Oncologist-to-Oncologist: How to Treat Your Patients with Immunotherapy Michael A. Postow, M.D. Memorial Sloan Kettering Cancer Center Wednesday, June 10, 2015 11:00 a.m. EDT Brought to you by the Cancer Research Institute
Tweet your comments and questions to us @CancerResearch using #CRIwebinar
Today s Host Brian M. Brewer Director of Marketing and Communications Cancer Research Institute
Today s Presenter Michael A. Postow, M.D. Medical Oncologist, Melanoma and Immunotherapeutics Service Memorial Sloan Kettering Cancer Center
Putting Cancer in Check with Immunotherapy: Melanoma and Beyond Michael Postow, M.D. Melanoma and Immunotherapeutics Service Memorial Sloan Kettering Cancer Center
Bristol-Myers Squibb: Research support Participated in an advisory council (non-paid) Amgen: Participated in an advisory council (non-paid)
2013 Breakthrough of the Year
What happened in 1891?
What happened in 1891?
What happened in 1891?
Main Questions 1. How can the immune system treat cancer? 2. What have we learned from clinical experience in melanoma? 3. How can we improve?
Immunotherapy = T cell kills a cancer cell
Immunity in tumor control Mellman et al. Nature 2011
Immunity in tumor control Vaccines Cytokines Adoptive cell transfer Immunomodulatory antibodies Mellman et al. Nature 2011
Sipuleucel-T vaccine improves survival in metastatic prostate cancer Kantoff PW et al. NEJM 2010
HD IL-2 Therapy: Durable Responses HD IL-2 produces durable responses in 6% to 10% of patients with advanced melanoma or RCC Few relapses in patients responding for over 2.5 years (likely cured) FDA approval in 1992 (RCC) and 1997 (melanoma) Metastatic Melanoma (N = 270) Metastatic RCC (N = 255) Probability of Continuing Response 1.0 0.8 0.6 0.4 0.2 CR (n = 17) PR (n = 26) CR + PR (n = 43) 0.0 0 10 20 30 40 50 60 70 80 90 100 110 120 130 Duration of Response (Mos) Probability of Continuing Response 1.0 0.8 0.6 0.4 0.2 0.0 CR PR All 0 10 20 30 40 50 60 70 80 90 100 110120130140150 160170 180 Duration of Response (Mos) Atkins MB et al. J Clin Oncol 1999
Immunity in tumor control Vaccines Cytokines Adoptive cell transfer Immunomodulatory antibodies Mellman et al. Nature 2011
Ways to keeping the T cells active Turning up the Activating Blocking the Inhibiting Mellman et al. Nature 2011
Ways to keeping the T cells active Turning up the Activating Blocking the Inhibiting Mellman et al. Nature 2011
Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) Postow et al. JCO 2015
PD-1 Immune Checkpoints Postow et al. JCO 2015
Blocking immunologic checkpoints Kyi and Postow FEBS Letters 2014
Adverse Events CTLA-4: Rash, diarrhea, hepatitis, endocrine 24% grade 3/4 (1) PD-1/PD-L1: Rash, fatigue, arthralgias 6-12% grade 3/4 (2-4) Chemotherapy: Alopecia, nausea, myelosuppression ~50% grade 3/4 (5) (1) Hodi et al. NEJM 2010 (2) Hamid et al. NEJM 2013 (3) Topalian et al. NEJM 2012 (4) Weber et al. Lancet Oncol 2015 (5) Kelly et al. JCO 2001
Ipilimumab rashes Can be treated with topical corticosteroids
Diarrhea and Colitis Slangen et al. World J Gastrointest Pharmacol Ther 2013
Diarrhea and Colitis Focal Active Colitis Alterations in Crypt Epithelium Maker AV Ann Surg Oncol 2005
Enlarged pituitary due to hypophysitis Weber et al. JCO 2012, reprinted from Blansfield J Immunother 2005
Pneumonitis 2/21/2011 3/30/2011 Two doses of ipilimumab and four of nivolumab
Kinetics of iraes with ipilimumab Weber JS J Clin Oncol 2012
Diarrhea/Colitis Management
