Fifteenth International Kidney Cancer Symposium

Transcription

1 The following presentation should not be regarded as an endorsement of a particular product/drug/technique by the speaker. The presentation topics were assigned to the speakers by the scientific committee of the KCA, to be presented/interpreted as part of a comprehensive scientific debate. Therefore, this presentation should not be viewed/interpreted in isolation, and should be considered in context with the other presentations in the same session. "

2 PD-1/PD-L1 Blockage in Non-Clear Cell RCC Rana McKay, MD November 5, 2016 Assistant Professor of Medicine HMS/DFCI/BWH

3 Disclosures Research funding from Bayer and Pfizer

4 Outline Current treatment landscape for non-clear cell RCC Activity of PD-1/PD-L1 targeted therapies in other cancers Rationale for PD-1/PD-L1 blockade in non-clear cell RCC Activity of PD-1/PD-L1 targeted therapies in non-clear cell RCC Ongoing immunotherapy based trials in non-clear cell RCC

5 Non-Clear Cell RCC 20-25% of all RCC cases Heterogeneous group of diseases with differing tumor biology and molecular characterization Expanding list of entities based on WHO classification Lineham et al, J Urol, 2003 Moch et al, European Urology, 2016

6 Outcomes of Non-Clear Cell RCC Patients IMDC database of patients receiving targeted therapy Pfizer clinical trials database of phase 2-3 trials in modern era N Median, mo Non-clear cell Clear cell HR 1.41 (95% ), p< Kroeger et al, Cancer, 2013 De Velasco et al, Presented at KCA, 2016

7 Trials of Non-Clear Cell RCC Patients Trial Phase N Subtype Prior Treatment Treatment PFS OS (months) (months) Hudes, Any None IFN-α vs. Temsirolimus 3.1 vs vs vs. IFN-α + Temsirolimus vs. 4.7 vs. 8.4 Tannir, Any Max 2, No VEGF TT Sunitinib Lee, Any No TT Sunitinib Koh, Any Any VEGF, No mtor Everolimus Molina, Any Any Sunitinib 5.5 NR Escudier, Papillary None Everolimus Ravaud, Papillary None Sunitinib Tannir, 2015 (ESPN) 2 68 Any None Sunitinib vs. Everolimus 6.1 vs vs Armstrong, 2016 (ASPEN) Papillary, Chromophobe, Unclassified None Sunitinib vs. Everolimus 8.3 vs vs PFS=Progression-free survival, OS=Overall survival, IFN-α=Interferon alpha, VEGF=Vascular endothelial growth factor, TT=Targeted therapy, mtor=mammalian target of rapamycin

8 Treatment Guidelines for Non-Clear Cell RCC

9 Efficacy of PD-1/PD-L1 Therapies in Cancer Trial Disease Phase Patient Population N Therapy OS PFS ORR (months) (months) (%) Ansell, chl 1 Progressed post HSCT and posttransplant 23 Nivolumab NA 86% at 24 87% 2015 brentuximab weeks Robert, 2015 Melanoma 3 Untreated without a BRAF mutation 418 Nivolumab vs. Dacarbazine NR vs vs % vs. 14% Weber, 2015 Melanoma 3 Progressed after ipilimumab or ipilimumab and a BRAF inhibitor 405 Nivolumab vs ICC (2:1) NA 4.7 vs % vs. 11% Borghaei, Non-Squamous 3 Progressed on platinum-based 582 Nivolumab vs vs. 2.3 vs % vs NSCLC chemotherapy Docetaxel % Brahmer, 2015 Squamous NSCLC 3 Progressed on platinum-based chemotherapy 272 Nivolumab vs. Docetaxel 9.2 vs vs % vs. 9% Postow, 2015 NA Melanoma 3 Untreated 945 Nivolumab + Ipilimumab vs. Ipilimumab vs. Nivolumab chl=classical Hodgkins Lymphoma, HSCT=Hematopoetic stem cell transplant, NA=Not available, NR=Not recorded, ICC=Investigator choice of chemotherapy, NSCLC=Non-small cell lung cancer vs. 2.9 vs % vs. 19% vs. 44%

