Are immune checkpoint inhibitors a valid option for papillary renal cell carcinoma? Transcriptomic characterization of the immune infiltrate

abstracts

Annals of Oncology

to-TRT was 2.5 mo (95%CI 2.1-3.3; 74.7% events) and median overall survival was 20.1 mo (95%CI 18.0-NE; 35.8% deaths). Both endpoints were not associated to sarcopenia at CABO start. Conclusions: We reported the first cohort assessing sarcopenia in pt treated with CABO for mRCC. Baseline sarcopenia is underestimated in this setting. Furthermore, half of non-sarcopenic patients at baseline develop sarcopenia during treatment requiring physician awareness and interventional studies. Legal entity responsible for the study: The authors. Funding: Onco-urology department of Gustave Roussy. Disclosure: E. Colomba: Travel / Accommodation / Expenses: BMS; Travel / Accommodation /

968P

Long term relative survival (RS) in patients with primary metastatic kidney cancer (primary mRCC): An analysis of 2,167 patients from the Austrian National Cancer Registry (ANCR)

M. Hackl1, H. Karim-Kos2, S. Madersbacher3, M. Rauchenwald4, M. Marszalek4 Austrian National Cancer Registry, Statistic Austria, Vienna, Austria, 2Department of Public Health, Erasmus MC University Medical Center, Rotterdam, Netherlands, 3 Urology, KFJ, Vienna, Austria, 4Urology, Sozialmedizinisches Zentrum Ost Donauspital, Vienna, Austria

1

Background: The introduction of thyrosinkinase inhibitors (TKI) changed the treatment of mRCC. To elaborate the potential impact of TKI therapies, we studied trends in OS for patients diagnosed with primary mRCC between 1998 - 2015 in Austria. Methods: All patients with primary mRCC (18 years), diagnosed from 1998 - 2015 were derived from the ANCR (n ¼ 2,490). Patients diagnosed from 2004-2005 (n ¼ 323) were excluded (transition period of systemic therapies). To evaluate survival differences between patients treated before and after the introduction of Sunitinib (preTKI-era and TKI-era), 3 periods were defined: 1998 - 2003 (preTKI-era; N ¼ 937), 2006 - 2010 (TKI-era P1; N ¼ 687) and 2011 - 2015 (TKI-era P2; N ¼ 543). Follow-up was complete until Dec. 31st, 2016. The Cox proportional hazard model was used to calculate hazard ratios (HR). Results: A total of 2,167 patients were included, median age was 70 yrs in the 3 eras. The incidence of T1 tumors increased from 6.9% in the preTKI-era to 10% in the TKIera while T4 tumors decreased from 15% to 8% (p <.001). Surgery rate declined from 50% in the preTKI-era to 43% in 2011-2015 (p ¼.02). 5-year RS for patients undergoing surgery slightly increased from 18% in the preTKI-era to 23% in TKI-era P1 (p ¼.04). For patients without surgery 5-year OS improved from 5.2% in the preTKI-era to 9.1% in TKI-era P1 (p <.001). Further survival gain was observed in patients < 75 yrs of þ 6% (p ¼.01), patients > ¼ 75 years of þ 0.2% (p ¼.03) and for T3/T4 tumors of þ 6% (p ¼.002). The Relative Excess Risk of dying (RER) for patients treated in the TKI-eras was reduced compared to the preTKI-era (HR 0.78, 95% CI 0.76-0.95) adjusted for sex, age, T-stage and surgery. Survival advantage for patients undergoing surgery remained significant (HR: 0.46, 95% CI 0.41-0.52) after adjustment for TKIera, sex, age, T-stage. Conclusions: Patients treated in the TKI era show improved RS compared to the cytokine era. Most benefit was observed in non-surgical patients, younger patients and for T3/T4 disease. Surgery contributed to an additional survival benefit. Legal entity responsible for the study: Priv. Doz. Dr. Martin Marszalek. Funding: Pfizer Austria. Disclosure: All authors have declared no conflicts of interest.

