GU CANCERS 2019… There Is Always Something New to Talk About…
GU CANCERS 2019… There is always something new to talk about…
Alexandra Drakaki, MD, PhD Assistant Professor of Medicine and Urology Division of Hematology/Oncology Lake Arrowhead 2019 Conflict of Interest
• Consulting: Astra Zeneca, BMS, Radmetrix, Medicus • Travel reimbursement: Astra Zeneca, Eli Lilly • Equity: Allogene, Urogen, Kynan Pharma The GU TEAM…
Alexandra Drakaki Sandy Liu, MD John Shen, MD MD, PhD AGENDA
BLADDER CANCER: *Neoadjuvant to Adjuvant trials *First/Second/Third Line studies…. what are we offering???
KIDNEY CANCER: *The new SOC in RCC…advancing the field *Our upcoming studies…
PROSTATE CANCER: *How to treat Non Metastatic CRPC & Castrate Sensitive Disease *Our Immunotherapy trials for CRPC CISPLATIN 40‐Year History??? There must be a reason…
Alexandra Drakaki, MD, PhD 5 BLADDER CANCER THE IMPACT OF THE NEOADJUVANT APPROACH
Dose Dense MVAC Gemcitabine/Cisplatin BLADDER CANCER THE IMPACT OF THE NEOADJUVANT APPROACH
(ABACUS): A phase II Study Investigating Safety and Efficacy of Neoadjuvant Atezolizumab in Muscle Invasive Bladder Cancer Powles T. ASCO 2018
Dose Dense MVAC PEMBROLIZUMAB/ATEZOLIZUMAB Gemcitabine/Cisplatin (Not FDA Approved for this indication) BLADDER CANCER THE IMPACT OF THE NEOADJUVANT APPROACH
CISPLATIN ELIGIBLE
(ABACUS): A phase II Study Investigating Safety and Efficacy of Neoadjuvant Atezolizumab in Muscle Invasive Bladder Cancer Powles T. ASCO 2018 Dose Dense MVAC PEMBROLIZUMAB/ATEZOLIZUMAB Gemcitabine/Cisplatin (Not FDA Approved for this indication) RE‐DESIGNING NEOADJUVANT TRIALS IN BLADDER CANCER NIAGARA A Phase III study of Neodjuvant Durvalumab & Gemcitabine+Cisplatin vs Gemcitabine+Cisplatin Followed by Adjuvant Durvalumab Alone in MIBC Porter Ranch Ventura Encino Burbank BLADDER CANCER Should we Combine Chemotherapy & Immunotherapy ??? BLADDER CANCER Should we Combine Chemotherapy & Immunotherapy ??? Chemotherapy effect: Old Paradigm: Directly kills tumor cells BUT could be Immunosuppressive New Paradigm: Pleiotropic Effects: Stimulates Innate & Adaptive Immune System via: * Cell death & Antigen release Dendritic Cell activation * Decrease of the Myeloid Derived Suppressor Cells (MDSCs) * Alteration in tumor microenvironment Lesterhuis J et al, Journal of Clinical Investigation 2011 Heinhuis K.M. et al, Annals of Oncology 2019 Bracci L, et al, Cell Death and Differentiation 2014 Wang Z, et al, OncoImmunology 2017 BLADDER FIRST LINE CANCER CHEMOTHERAPY COMBINATION TRIALS KEYNOTE 361 PEMBROLIZUMAB with or without Chemotherapy vs Chemotherapy in Unresectable Stage IV Urothelial Cancer IMVIGOR ATEZOLIZUMAB with or without Chemotherapy vs Chemotherapy TRIO 130 in Unresectable Stage IV Urothelial Cancer US DANUBE DURVALUMAB vs DURVALUMAB / TREMELIMUMAB vs Chemotherapy in Unresectable Stage IV Urothelial Cancer CHECKMATE NIVOLUMAB in combination with IPILIMUMAB or Chemotherapy vs Chemotherapy alone 901 in Unresectable Stage IV Urothelial Cancer (OPEN TO ACCRUAL) BLADDER FIRST LINE CANCER CHEMOTHERAPY COMBINATION TRIALS KEYNOTE 361 