10 Efficacy of PD-1/PD-L1 Therapies in Cancer Trial Disease Phase Patient Population N Therapy Ribas, 2015 Melanoma 2 Ipilimumab-refractory 540 Pembrolizumab 2 mg/kg vs. Pembrolizumab 10 mg/kg v.s ICC Schachter, 2015 Herbst, 2016 Mehra, 2016 Rosenberg, 2016 Melanoma 3 Untreated 834 Pembrolizumab 10 mg/kg q2w vs. Pembrolizumab 10 mg/kg q3w vs. Ipilimumab NSCLC 2/3 PD-L1 positive, progressed on platinumbased chemotherapy HNSCC 1b Progressed on platinumbased chemotherapy Urothelial 2 Progressed on platinumbased cancer chemotherapy NA=Not available, NSCLC=Non-small cell lung cancer, HNSCC=Head and neck squamous cell carcinoma. *6-month PFS Pembrolizumab 2 mg/kg vs. Pembrolizumab 10 mg/kg vs Docetaxel OS (months) NA NA 10.4 vs vs. 8.5 PFS (months) 34% vs. 38% vs. 16%* 47% vs. 46% vs. 27%* 3.9 vs. 4.0 vs. 4.0 ORR (%) 21% vs. 26% vs. 4% 34% vs. 33% vs. 12% 18% vs. 18% vs. 9% 174 Pembrolizumab %* 16% 310 Atezolizumab %

11 Efficacy of Nivolumab in Clear Cell RCC Multicenter Randomized Open-Label Phase 3 Trial Metastatic RCC - Clear cell -1-3 prior regimens 1:1 Nivolumab 3 mg/kg every 2 weeks n=410 Everolimus 10 mg daily n=410 Primary Endpoint: Overall Survival Motzer et al, NEJM, 2015

12 Efficacy of Nivolumab in Clear Cell RCC ORR: 25% vs. 5% Median PFS: 4.6 vs. 4.4 months Median OS: 25.0 vs months Region MSKCC prognostic score Number of prior anti-angiogenic treatments Treatment-related AEs: Nivolumab Fatigue (33%) Nausea (14%) Pruritus (14%) Grade 3-4 (19%) Most common fatigue (2%), led to discontinuation (8%) Everolimus Fatigue (34%) Stomatitis (29%) Anemia (24%) Grade 3-4 (37%) Most common anemia (8%), led to discontinuation (18%) ORR=Objective response rate, PFS=Progression-free survival, OS=Overall survival, MSKCC=Memorial Sloan Kettering Cancer Center, AE=Adverse events. Motzer et al, NEJM, 2015

13 PD-L1 Expression in Non-Clear Cell RCC 11/101 (10.9%) were PD-L1+ in tumor cells: 2/36 (5.6%) of chromophobe RCC 5/50 (10%) of papillary RCC 3/10 (30%) of Xp11.2 translocation RCC 1/5 (20%) of collecting duct carcinoma PD-L1+ in tumor cells was significantly associated with higher stage and grade, and shorter OS 57/101 (56.4%) were PD-L1+ in TIMC: 13/36 (36.1%) of chromophobe RCC 30/50 (60%) of papillary RCC 9/10 (90%) of Xp11.2 translocation RCC 5/5 (100%) of collecting duct carcinoma Positive Control Chromophobe +TC Xp11.2 translocation +TC Negative Control Papillary +TC Xp11.2 translocation +TIMC TC=Tumor cells, TIMC=Tumor Infiltrating Mononuclear Cells Choueiri et al, Ann Oncol, 2014

14 Rationale for PD-1/PD-L1 Therapies in Non-Clear Cell RCC The management of patients with non-clear cell RCC represents an unmet need in the field Therapies blocking the PD-1/PD-L1 pathway are tumor agonistic and have demonstrated efficacy across multiple tumor types PD-L1 expression in tumor and tumor infiltrating mononuclear cells occurs in non-clear cell RCC

15 Phase 1 Study of Atezolizumab Phase Ia Expansion RCC NSCLC Melanoma Bladder Other Tumor Types 1. Allcomers 2. PD-L1+ patients 1. Allcomers 2. PD-L1+ patients All-comers 1. PD-L1+ patients 2. Allcomers 1. PD-L1+ patients 2. Allcomers Atezolizumab given every 3 weeks for up to 16 weeks Key Eligibility: Measurable disease, ECOG 0-1 Subgroup analysis from large phase 1 study included 70 previously treated RCC patients ECOG=Eastern Cooperative Oncology Group McDermott et al, JCO, 2016

16 Phase 1 Study of Atezolizumab 10% non-clear cell; 29% Fuhrman grade 4 or sarcomatoid histology 34% had MSKCC poor-risk disease 57% with 2 prior lines of therapy 67% PD-L1 IC score 1-3 N (%) Objective Response PFS (months) OS (months) Clear Cell RCC 63 (90%) 15% Non-Clear Cell RCC 7 (10%) 0%* NR NR Clear Cell Grade 4/ Sarcomatoid 18 (26%) 22% MTD not reached/no DLTs Median number of doses 12 iraes reported in 30% 3 patients had grade 3 iraes Safety (n=70) N (%) TR Grade 3-4 AEs 12 (17%) Fatigue 20 (29%) Decreased appetite 11 (16%) Arthralgia 10 (14%) Rash 10 (14%) PFS=Progression-free survival, OS=Overall survival, MTD=Maximum tolerated dose, DLT-Dose limiting toxicity, irae=immune-related adverse event, TR=Treatment-related. *There was one response by immune-related response criteria. McDermott et al, JCO, 2016