Background: For patients (pts) with advanced or metastatic renal cell carcinoma (mRCC), approval of novel therapies led to continuous changes in treatment options. The Tumour Registry Renal Cell Carcinoma (TNK) analysed treatment and outcome of pts treated in Germany from 2007-2017. CARAT is the successor registry, which continues to assess longitudinal real world clinical outcome, incl. patient-reported outcomes (PROs) and decentralized biobanking. Today, we introduce CARAT and report on current changes of the treatment landscape in mRCC in Germany. Methods: Since Dec 2017 150 pts have been enrolled in CARAT, expanding the previous TNK (2007-17, 1500 pts). CARAT is an observational, prospective, open, multicentre clinical research platform aiming to enrol 1000 pts by 150 sites. Pts with mRCC who start systemic 1stline treatment are eligible. Treatment characteristics, clinical outcome and physician-reported factors on treatment decision making are collected. Overall survival (OS) is assessed by the KM-method. Changes of the treatment landscape are shown descriptively. Results: By April 2019 >1650 pts with mRCC have been recruited. Median age is 68 years. 60% had intermediate risk (MSKCC) at start of 1st-line. Median OS for pts with start of 1st-line 2007-17 is 19 months (>60% events). If selected by trial eligibility criteria, the median OS is 27 months. Pts who started treatment in 2018 mostly received pazopanib or sunitinib (38%/34%). Since the approval (May 2018) 18% are treated with cabozantinib. Preferred 2nd-line treatment changed from sorafenib/temsirolimus (35%/21%, 2007-09), everolimus (33% 2010-12), everolimus/axitinib/sunitinib (29%/ 19%/18%, 2013-15) to nivolumab (>60% since 2016). The impact of new treatment options on OS will be analysed. Conclusions: Pts in routine care in Germany are older and have inferior prognosis than trial-eligible pts. CARAT complements results of RCTs with prospective data on clinical and PROs for pts with mRCC in routine care. CARAT will show changes in the choice of treatment due to new approvals, applied sequences and investigate the effectiveness in a “real world” setting. For the first time, these data will be combined with PROs and a decentralized biobank for translational research. Legal entity responsible for the study: IOMEDICO. Funding: Ipsen. Disclosure: P.J. Goebell: Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: Astellas; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Janssen; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self): IOMEDICO. M. Bo¨gemann: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Janssen; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Astellas; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ipsen; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Eisai; Honoraria (self), Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Eusa Pharma; Honoraria (self), Advisory / Consultancy: ABX; Honoraria (self), Advisory / Consultancy: Sanofi; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: Amgen. S. Do¨rfel: Shareholder / Stockholder / Stock options: IOMEDICO. N.W. Marschner: Advisory / Consultancy, Leadership role, Research grant / Funding (institution), Shareholder / Stockholder / Stock options: IOMEDICO; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ipsen. M. Staehler: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Pfizer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Novartis; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): GSK; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche. V. Gru¨nwald: Honoraria (self), Research grant / Funding (self), Shareholder / Stockholder / Stock options, Non-remunerated activity/ies: MSD; Research grant / Funding (self): Novartis; Honoraria (self), Research grant / Funding (self), Shareholder / Stockholder / Stock options: AstraZeneca; Honoraria (self), Research grant / Funding (self), Shareholder / Stockholder / Stock options, Non-remunerated activity/ies: BMS; Honoraria (self), Non-remunerated activity/ies: Merck Serono; Honoraria (self): Roche; Honoraria (self): Pfizer; Honoraria (self): Lilly; Honoraria (self), Non-remunerated activity/ies: PharmaMar; Honoraria (self): Nanobiotix; Honoraria (self): Janssen. All other authors have declared no conflicts of interest.

