Oncologist-to-Oncologist: How to Treat Your Patients with Immunotherapy

Transcription

1 Oncologist-to-Oncologist: How to Treat Your Patients with Immunotherapy Michael A. Postow, M.D. Memorial Sloan Kettering Cancer Center Wednesday, June 10, :00 a.m. EDT Brought to you by the Cancer Research Institute

2 Tweet your comments and questions to using #CRIwebinar

3 Today s Host Brian M. Brewer Director of Marketing and Communications Cancer Research Institute

4 Today s Presenter Michael A. Postow, M.D. Medical Oncologist, Melanoma and Immunotherapeutics Service Memorial Sloan Kettering Cancer Center

5 Putting Cancer in Check with Immunotherapy: Melanoma and Beyond Michael Postow, M.D. Melanoma and Immunotherapeutics Service Memorial Sloan Kettering Cancer Center

6 Bristol-Myers Squibb: Research support Participated in an advisory council (non-paid) Amgen: Participated in an advisory council (non-paid)

7 2013 Breakthrough of the Year

8 What happened in 1891?

9 What happened in 1891?

10 What happened in 1891?

11 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?

12 Immunotherapy = T cell kills a cancer cell

13 Immunity in tumor control Mellman et al. Nature 2011

14

15 Immunity in tumor control Vaccines Cytokines Adoptive cell transfer Immunomodulatory antibodies Mellman et al. Nature 2011

16 Sipuleucel-T vaccine improves survival in metastatic prostate cancer Kantoff PW et al. NEJM 2010

17 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 CR (n = 17) PR (n = 26) CR + PR (n = 43) Duration of Response (Mos) Probability of Continuing Response CR PR All Duration of Response (Mos) Atkins MB et al. J Clin Oncol 1999

18 Immunity in tumor control Vaccines Cytokines Adoptive cell transfer Immunomodulatory antibodies Mellman et al. Nature 2011

19 Ways to keeping the T cells active Turning up the Activating Blocking the Inhibiting Mellman et al. Nature 2011

20 Ways to keeping the T cells active Turning up the Activating Blocking the Inhibiting Mellman et al. Nature 2011

21 Cytotoxic T Lymphocyte Antigen 4 (CTLA-4) Postow et al. JCO 2015

22 PD-1 Immune Checkpoints Postow et al. JCO 2015

23 Blocking immunologic checkpoints Kyi and Postow FEBS Letters 2014

24 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

25 Ipilimumab rashes Can be treated with topical corticosteroids

26 Diarrhea and Colitis Slangen et al. World J Gastrointest Pharmacol Ther 2013

27 Diarrhea and Colitis Focal Active Colitis Alterations in Crypt Epithelium Maker AV Ann Surg Oncol 2005

28 Enlarged pituitary due to hypophysitis Weber et al. JCO 2012, reprinted from Blansfield J Immunother 2005

29 Pneumonitis 2/21/2011 3/30/2011 Two doses of ipilimumab and four of nivolumab

30 Kinetics of iraes with ipilimumab Weber JS J Clin Oncol 2012

31

32 Diarrhea/Colitis Management

33 Blocking immunologic checkpoints

34 Antibodies that block CTLA-4 Ipilimumab Tremelimumab

35 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

36 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

37 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

38 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

39 Blocking immunologic checkpoints Kyi and Postow FEBS Letters 2014

40 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

41 PD-1/PD-L1 agents in development Target Agent Class PD-1 PD-L1 Nivolumab (MDX-1106, BMS ) Pembrolizumab (MK-3475) Pidilizumab (CT-011) AMP-224 BMS (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 (MSB C) IgG1 fully human Ab

42 Responses with Nivolumab Response rate: ~30% Nivolumab: 1mg/kg every 2 weeks in melanoma patients Topalian et al. NEJM 2012

43 Nivolumab improves OS Nivolumab vs. DTIC - HR: 0.42 Robert et al. NEJM 2015

44 Pembrolizumab: Clinical Activity Baseline: April 13, 2012 April 9, year-old male with symptomatic progression after bio-chemotherapy, HD IL-2, and ipilimumab Images courtesy of A. Ribas, UCLA

45 Pembrolizumab improves OS compared to ipilimumab Robert et al. NEJM 2015

46 Efficacy of PD-1 Agents

47 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

48 Efficacy of PD-L1 Agents Drug Sponsor Target Disease Type Response (n) Reference Atezolizumab (MPDL3280A) Genentech PD-L1 MEDI4736 MedImmune PD-L1 Avelumab (MSB C) 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

49 Efficacy of PD-L1 Agents Drug Sponsor Target Disease Type Response (n) Reference Atezolizumab (MPDL3280A) Genentech PD-L1 MEDI4736 MedImmune PD-L1 Avelumab (MSB C) 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

50 Response in Patient with Head and Neck Cancer Baseline Day y.o. female Progressed on previous cetuximab HPV negative, PD-L1 positive Treatment ongoing at 8 weeks Segal et al. ASCO 2014

51 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

52 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

53 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

54 Nivolumab in NSCLC: PD-L1 is not associated with overall survival PD-L1 + PD-L1 - Julie Brahmer ASCO 2014

55 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

56 Pre-treatment immunologic biomarkers Square peg into a round hole?

57 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

58 Ipilimumab + Nivolumab vs. Ipilimumab Response rate: 61% vs. 11% Postow et al. NEJM 2015

59 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?

60 1891 to 2015

61 1891 to 2015

62 Q&A: Ask an Expert Michael A. Postow, M.D. Medical Oncologist, Melanoma-Sarcoma Oncology Service Memorial Sloan Kettering Cancer Center Follow along using #CRIwebinar

63 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

64

65

66