previous therapies, ECOG PS and related toxicity were evaluated with a logistic regression model that identified only age 65 years (Odds Ratio¼ 1.54 (1.00-2.38; P ¼ 0.05).
Results: A total of 389 pts were enrolled between July 2015 and April 2016, 79% after 2 or more lines of therapy. The most common any-grade treatment-related AEs were fatigue (13%) and rash (9%). Twenty-two (5.7%) pts discontinued treatment due to AEs. There were no treatment-related deaths. Treatment-related AEs (grade 1-4) were reported in 32% of pts. Median time to appearance of AEs was 1.4 months (range 0-11.4). Grade 3–4 AEs occurred in 27 (7%) pts. Of the 22 serious AEs who induced treat-ment discontinuation, 11 (50%) were considered irAEs including: grade 4 hyperglice-mia (n¼ 1), grade 3 diarrhea (n ¼ 1), grade 3 pulmonitis (n ¼ 1), grade 3 bronchiolitis obliterans organising pneumonia (BOOP) (n¼ 1), grade 3 asthenia (n ¼ 1), grade 3 hypertension (n¼ 1), grade 3 skin toxicity (n ¼ 1), grade 3 tremor (n ¼ 1), grade 2 eye-lid ptosis (n¼ 1), grade 2 liver toxicity (n ¼ 1), grade 2 hypothyroidism (n ¼ 1). AEs were generally manageable with treatment as per protocol-specific guidelines. At a median follow-up of 12 months, the median progression-free survival was 4.5 months (95% CI 3.7 - 6.2), the 12-months overall survival rate was 63%. Pts with toxicity (124 pts) had a significant (P¼ 0.01) longer survival (1 year OS 69%) in comparison to pts who did not experience AEs (1 year OS 59%).
Conclusions: The appearance of AEs strongly correlates with survival benefit in a real-life population of mRCC pts treated with Nivolumab.
Legal entity responsible for the study: Italian Renal Cell Cancer Early Access Program Group.
Funding: BMS.
Disclosure: E. Verzoni: Honoraria/Consultancy: Novartis, Pfizer, Ipsen, BMS. C.N. Sternberg: Honoraria/Consultancy: Novartis, Pfizer, Ipsen, Eisai, BMS. G. Procopio: Honoraria/Consultancy: Ipsen, BMS, Pfizer, Novartis. All other authors have declared no conflicts of interest.
886P Adiponectin-AdipoR1 axis in renal cell carcinoma plays a pivotal role in tumor progression and drug resistance
G. Sun, X. Zhang, J. Zhao, J. Chen, P. Shen, Z. Liu, H. Zeng Urology, West China Hospital, Sichuan University, Chengdu, China
Background: It is well established that renal cell carcinoma (RCC) is an obesity-associ-ated cancer. Adiponectin, a major adipocyte-secreted adipokine, plays anti-tumor properties in many malignancies, but exerted paradoxical actions on RCC. Herein, we investigated the effects of adiponectin on RCC progression and resistance to sunitinib, and to exploit this molecular mechanism.
Methods: Tissues were collected from 126 patients with metastatic renal cell carcinoma (mRCC) treated with tyrosine kinase inhibitor (TKI) therapy. Tumor Adiponectine receptor 1 (AdipoR1) and Adiponectine receptor 2 (AdipoR2) were detected by immu-nohistochemistry. Assays with RCC cell lines were used to examine the signal transduc-tion pathways of adiponectin in RCC.
Results: AdipoR2 was generally lower expressed than AdipoR1 in mRCC tumor (15.6% vs 89.1%, p < 0.001). AdipoR1 expression, but not AdipoR2, was a significant
independent predictor of favorable responding to TKI and good survival outcomes. In cultured RCC cells adiponectin inhibited migration and invasion of RCC cells and sen-sitized cells to killing by sunitinib. Mechanistic investigations of ligand–receptor inter-actions revealed that AdipoR1 could hinder migration and invasion of RCC cells by blocking GSK3b and b-Catenin pathway and increase cells sensitivity to sunitinib through inhibiting AKT and NF-jB pathway. However, AdipoR2 was not associated with the tumor-limiting properties of adiponectin.
Conclusions: These results show that AdipoR1 is a potential prognostic marker for favorable outcomes of mRCC patients. Adiponectin-AdipoR1 axis could be a plausible target to impede tumor progression and sensitize tumors to TKI therapy.
Legal entity responsible for the study: Guangxi Sun.
Funding: National Natural Science Foundation of China (NSFC 81672547, 81402110), the Science and Technology Support Program of Sichuan Province (2015SZ0230-3) and 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University.