PEMBROLIZUMAB with or without Chemotherapy vs Chemotherapy in Unresectable Stage IV Urothelial Cancer IMVIGOR ATEZOLIZUMAB with or without Chemotherapy vs Chemotherapy TRIO 130 in Unresectable Stage IV Urothelial Cancer US DANUBE DURVALUMAB vs DURVALUMAB / TREMELIMUMAB vs Chemotherapy in Unresectable Stage IV Urothelial Cancer CHECKMATE NIVOLUMAB in combination with IPILIMUMAB or Chemotherapy vs Chemotherapy alone 901 in Unresectable Stage IV Urothelial Cancer (OPEN TO ACCRUAL) BLADDER FIRST LINE CANCER CHEMOTHERAPY COMBINATION TRIALS KEYNOTE 361 PEMBROLIZUMAB with or without Chemotherapy vs Chemotherapy in Unresectable Stage IV Urothelial Cancer IMVIGOR ATEZOLIZUMAB with or without Chemotherapy vs Chemotherapy TRIO 130 in Unresectable Stage IV Urothelial Cancer US DANUBE DURVALUMAB vs DURVALUMABATEZOLIZUMAB / &TREMELIMUMAB CHEMO PLACEBO vs Chemotherapy & CHEMO in Unresectable Stage IV Urothelial Cancer CHECKMATE NIVOLUMAB in combination with IPILIMUMAB or Chemotherapy vs Chemotherapy alone 901 in Unresectable Stage IV Urothelial Cancer (OPEN TO ACCRUAL) BLADDER FIRST LINE CANCER CHEMOTHERAPY COMBINATION TRIALS KEYNOTE 361 PEMBROLIZUMAB with or without Chemotherapy vs Chemotherapy in Unresectable Stage IV Urothelial Cancer IMVIGOR ATEZOLIZUMAB with or without Chemotherapy vs Chemotherapy 130 in Unresectable Stage IV Urothelial Cancer DANUBE DURVALUMAB vs DURVALUMAB / TREMELIMUMAB vs Chemotherapy in Unresectable Stage IV Urothelial Cancer CHECKMATE NIVOLUMAB in combination with IPILIMUMAB or Chemotherapy vs Chemotherapy alone 901 in Unresectable Stage IV Urothelial Cancer (OPEN TO ACCRUAL) Chemotherapy vs Chemotherapy / DURVALUMAB / TREMELIMUMAB vs NILE Chemotherapy / DURVALUMAB in Unresectable Stage IV Urothelial Cancer Chemotherapy vs Chemotherapy / DURVALUMAB / TREMELIMUMAB vs NILE Chemotherapy / DURVALUMAB in Unresectable Stage IV Urothelial Cancer Cisplatin/Gemcitabine ELIGIBILITY Metastatic ENDPOINTS Urothelial cancer Cisplatin/Gemcitabine & PFS Chemo Naive Durvalumab IO Naïve OS GFR > 60 Cisplatin/Gemcitabine & 1ST Durvalumab/Tremelimumab TRIO LINE US Multiple Immunotherapy‐based Combinations in Locally Advanced or MORPHEUS Metastatic Urothelial Cancer post Platinum‐based therapy ELIGIBILITY ATEZOLIZUMAB ENDPOINTS Metastatic ATEZOLIZUMAB + Niraparib ORR Urothelial cancer ATEZOLIZUMAB + Tocilizumab PFS Post Platinum therapy ATEZOLIZUMAB + Isatuximab (anti‐CD38) OS IO Naïve ATEZOLIZUMAB + Hu5F9‐G4 (anti‐CD47) GFR > 30 2nd LINE Multiple Immunotherapy‐based Combinations in Locally Advanced or MORPHEUS Metastatic Urothelial Cancer post Platinum‐based therapy ELIGIBILITY ATEZOLIZUMAB ENDPOINTS Metastatic ATEZOLIZUMAB + Niraparib ORR Urothelial cancer ATEZOLIZUMAB + Tocilizumab PFS Post Platinum therapy ATEZOLIZUMAB + Isatuximab (anti‐CD38) OS IO Naïve ATEZOLIZUMAB + Hu5F9‐G4 (anti‐CD47) GFR > 30 UPON PROGRESSION TRANSITION TO STAGE 2 ATEZOLIZUMAB + Linagliptin 2nd LINE ATEZOLIZUMAB + Enfortumab Vedotin Vopratelimab and Ipilimumab post platinum and PD‐1/PD‐L1 Inhibitor in EMERGE metastatic Urothelial Ca and NCSLC • ICOS (Inducible