970P 969P

Advanced renal cell carcinoma: First results from the prospective research platform CARAT for patients with mRCC in Germany 1

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3

4

5

6

P.J. Goebell , L. Mueller , C. Gru¨llich , D. Reichert , M. Bo¨gemann , S. Do¨rfel , E. von der Heyde7, A. Binninger8, M. J€anicke8, M. Merling8, N.W. Marschner9, M. Staehler10, V. Gru¨nwald11 1 Urology, Urologische und Kinderurologische Universit€ atsklinik Erlangen, Erlangen, Germany, 2Onkologie UnterEms Leer Emden Papenburg, Onkologische 3 Schwerpunktpraxis Leer-Emden, Leer, Germany, Klinik und Poliklinik fu¨r Urologie, 3Universit€atsklinikum Carl Gustav Carus, Dresden, Baden Wu¨rttemberg, Germany, 4 Onkologie, Gemeinschaftspraxis fu¨r H€ amatologie und Onkolgie, Westerstede, atsklinikum Mu¨nster Ao¨R, Germany, 5Klinik fu¨r Urologie, Kinderurologie, Universit€ 6 Mu¨nster, Germany, Hematology and Oncology, Onkozentrum Dresden, Dresden, 7 Germany, Oncology, Onkologische Schwerpunktpraxis, Hannover, Germany, 8Clinical Epidemiology and Health Economics, IOMEDICO, Freiburg, Germany, 9Oncology, Praxis fu¨r Interdisziplin€are Onkologie & H€ amatologie, Freiburg, Germany, 10Oncology,

v392 | Genitourinary Tumours, Non-Prostate

Are immune checkpoint inhibitors a valid option for papillary renal cell carcinoma? Transcriptomic characterization of the immune infiltrate

M. De Vries-brilland1, E. Menand2, V. Seegers3, J. Dauve´2, C. Passot2, J-M. Marion4, P. Chauvet4, A. Morel2, M. Gross-Goupil5, A. Ravaud5, E. Boughalem1, B. Escudier6, L. Albiges7 1 Medical Oncology, Integrative Centre for Oncology, Angers, France, 2Clinical biology, Integrative Centre for Oncology, Angers, France, 3Biostatistics Department, Integrative Centre for Oncology, Angers, France, 4LARIS, Universite´ Catholique de l’Ouest, Angers, France, 5Medical Oncology, CHU Bordeaux Hopital St. Andre´, Bordeaux, France, 6 Medical Oncology, Gustave Roussy - Cancer Campus, Villejuif, France, 7Medical Oncology, Institut Gustave Roussy, Villejuif, France Background: Papillary Renal Cell Carcinoma (pRCC) is the most common non-clear cell RCC (nccRCC). Pivotal studies evaluating immune checkpoint inhibitors mostly excluded nccRCC. PD-1/PD-L1 inhibitors exhibit limited activity in metastatic pRCC. The immune microenvironment in pRCC is unknown.

Volume 30 | Supplement 5 | October 2019

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Expenses: Ipsen; Travel / Accommodation / Expenses: PFIZER; Travel / Accommodation / Expenses: SANOFI. B. Escudier: Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Ipsen; Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: Oncorena. L. Albiges: Honoraria (institution), Advisory / Consultancy: Novartis; Honoraria (institution), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (institution), Advisory / Consultancy: Merck; Honoraria (institution), Advisory / Consultancy: Roche; Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (institution), Advisory / Consultancy: Amgen; Honoraria (institution), Advisory / Consultancy: Ipsen; Honoraria (institution), Advisory / Consultancy: Astellas Pharma. All other authors have declared no conflicts of interest.

University of Munich, Munich, Germany, 11Clinic for Cancer Research and Clinic for Urology, University Hospital Essen Westdeutsches Tumorzentrum, Essen, Germany