Disclosure: All authors have declared no conflicts of interest.
887P Identification of IMDC intermediate-risk subgroups in patients with metastatic clear-cell renal cell carcinoma (ccRCC)
A. Guida1 , G. Le Teuff2 , E. Colomba3 , G. Baciarello3 , L. Derosa4 , Y. Loriot3 , K. Fizazi3 , C. Massard5 , B. Escudier3 , L. Albiges3 1
Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy,2
Statistics, Gustave Roussy, Villejuif, France,3 Department of Medical Oncology, Gustave Roussy, Villejuif, France,4
INSERM, Gustave Roussy, Villejuif, France,5
DITEP, Gustave Roussy Institut de Cance´rologie, Villejuif, France Background: Majority of patients (pts) with ccRCC at first line (1L) treatment are clas-sified in the IR subgroup according to International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model. IR represents a heterogeneous class of pts while frontline strategies will be chosen on prognostic selection. The aim of this study is to better characterize IR pts.
Methods: Retrospective analysis was performed from IGReCC (Institut Gustave Roussy Renal Cell Carcinoma) database. Overall survival (OS) was defined from start of 1L therapy to death or last follow-up. A multivariable Cox model with backward selection procedure (alpha level¼ 0.01) and a Classification and Regression Tree (CART) analysis were performed to identify which prognostic factors of IMDC score (time from diagnosis to treatment [DDT] < 1 year, Karnofsky Performance Status [KPS] < 80%, Hemoglobin < lower limit of normal [LNL], neutrophils > upper nor-mal level [UNL], platelet > UNL, calcium > UNL) were associated to OS in IR pts. Results: From 2005 to 2016, 777 pts with ccRCC were treated with an anti-VEGF first line therapy. Among 571 evaluable pts for IMDC score, 199 (35%) pts were classified as good risk, 82 (14%) as poor risk and 290 (51%) as IR. Median OS for IR pts was 24 months (mo). Within the IR population, only platelet (PLT) count was significantly associated to OS with a hazard ratio 1.88 (95%CI 1.27-2.88) p¼ 0.0017. Median OS for pts with PLT > UNL was 18 months (mo) [95%CI 12-23] versus 29 mo [95%CI 21.4-35.7] for pts with normal PLT count. Therefore, the selection of PLT count was con-firmed on bootstrap samples and was also selected for the first split of the CART-tree analysis.
Conclusions: Pts in the IR group have a heterogeneous prognosis. Elevated PLT count seems identifies a subgroup of pts with poor outcome in the IMDC intermediate-risk population with ccRCC.
Legal entity responsible for the study: Laurence Albiges. Funding: Has not received any funding.
Disclosure: All authors have declared no conflicts of interest.
888P Lesion detection by ceCT, 89Zr-girentuximab and FDG PET/CT in newly diagnosed patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) S.R. Verhoeff1 , S. Es2 , E. Boon1 , E. van Helden3 , L. Angus4 , S. Elias5 , S. Oosting2 , E. Aarntzen6 , A. Brouwers2 , S. Heskamp6 , O.S. Hoekstra7 , H.M. Verheul3
, A.A.M. Van der Veldt4
, E.G.E. de Vries2
, O. Boerman6
, W.T.A. van der Graaf8
, W.J.G. Oyen1 , C.M.L. van Herpen1
1
Medical Oncology, Radboud University Medical Centre Nijmegen, Nijmegen, Netherlands,2
Medical Oncology, University Hospital Groningen (UMCG), Groningen, Netherlands,3
Medical Oncology, Vrije University Medical Centre (VUMC), Amsterdam, Netherlands,4
Medical Oncology, Erasmus University Medical Center, Rotterdam, Netherlands,5
Epidemiolgy, Julius Center of Health Academy, Utrecht, Netherlands, 6
Radiology and Nuclear Medicine, Radboud University Medical Centre Nijmegen, Nijmegen, Netherlands,7
Radiology & Nuclear Medicine, Vrije University Medical Centre (VUMC), Amsterdam, Netherlands,8
Division of Clinical Studies, Royal Marsden Hospital Institute of Cancer Research, Sutton, Surrey, UK
Background:As slow disease progression is observed in a subset of mccRCC patients, watchful waiting can be considered, thereby postponing toxicity of systemic treatment. To identify those patients, the IMPACT trial evaluated the role of anti-Carbonic
abstracts
Annals of Oncology
viii314 | Genitourinary tumours, non-prostate
Volume 29 | Supplement 8 | October 2018
Anhydrase IX antibody89Zr-girentuximab and18F-fluorodeoxyglucose (FDG) PET/ CT (PET). Here, we report preliminary analyses of a secondary endpoint: comparison of baseline contrast-enhanced(ce)CT,89Zr-girentuximab and FDG PET to detect metastases.