17 Phase 1 Study of Atezolizumab 72-year-old woman with metastatic oncocytic papillary RCC status post right nephrectomy and sunitinib Demonstrated irrc partial response which was ongoing at data cutoff PD-L1 IHC negative irrc=immune-related response criteria, IHC=Immunohistochemistry. McDermott et al, Presented at ESMO, 2014

18 Phase 1 Study of Atezolizumab 51-year-old man with metastatic RCC (75% sarcomatoid variant) diagnosed 10/2011 with T3aN2 disease, s/p left nephrectomy and developed metastases to the lungs, skin and bone Prior sunitinib, temsirolimus and XRT to T9 Poor MSKCC risk and ECOG 1 PD-L1 IHC positive (IHC 3) Duration of response was 76 weeks Pre-treatment (9 Mar 2012) Post cycle 2 (20 Apr 2012) Pre-Treatment Tumor Specimen H&E PD-L1 MSKCC=Memorial Sloan Kettering Cancer Center, ECOG=Eastern Cooperative Oncology Group, IHC=Immunohistochemistry. McDermott et al, Presented at ESMO, 2014

19 Activity of Nivolumab in Papillary RCC 34-yr-old man presented with night sweats, fevers, pulmonary masses, bony disease, and a left renal mass Lung biopsy: Poorly differentiated carcinoma with rhabdoid features consistent with high-grade RCC Carboplatin and gemcitabine Renal mass biopsy: Papillary RCC with sarcomatoid and rhabdoid features. Genomic profiling revealed alterations in FAT1, DICER1, FANCL, SPTA1, WISP3, and PBRM1. Sunitinib then gemcitabine added Nivolumab with improved performance status, resolution of anemia, thrombocytosis, with significant response on imaging Geynisman, Eur Urol, 2015

20 Preliminary Data of PD-1/PD-L1 Blockade Retrospective multi-center study of patients with metastatic non-clear cell RCC receiving PD-1/PD-L1 inhibitors 40 patients across 8 institutions 30 (75%) received PD-1/PD-L1 monotherapy Total cohort objective response rate 18% Median follow up 5.6 months Total cohort 6-month overall survival was 81% IMDC=International Metastatic RCC Database Consortium Baseline Characteristics N % Age < % Male 24 60% ECOG % Performance % Status 2 1 3% Prior Nephrectomy 39 98% Histology Papillary 14 35% Chromophobe 10 25% Unclassified 7 18% Translocation 3 8% ccrcc > 30% sarcomatoid 6 15% Bone Metastases 13 33% Liver Metastases 13 33% IMDC Poor Risk Disease 8 20% Line of Therapy > % ECOG=Eastern Cooperative Oncology Group, ccrcc=clear cell RCC. Moreira et al, Submitted to GU ASCO, 2017

21 Ongoing Immunotherapy Trials in Non-Clear Cell Trial Phase Agent Non-Clear Cell Histology NCT /2 MEDI4736 (PD-L1 inhibitor) + Papillary; treatment Savolitinib (c-met inhibitor) naïve or VEGF refractory NCT Atezolizumab + Bevacizumab Any non-clear cell histology; any line of therapy NCT Nivolumab Any non-clear cell histology; 0-3 prior systemic therapies NCT Pembrolizumab Any non-clear cell histology; treatment naïve VEGF=Vascular endothelial growth factor. Status Recruiting Recruiting Recruiting Not yet recruiting

22 Phase 2 Atezolizumab and Bevacizumab Multicenter Single-Arm Open-Label Phase 2 Trial Metastatic RCC - Non-clear cell only -Any line of therapy Mandatory Pretreatment Biopsy Atezolizumab + Bevacizumab Every 3 weeks Progression Mandatory Progression Biopsy in Responders Primary Endpoint: Objective response rate Target Accrual: 40 4 Total Sites

23 Conclusions Preliminary data of PD-1/PD-L1 inhibitors demonstrate some activity in patients with non-clear cell histology Current ongoing clinical trials evaluating various PD-1/PD-L1 therapies alone and in combination will be informative regarding the impact of these agents for patients with non-clear cell disease

24 Acknowledgements Kidney cancer patients and their families Dana Farber Lank Center for Genitourinary Oncology Dana-Farber/Harvard Cancer Center Kidney Cancer Program