Annals of Oncology

(institution), Advisory / Consultancy, Research grant / Funding (institution): Janssen; Honoraria (institution), Advisory / Consultancy: Astellas; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: MSD; Research grant / Funding (institution): BMS; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Sanofi; Travel / Accommodation / Expenses: Amgen. A. Ravaud: Research grant / Funding (institution), Travel / Accommodation / Expenses, Officer / Board of Directors: Pfizer; Travel / Accommodation / Expenses, Officer / Board of Directors: BMS; Travel / Accommodation / Expenses, Officer / Board of Directors: AstraZeneca; Travel / Accommodation / Expenses, Officer / Board of Directors: Roche; Travel / Accommodation / Expenses, Officer / Board of Directors: MSD; Travel / Accommodation / Expenses, Officer / Board of Directors: Ipsen. B. Escudier: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Pfizer; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (self): Aveo; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche; Advisory / Consultancy: EUSA. L. Albiges: Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: BMS; Advisory / Consultancy: Ipsen; Advisory / Consultancy: Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca. All other authors have declared no conflicts of interest.

971P

Treatment-free survival, with and without toxicity, as a novel outcome applied to immuno-oncology agents in advanced renal cell carcinoma

M.M. Regan1, M.B. Atkins2, T. Powles3, L. Werner4, C. Mantia5, S. Yang6, J.L. Johansen7, S. Rao8, K.M. Gooden8, D.F. McDermott9 1 Division of Biostatistics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA, 2Department of Internal Medicine - Medical Oncology, Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC, USA, 3Department of Medicine, Barts Cancer Institute, Queen Mary University of London, Royal Free NHS Trust, London, UK, 4 Division of Biostatistics, Dana-Farber Cancer Institute, Harvard University, Boston, MA, USA, 5Department of Internal Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA, 6Health Economics Outcomes Research, Bristol-Myers Squibb, Princeton, NJ, USA, 7Immuno-Oncology Genitourinary Tumours, Bristol-Myers Squibb, Princeton, NJ, USA, 8Health Outcomes Economics Research, Bristol-Myers Squibb, Princeton, NJ, USA, 9 Department of Medicine, Beth Israel Deaconess Medical Center, Dana Farber/Harvard Cancer Center, Boston, MA, USA