Methods:mccRCC pts with good or intermediate prognosis (according to IMDC) and eligible for watchful waiting were included. Patients underwent 3 scans, i.e. ceCT,89 Zr-girentuximab and18F-FDG PET. So far, baseline scans of 29 of the 40 pts to be accrued were independently reviewed by 3 experienced readers. Lesions by ceCT were defined positive according to RECIST1.1. For lesions with prominent uptake of89 Zr-girentuxi-mab or18F-FDG, maximum Standardized Uptake Values (SUVmax) were calculated. Analyses were performed on a lesion level, taking clustering of data within patients and lesions into account.
Results:In total 325 lesions were detected by at least one modality (mean 11(2-33) per pt); ceCT detected 52% (95%CI:45;58),18F-FDG PET 61% (95%CI:55;67) and89 Zr-girentuximab PET 69% (95%CI:63;74). Differences in lesion detection varied across organ sites(p < 0.001). Lesions were visualized by ceCT and18F-FDG PET in all pts,whereas89Zr-girentuximab PET detected lesions in 27 of 29 pts. Compared to ceCT,89Zr-girentuximab PET visualized additional lesions in all organ sites. Location was strongly related with89Zr-girentuximab uptake; highest uptake in kidney and adre-nal gland tumor (mean SUVmax 63.2 and 70.3, resp) and lowest uptake in lung and lymph nodes (mean SUVmax 10.9 and 15.0, resp). After correction for location, no relation was observed between89Zr-girentuximab SUVmax and tumor size, as meas-ured by ceCT, and18F-FDG SUVmax.
Conclusions:89Zr-girentuximab and18F-FDG PET visualize additional lesions com-pared to ceCT, however correlation was poor. The addition of89Zr-girentuximab or 18F-FDG PET might aid in deciding to either delay or start systemic treatment. Clinical trial identification:NCT02228954.
Legal entity responsible for the study:Radboud University Medical Center (Radboudumc).
Funding:Supported by the Dutch Cancer Society. Disclosure:All authors have declared no conflicts of interest.
889P Clinical outcomes of patients with metastatic renal cell carcinoma (mRCC) treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKI) and mammalian target of rapamycin inhibitors (mTORI) after immuno-oncology (IO) checkpoint inhibitors J. Graham1 , J.C. Wells1 , R. McKay2 , U.N. Vaishampayan3 , A. Hansen4 , F. Donskov5 , G.A. Bjarnason6 , B. Beuselinck7 , G. De Velasco8 , M.S. Duh9 , L. Huynh9 , R. Chang9 , G. Zanotti10 , K. Ramaswamy10 , T.K. Choueiri11 , D.Y.C. Heng1 1
Medical Oncology, University of Calgary, Calgary, AB, Canada,2
Medical Oncology, University of California San Diego, San Diego, CA, USA,3
Oncology, Karmanos Cancer Institute, Detroit, MI, USA,4
Medical Oncology, Princess Margaret Hospital, Toronto, ON, Canada,5
Department of Oncology, Aarhus University Hospital, Aarhus, Denmark, 6
Medical Oncology, Sunnybrook Odette Cancer Center, Sunnybrook HSC, Toronto, ON, Canada,7
General Medical Oncology, University Hospitals Leuven, Leuven, Belgium, 8
Medical Oncology, University Hospital 12 de Octubre, Madrid, Spain,9 Health Economics and Outcomes Research, Analysis Group, Inc, Boston, MA, USA,10
Global HEOR, Oncology, Pfizer, Inc., New York, NY, USA,11
Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Background: In an era of increasing treatment options for mRCC, optimal treatment sequence after IO therapy has not been well established. This study compares the effect of targeted therapy (TT) (VEGFR TKI [axitinib, sunitinib, cabozantinib, pazopanib, bevacizumab, and sorafenib] vs mTORI [everolimus and temsirolimus]) after progres-sion on IO therapy.
Methods: Data from 7 International mRCC Database Consortium (IMDC) centers were used to examine time to treatment discontinuation (TTD: time from TT initiation to discontinuation for any reason) and objective response rate (ORR: complete or par-tial tumor response) among mRCC patients (pts) treated with TT after IO between 2010-2018. Kaplan Meier analysis and Cox proportional hazards model adjusting for age, sex, IMDC risk score, and line of therapy were conducted. Overall survival will be reported when data is more mature.