CO‐Stimulator of T‐cells) ligand is member of B7 superfamily • ICOS activates T effector cells within tumor • Sustaining ICOS correlates with survival benefit in Melanoma ***Ipilimumab leads to upregulation of ICOS Vopratelimab sustains levels of ICOS ELIGIBILITY *Metastatic NSCLC Urothelial cancer ENDPOINTS *Post chemo PFS /OS *Post IO *GFR > 30 3rd LINE BLADDER CANCER TRIALS STRATEGY… KIDNEY CANCER…Choosing the right 1st option Interleukin‐2 Nivolumab/Ipilimumab Pazopanib Cabozantinib Sunitinib Sorafenib KIDNEY CANCER…Choosing the right 1st option Interleukin‐2 Nivolumab/Ipilimumab Pazopanib 2019 Avelumab/Axitinib Cabozantinib NEW Pembrolizumab/Axitinib SOC Sunitinib Sorafenib PEMBROLIZUMAB/AXITINIB SUNITINIB ORR 59% 35% m PFS 15 mo 11 mo AVELUMAB/AXITINIB SUNITINIB ORR 55% 25% m PFS 13 mo 8 mo A Phase 2 trial of IPI‐549 with IO combination in Advanced and/or Metastatic Renal Cell Carcinoma or Triple‐Negative Breast Cancer PI3K (Phosphoinositide‐3‐kinases) gamma isoform is: * expressed in immune cells but not in normal/malignant epithelial cells. * involved in Tumor Microenvironment Immunosuppression Prevent Immune cells attack tumors IPI‐549: PI3Kg inhibitor: Inhibits immune suppressive macrophages ENDPOINTS ELIGIBILITY mRCC: IPI549 + ATEZOLIZUMAB + BEVACIZUMAB Metastatic TNBC CR ORR Metastatic RCC PFS Immunotherapy mTNBC: IPI549 + Naive ATEZOLIZUMAB + NAB‐PACLITAXEL Tx related AEs 1ST TRIO LINE US Phase 1, open‐label, dose‐escalation and expansion study of AB928 in combination with AB122 in RCC and advanced malignancies. • Adenosine is produced by ATP and has immunosuppressive effect in tumor microenvironment • Adenosine Receptor blockade stimulates antitumor immunity • AB928: is an oral dual antagonist of A2aR and A2bR • AB122: is a PD‐1 inhibitor ELIGIBILITY ENDPOINTS mRCC & others Safety POST IO AB928 + AB122 Pharmacokinetics POST TKI/SOC Pharmacodynamics Up to 5 lines Clinical Activity 3rd PI: Dr. Liu LINE PROSTATE CANCER HOW TO THINK IN PROSTATE CANCER BIOCHEMICAL CASTRATE SENSITIVE CASTRATE RESISTANT RECURRENCE / METASTATIC METASTATIC NON MET CRPC • ADT ‐/+ • ADT + • ADT +/‐ • DOCETAXEL • DOCETAXEL • APALUTAMIDE • ABIRATERONE • ENZALUTAMIDE • ENZALUTAMIDE • APALUTAMIDE • ABIRATERONE • DAROLUTAMIDE • RADIUM 223 • Salvage RT COMBO IS BETTER • PROVENGE KEYNOTE A Phase Ib/II study of Pembrolizumab Combination 365 Therapies in Metastatic Castration‐Resistant Prostate Cancer ELIGIBILITY Cohort D Pembrolizumab + Abiraterone ENDPOINTS mCRPC ORR Pembrolizumab + Chemotherapy Immunotherapy Naïve PSA Decrease > 50% No chemotherapy for CRPC Pembrolizumab + Enzalutamide DCR, OS, DoR Tx related AEs +/‐ Enzalutamide Pembrolizumab + olaparib KEYNOTE A Phase Ib/II study of Pembrolizumab Combination 365 Therapies in Metastatic Castration‐Resistant Prostate Cancer ELIGIBILITY Cohort D Pembrolizumab + Abiraterone ENDPOINTS mCRPC ORR Pembrolizumab + Chemotherapy Immunotherapy Naïve PSA Decrease > 50% No chemotherapy for CRPC Pembrolizumab + Enzalutamide DCR, OS, DoR Tx related Aes +/‐ Enzalutamide Pembrolizumab + olaparib PRELIMINARY DATA ASCO 2019 