Volume 30 | Supplement 5 | October 2019

Background: Conventional measures such as median progression-free survival may suboptimally characterize the full impact of immuno-oncology (I-O) agents vs other systemic anticancer therapies. Patients discontinuing I-O agents may experience periods of disease control without needing subsequent systemic anticancer therapy (Rx) but may still experience toxicity (TOX). Treatment-free survival (TFS) 6 TOX can simultaneously characterize disease control and TOX for this off-treatment period. Methods: Data were analyzed from all 1082 patients initiating Rx on the randomized phase 3 CheckMate 214 trial of nivolumab þ ipilimumab (NIVOþIPI) vs sunitinib (SUN) for treatment-naı¨ve predominantly clear cell advanced renal cell carcinoma. TFS is defined as the area between Kaplan–Meier (KM) curves for 2 conventional timeto-event endpoints defined from randomization: time to protocol Rx cessation and time to subsequent Rx or death. TFS was subdivided as TFS with and without TOX by defining a third endpoint: time to cessation of Rx and TOX. TOX was defined as grade 3 Rx-related adverse events. Area under each KM curve was estimated by the 36month restricted mean time to event. Results: At 36 months, 60% of NIVOþIPI and 51% of SUN patients were alive, 15% NIVOþIPI and 9% SUN remained on original Rx, and 34% NIVOþIPI and 19% SUN patients were surviving free of subsequent Rx. The 36-month restricted mean TFS was 6.7 and 2.9 months for all NIVOþIPI and SUN patients, respectively (6.4 vs 2.8 months TFS without TOX). The table shows time by TFS subdivision and IMDC risk. Conclusions: NIVOþIPI provides longer survival and delayed time to subsequent Rx vs SUN. More importantly, NIVOþIPI provides longer TFS without TOX, during which patients do not require Rx and are free from TOX. Given the durability of I-O responses relative to SUN after Rx cessation, it will be of interest to measure TFS over time. Clinical trial identification: NCT02231749. Editorial acknowledgement: Nicolette Belletier, PhD, and Lawrence Hargett of Parexel. Legal entity responsible for the study: Bristol-Myers Squibb. Funding: Bristol-Myers Squibb and ONO Pharmaceutical Company Limited. Disclosure: M.M. Regan: Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): IPSEN; Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution): Veridex; Research grant / Funding (institution): OncoGenex; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Ferring; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pierre Fabre; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Roche; Research grant / Funding (institution): Astellas Pharma; Research grant / Funding (institution): Janssen; Research grant / Funding (institution): Millennium Pharmaceuticals; Research grant / Funding (institution): Sanofi; Research grant / Funding (institution): Sotio; Research grant / Funding (institution): Dendreon; Research grant / Funding (institution): Medivation. M.B. Atkins: Honoraria (self), Advisory / Consultancy: BMS; Advisory / Consultancy: Genentech; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Novartis; Advisory / Consultancy: X4 Pharma; Advisory / Consultancy: Merck; Advisory / Consultancy: Exelixis; Advisory / Consultancy: Acceleron; Advisory / Consultancy: Eisai; Advisory / Consultancy: Glactone Pharma; Advisory / Consultancy: Agenus; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: Boehringer Ingelheim; Advisory / Consultancy: Aduro Biotech; Advisory / Consultancy: Newlink Genetics/Pharmatech; Advisory / Consultancy: Arrowhead Pharmaceuticals; Advisory / Consultancy: Werewolf Pharma; Advisory / Consultancy: Oncolys BioPharma; Advisory / Consultancy: Surface; Advisory / Consultancy: Iovance Biotherapeutics. T. Powles: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self): Merck; Honoraria (self): BMS; Honoraria (self): Pfizer; Honoraria (self): IPSEN; Honoraria (self): Novartis; Honoraria (self): Exelixis. S. Yang: Shareholder / Stockholder / Stock options, Full / Part-time employment: BMS. J.L. Johansen: Shareholder / Stockholder / Stock options, Full / Part-time employment: BMS. S. Rao: Shareholder / Stockholder / Stock options, Full / Part-time employment: BMS. K.M. Gooden: Shareholder / Stockholder / Stock options, Full / Part-time employment: BMS. D.F. McDermott: Advisory / Consultancy, Research grant / Funding (institution): BMS; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy, Research grant / Funding (institution): Genentech/Roche; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Exelixis; Advisory / Consultancy, Research grant / Funding (institution): Novartis; Advisory / Consultancy: X4 Pharma; Advisory / Consultancy: Array

doi:10.1093/annonc/mdz249 | v393

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Methods: In silico, we studied the expression of cytotoxic lymphocyte infiltration (CYT), using a descriptive (by CIBERSORT) and specific quantitative approach, as well as the expression of inhibitors checkpoint immune markers (ICI), in 258 localized papillary renal cell tumors using RNA-seq data from The Cancer Genome Atlas (TCGA) as training set. Based on previous report, we selected 8 genes of interest (CD8a, CD8b, GZMA, PRF1, PD1, PDL1, PDL2 and CTLA4). An independent data set of 34 localized pRCC (gene expression) was used as a validation set. Results: Using a clustering method based on the expression level of 8 predefined genes of interest, we identified 3 groups, differentiated by CYT and ICI expression. In validation cohort, we observed similar clustering. Cluster 3, characterized by a CYT and ICI high expression, was significantly associated with increased population of TCD8, TCD4 helper, M1 macrophages and dendritic cells in CIBERSORT analysis. Additionally, these immune clusters were not associated with indels neo-antigen load but were significantly correlated with the MHC class I antigen presenting machinery expression (APM) (p ¼ 1.1.10-11) and interferon-gamma gene expression (p ¼ 1.6.1013). Conclusions: We characterized cytotoxic immune infiltration in pRCCs. Cluster 3 could correspond to a population of immunotherapy responders. Transcriptomic immune signature validation in pRCCs patients treated with immunotherapy is warranted. Legal entity responsible for the study: Manon de Vries-Brilland. Funding: Has not received any funding. Disclosure: M. Gross-Goupil: Honoraria (institution), Advisory / Consultancy: Ipsen; Honoraria

abstracts