Results: Pts treated with VEGFR TKI (N¼ 156 [85%]) and mTORI (N ¼ 28 [15%]) post IO had similar age and IMDC risk scores (mean age: 61 vs 63 years; IMDC favor-able: 5% vs 8%; IMDC intermediate: 62% vs 48%). Most common TT post IO were axi-tinib (35%), cabozanaxi-tinib (18%), and suniaxi-tinib (15%). Unadjusted median TTD was significantly longer for VEGFR TKI vs mTORI (5.3 vs 2.5 months, p¼ 0.002). VEGFR TKI vs mTORI post IO was significantly associated with a longer TTD (adjusted hazard ratio [aHR]: 0.44, p¼ 0.002). A trend toward better TTD with axitinib post IO vs other TT was observed (aHR: 0.66, p¼ 0.08). ORR was numerically higher in VEGFR TKI vs mTORI. Reported results are across all lines of therapy. The table has descriptive statistics.
Table: 889P Descriptive statistics of clinical outcomes among patients treated with targeted therapy (i.e., VEGFR TKI, mTORI) subsequent to IO treatment
Total N Number of treatment
dis-continuation for any reason
(%) Median TTD, (95% CI) months Objective response rate1N (%) All 184 118 (64) 4.9 (4.0, 5.6) 20 (17) By class VEGFR TKI2 All lines 156 93 (60) 5.3 (4.3, 6.9) 19 (20) 2nd line 44 28 (64) 3.8 (3.2, 5.4) 7 (23) 3rd line 72 43 (60) 5.7 (4.3, 9.8) 10 (22) 4th line 40 22 (55) 6.1 (4.2, 10.9) 2 (10) mTORI3 All lines 28 25 (89) 2.5 (1.4, 3.4) 1 (5) 2nd line 0 - - -3rd line 20 19 (95) 2.3 (1.0, 4.9) 1 (6) 4th line 8 6 (75) 3.2 (1.3, 4.9) 0 (0)
IO: immuno-oncology; VEGFR TKI: vascular endothelial growth factor receptor tyrosine kinase inhibitor; mTORI: mammalian target of rapamycin inhibitor; CI: confidence interval; ORR: objective response rate; TTD: time to treatment discontinuation Notes: [1] Objective response rate, defined as the sum of partial responses and complete responses, was assessed during the line of targeted therapy subsequent to IO treatment. The total number of patients assessed was 116. [2] VEGFR TKI included axitinib, sunitinib, cabozantinib, pazopanib, bevacizumab, and sorafenib. [3] mTORI included everolimus and temsirolimus.
Conclusions: Subsequent to IO therapy, VEGFR TKI pts had significantly longer adjusted TTD than mTORI pts. When larger sample sizes are available for TT, further examination of sequences is warranted.
Legal entity responsible for the study: Pfizer, Inc. Funding: Pfizer, Inc.
Disclosure: R. McKay: Research funding: Pfizer and Bayer; Ad board: Janssen, Novartis. U.N. Vaishampayan: Research funding, Honoraria, and Consulting: Pfizer. A. Hansen: Research funding: Genentech/Roche, Merck, GlaxoSmithKline, Bristol Myers Squibb, Novartis; Advisory board: Pfizer, Roche, Merck, AstraZeneca, Ipsen, Bristol Myers Squibb. F. Donskov: Research funding: Pfizer, Novartis, Ipsen. G.A. Bjarnason: Research funding: Pfizer, Merck; Honoraria: Pfizer, Novartis, Bristol-Myers Squibb, Eisai, Ipsen; Consulting: Pfizer, Novartis, Bristol-Myers Squibb, Eisai, Ipsen; Travel funding: Pfizer, Novartis. B. Beuselinck: Research funding: Pfizer; Speaker’s fee: Ipsen, Amgen, Pfizer. G. De Velasco: Research funding: Ipsen; Consulting or advisory role: Janssen, Pfizer, Novartis, Bayer, Astellas Medivation, Bristol-Myers-Squibb, Pierre Fabre. M.S. Duh, L. Huynh: M. Duh R. Chang: Employee of Analysis Group, which received funding from Pfizer for this project. G. Zanotti, K. Ramaswamy: Employee of Pfizer. T.K. Choueiri: Research funding: AstraZeneca, BMS, Exelixis, Genentech, GSK, Merck, Novartis, Peloton, Pfizer, Roche, Tracon, Eisai; Consulting and Advisory Role: AstraZeneca, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc., Exelixis, Genentech, Roche, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Labs, Corvus, Ipsen. D.Y.C. Heng: Consultancies and Honoraria: Pfizer, Novartis, BMS, Ipsen. All other authors have declared no conflicts of interest.