KEYNOTE A Phase Ib/II study of Pembrolizumab & Enzalutamide 365 in Metastatic Castration‐Resistant Prostate Cancer Fong P, Retz M, Drakaki A , Massard C, Berry W, Romano E, De Bono J, Feyerabend S, Appleman L, Conter W, Sridhar S, Shore N, Linch M, Joshua A, Gurney H, Wu H, Schloss C, Poehlein C, Yu E *Safe combination. Increased incidence of rash (23%) *ORR of 20% in RECIST measurable *DCR of 33% *Median r PFS 6mo *Median OS not reached KEYNOTE Randomized Phase 3 study of Enzalutamide with or without Pembrolizumab 641 in Chemotherapy Naive mCRPC that progressed on ADT+/- Abiraterone PI: Dr. Shen PARP INHIBITORS IN PROSTATE CANCER * OLAPARIB (Jan 2016) * RUCAPARIB (Oct 2018) * NIRAPARIB (Oct 2019) A Phase 3 study of Pembrolizumab & Olaparib vs Abireterone or Enzalutamide in KEYLYNK‐010 Metastatic Castration Resistant Prostate Cancer (mCRPC) unselected for HRD after Hormonal Therapy & Chemotherapy • KEYNOTE 199: Pembrolizumab monotherapy in heavily pretreated: 11% ORR, >6mo DCR • TOPARP: Olaparib in heavily pretreated: 88% in HRD+, 6% in HRD‐ ENDPOINTS ELIGIBILITY Pembrolizumab + Olaparib mCRPC CR Unselected for HRD ORR Prior Chemotherapy Prior Enza OR Abi PFS Immunotherapy Naive Abiraterone or Enzalutamide Tx related AEs PI: Dr. Shen A Phase 2, Randomized, Double‐blind, Placebo‐Controlled Study of Abiraterone with or JPCM without Abemaciclib in Patients with Metastatic Castration‐Resistant Prostate Cancer • AR signaling pathway interacts with CDK4/6 axis to sustain prostate cancer cell proliferation & survival • Upregulation of cycle D1 is a potential mechanism of resistance to ADT • Abemaciclib as single agent/combo with ADT inhibits proliferation and delays progression. TRIO US IO Chemo T‐cell Therapy Therapy Hormonal therapy UCLA –MAGE A3 TissueMicroArray Study * MAGE A3 is the most frequently expressed Cancer Testis Antigen * Expressed in Multiple Cancer types * Restricted Expression in Normal Adult Tissue * 422 samples : 23% MAGE A3 + * High Expression correlates with ‐ Advanced stage ‐ High Grade disease ‐ Worse PFS & RFS * Frequent Co‐Expression of MAGE A3/ PDL1 ‐ MP/PP worst PFS (HR 17) MAGE A3 + MAGE A3 ‐ Faiena I. & Drakaki A. unpublished A Phase I study Evaluating the Safety and Efficacy of MAGE A3/A6 T Cell Receptor Engineered T Cells (KITE‐718) in HLA‐DPB1*04:01 Positive Subjects with Advanced Cancers LYMPHODEPLETING CHEMOTHERAPY KITE 718 INFUSION SCREENING DAY -7 DAY DAY DAY TO O 13 28 DAY -1 LEUKAPHERESIS ENROLLMENT IL-2 FIRST TUMOR ASSESSMENT The GU TEAM…BEHIND THE SCENES REGULATORY CRC/DM/RAs FINANCE • Kim Kelly • Kathy Hilburn • Marielena Solis • Sarah Rosales • Maurice Herring • Nancy Alvarez • Clara Ellison • Annabel Liu • Alexander Orellana • Greg Hamm • Joy Valadez • David Rodriquez • Magdalene • Anna Crosetti Lindenbaum • Bara Almomani SATELITES • Rebecca Alvarez • Sub‐Is TRIO‐US • Whitney Vuong • Research staff • Christine Kivork • Lauren Sauer • • Donna Katz Sandra Binder • Susan Mates • RESEARCH PHARMACY • Allison Muff We are evolving… THANK YOU FOR YOUR SUPPORT, CONTRIBUTION & INVOLVEMENT IN CHANGING THE FIELD…