Blocking immunologic checkpoints
Antibodies that block CTLA-4 Ipilimumab Tremelimumab
Ipilimumab confers OS benefit to gp100 vaccine in phase III study Median OS 10.1 mos 24% alive at 2 years Response rate of 10.9% Hodi et al. NEJM 2010
Long-term results of 2 nd phase III study Median OS 11.2 vs. 9.1 mos At 5 years, 18.2 vs. 8.8% alive, p=0.002 Maio et al. J Clin Oncol 2010
Ipilimumab responses can be delayed Pre-treatment Week 12: Progression 10 mg/kg ipilimumab Q3W X 4 July 2006 New lesions Week 20: Regression Week 36: Still Regressing Wolchok ASCO 2008
Immune-related response criteria New lesions are not counted automatically as progressive disease. Increase in tumor burden must be confirmed on subsequent scan. Wolchok et al. Clin Cancer Res 2009
Blocking immunologic checkpoints Kyi and Postow FEBS Letters 2014
PD-1 Immune Checkpoints MHC and Antigen T-Cell Receptor PD-1 PD-L1 Dendritic Cell B7 PD-L1/PD-L2 CD28 PD-L1 T Cell Tumor PD-1 PD-1 PD-L1 Lymph Node Tumor Microenvironment Postow et al. JCO 2015
PD-1/PD-L1 agents in development Target Agent Class PD-1 PD-L1 Nivolumab (MDX-1106, BMS-936558) Pembrolizumab (MK-3475) Pidilizumab (CT-011) AMP-224 BMS935559 (MDX-1105) Atezolizumab (MPDL3280A) MEDI4736 IgG4 fully human Ab IgG4 engineered humanized Ab IgG1 humanized Ab Fc of human IgG-PD-L2 fusion IgG4 fully human Ab IgG1 engineered fully human Ab IgG1 engineered fully human Ab Avelumab (MSB0010718C) IgG1 fully human Ab
Responses with Nivolumab Response rate: ~30% Nivolumab: 1mg/kg every 2 weeks in melanoma patients Topalian et al. NEJM 2012
Nivolumab improves OS Nivolumab vs. DTIC - HR: 0.42 Robert et al. NEJM 2015
Pembrolizumab: Clinical Activity Baseline: April 13, 2012 April 9, 2013 72-year-old male with symptomatic progression after bio-chemotherapy, HD IL-2, and ipilimumab Images courtesy of A. Ribas, UCLA
Pembrolizumab improves OS compared to ipilimumab Robert et al. NEJM 2015
Efficacy of PD-1 Agents
Efficacy of PD-1 Agents Drug Sponsor Target Disease Type Response (n) Reference Solid Tumors 21% (42) Topalian et al. NEJM 2012 Melanoma 32% (44) Weber et al. JCO 2013 Nivolumab BMS PD-1 NSCLC 14% (63) Antonia et al. WCLC 2013 RCC 21% (168) Motzer et al. ASCO 2014 Ovarian 17% (18) Hamanishi et al. ASCO 2014 Melanoma 40% (113) Daud et al. AACR 2014 NSCLC 19% (146) Gandhi et al. AACR 2014 Pembrolizumab Merck PD-1 Melanoma 34% (411) Ribas ASCO 2014 NSCLC 26% (45) Rizvi et al. ASCO 2014 Head and Neck 18% (55) Selwert et al. ASCO 2014 CT-011 Curetech PD-1 Hematologic Cancers 33% (17) Berger et al. Clin Cancer Res 2008 Melanoma 6% (101) Atkins ASCO 2014 AMP-224 Amplimmune/ GSK PD-1 Solid tumors Response, SD (42) Infante et al. ASCO 2013
Efficacy of PD-L1 Agents Drug Sponsor Target Disease Type Response (n) Reference Atezolizumab (MPDL3280A) Genentech PD-L1 MEDI4736 MedImmune PD-L1 Avelumab (MSB0010718C) EMD Serono / Pfizer PD-L1 Solid Tumors 21% (103) Herbst et al. ASCO 2013 Melanoma 23% (30) Hamid et al. ASCO 2013 NSCLC 23% (53) Sorial et al. ECC 2013 Bladder 26% (65) Powels et al. ASCO 2014 Solid Tumors 11% (179) Segal et al. ASCO 2014 NSCLC 16% (58) Brahmer et al. ASCO 2014 Head & Neck 14% (22) Segal et al. ASCO 2014 Gastric 19% (16) Segal et al. ASCO 2014 Solid tumors Response (27) Heery et al. ASCO 2014 MDX-1105 BMS PD-L1 Solid Tumors 17% (135) Brahmer et al. NEJM 2012
Efficacy of PD-L1 Agents Drug Sponsor Target Disease Type Response (n) Reference Atezolizumab (MPDL3280A) Genentech PD-L1 MEDI4736 MedImmune PD-L1 Avelumab (MSB0010718C) EMD Serono / Pfizer PD-L1 Solid Tumors 21% (103) Herbst et al. ASCO 2013 Melanoma 23% (30) Hamid et al. ASCO 2013 NSCLC 23% (53) Sorial et al. ECC 2013 Bladder 26% (65) Powels et al. ASCO 2014 Solid Tumors 11% (179) Segal et al. ASCO 2014 NSCLC 16% (58) Brahmer et al. ASCO 2014 Head & Neck 14% (22) Segal et al. ASCO 2014 Gastric 19% (16) Segal et al. ASCO 2014 Solid tumors Response (27) Heery et al. ASCO 2014 MDX-1105 BMS PD-L1 Solid Tumors 17% (135) Brahmer et al. NEJM 2012
Response in Patient with Head and Neck Cancer Baseline Day 28 96 y.o. female Progressed on previous cetuximab HPV negative, PD-L1 positive Treatment ongoing at 8 weeks Segal et al. ASCO 2014
MPDL3280A: Urothelial Bladder Cancer Median time to first response was 42 days (range, 38 to 85 days) Median duration of response has not been reached T Powles et al. ASCO 2014
Pembrolizumab: AEs in > 5% of Patients Adverse Event (N = 135) All Grades, n (%) Grades 3/4, n (%) Any 107 (79.3) 17 (12.6) Fatigue 41 (30.4) 2 (1.5) Rash 28 (20.7) 3 (2.2) Pruritus 28 (20.7) 1 (0.7) Diarrhea 27 (20.0) 1 (0.7) Myalgia 16 (11.9) 0 Headache 14 (10.4) 0 Increased AST 13 (9.6) 2 (1.5) Asthenia 13 (9.6) 0 Nausea 13 (9.6) 0 Vitiligo 12 (8.9) 0 Hypothyroidism 11 (8.1) 1 (0.7) Increased ALT 11 (8.1) 0 Cough 11 (8.1) 0 Pyrexia 10 (7.4) 0 Chills 9 (6.7) 0 Abdominal pain 7 (5.2) 1 (0.7) A Ribas et al. ASCO 2013
Immunohistochemistry for PD-L1 expression PD-L1 Negative PD-L1 Positive PD-L1 tumor cell membrane staining: 0 3%, focal 5%, heterogeneous 80%, homogeneous Slide courtesy of Margaret Callahan
Nivolumab in NSCLC: PD-L1 is not associated with overall survival PD-L1 + PD-L1 - Julie Brahmer ASCO 2014
PD-L1 EGFR, BRAF, HER2, ER, KRAS Many different assays measure PD-L1 differently PD-L1 negative tumors can still respond PD-L1 is a dynamic immunologic marker Heterogeneity exists within individual patients [1] [1] Madore et al. Pigment Cell Melanoma Res 2014
Pre-treatment immunologic biomarkers Square peg into a round hole?
Immune Checkpoint Combinations Chemotherapy Carboplatin/Paclitaxel (Lynch et al. J Clin Oncol 2012) Anti-angiogenic agents Bevacizumab (Hodi et al. Cancer Immunol Res 2014) Hormonal Therapy Exemestane (Vonderheide et al. Clin Cancer Res 2010) Androgen deprivation (MDACC) Targeted therapy Vemurafenib (Ribas et al. NEJM 2013) Other immunotherapy GM-CSF (Hodi et al. JAMA 2014) Nivolumab (Wolchok et al. NEJM 2013 and Postow et al. NEJM 2015) Radiotherapy Postow et al. NEJM 2013
Ipilimumab + Nivolumab vs. Ipilimumab Response rate: 61% vs. 11% Postow et al. NEJM 2015
Summary Durable responses in melanoma and other cancers Biomarkers inform biology but not yet treatment selection Combinations have promise but are they better than single agents?
1891 to 2015
1891 to 2015
Q&A: Ask an Expert Michael A. Postow, M.D. Medical Oncologist, Melanoma-Sarcoma Oncology Service Memorial Sloan Kettering Cancer Center Follow along with @CancerResearch using #CRIwebinar
Upcoming Webinars Jeffrey S. Weber, M.D., Ph.D. Cancer Revealed: How Our Immune System Sees and Destroys Tumors June 16, 2015, at 2:00 p.m. EDT David A. Reardon, M.D. Aiming the Immune System at Brain Cancer June 23, 2015, at 12:00 p.m. EDT Jedd D. Wolchok, M.D., Ph.D. Getting to Cures: The Next Five Years in Immunotherapy June 25, 2015, at 2:00 p.m. EDT Register today at www.cancerresearch.org/webinars
www.theanswertocancer.org
www.cancerresearch.org