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Putting Cancer in Check with Immunotherapy: Melanoma and Beyond

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1 Putting Cancer in Check with Immunotherapy: Melanoma and Beyond
Michael Postow, MD Melanoma and Immunotherapeutics Service Memorial Sloan Kettering Cancer Center

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

3 2013 Breakthrough of the Year

4 What happened in 1891?

5 What happened in 1891?

6 What happened in 1891?

7 Main Questions How can the immune system treat cancer?
What have we learned from clinical experience in melanoma? How can we improve?

8 Immunity in tumor control
Mellman et al. Nature 2011

9

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

11 Sipuleucel-T vaccine improves survival in metastatic prostate cancer
100 Median OS benefit: 4.1 months HR : 0.78 (95% CI: ; P = .03) 80 60 Probability of Survival (%) Sipuleucel-T (n = 341) Median Survival: 25.8 Mos. 40 CI, confidence interval; HR, hazard ratio; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival. Speaker notes: Sip-T is a vaccine against PAP (prostatic acid phosphatase). It was approved based on improving mOS compared with placebo in this PIII study with 512 patients with mCRPC. 20 Placebo (n = 171) Median Survival: Mos. 12 24 36 48 60 72 Mos Since Randomization Kantoff PW, et al. N Engl J Med. 2010

12 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) 1.0 1.0 CR (n = 17) PR (n = 26) CR + PR (n = 43) CR PR All 0.8 0.8 0.6 0.6 Probability of Continuing Response HD, high-dose; IL-2, interleukin-2; RCC, renal cell carcinoma. Speaker notes: To show and emphasize the potential of immunotherapy with the prolonged responses. Also it was unclear why few patients were responding at the time of these studies. Probability of Continuing Response 0.4 0.4 0.2 0.2 0.0 0.0 10 20 30 40 50 60 70 80 90 100 110 120 130 10 20 30 40 50 60 70 80 90 100 110 120 130 140 150 160 170 180 Duration of Response (Mos) Duration of Response (Mos) Atkins MB, et al. J Clin Oncol. 1999

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

14 Ways to keeping the T cells “active”
Member of CD28 family involved in T cell regulation Expressed by activated T cells, memory T cells and regulatory T cells Down regulates T cell activity upon binding to PD-L1/L2 Tumor PD-L1 expression may correlate with negative prognosis potential mechanism of tumor self defense Turning up The Activating Blocking the Inhibiting Mellman et al. Nature 2011

15 ARSS Question 1 Which of the previously shown T cell co-regulatory targets has been targeted with FDA approved antibodies? CTLA-4 LAG-3 PD-1 CD 28 1 and 3 1, 3, and 4 1, 2, 3, and 4

16 Ways to keeping the T cells “active”
Member of CD28 family involved in T cell regulation Expressed by activated T cells, memory T cells and regulatory T cells Down regulates T cell activity upon binding to PD-L1/L2 Tumor PD-L1 expression may correlate with negative prognosis potential mechanism of tumor self defense Turning up The Activating Blocking the Inhibiting Mellman et al. Nature 2011

17 Cytotoxic T Lymphocyte Antigen 4
Dendritic Cell T Cell T-Cell Receptor MHC with Antigen B7 CD28 B7 CTLA-4 Lymph Node Postow et al. JCO 2015

18 Tumor Microenvironment
PD-1 Immune Checkpoints Dendritic Cell MHC and Antigen T-Cell Receptor T Cell PD-1 PD-L1 B7 Tumor CD28 PD-L1 PD-L1/PD-L2 PD-1 PD-1 PD-L1 Lymph Node Tumor Microenvironment Postow et al. JCO 2015

19 Blocking immunologic checkpoints
Nivolumab Pembrolizumab Pidilizumab Ipilimumab and Tremelimumab MPDL3280A MEDI4736 MSB C Kyi and Postow FEBS Letters 2014

20 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) Hodi et al. NEJM 2010 Hamid et al. NEJM 2013 Topalian et al. NEJM 2012 (4) Weber et al. Lancet Oncol 2015 (5) Kelly et al. JCO 2001

21 Can be treated with topical corticosteroids
Ipilimumab Rashes Can be treated with topical corticosteroids

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

23 Alterations in Crypt Epithelium
Diarrhea and Colitis Focal Active Colitis  Alterations in Crypt Epithelium Maker AV, Ann Surg Oncol. 2005

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

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

26 ARSS Question 2 A 55 year old man has completed 3 doses of ipilimumab and has developed significant diarrhea. Which do you recommend? Ciprofloxacin and Flagyl A several week course of oral steroids Observation for 1 week, and then oral steroids only if worsening to avoid blunting of immunotherapy effect. Infliximab

27 Kinetics of irAEs with ipilumumab
Rash, pruritis Liver toxicity Diarrhea, colitis Hypophysitis Toxicity Grade 2 4 6 8 10 12 14 Wks Weber JS, J Clin Oncol 2012

28

29 Diarrhea/Colitis Management
IPI IPILIMUMAB IPI IPI

30 Blocking immunologic checkpoints
Nivolumab Pembrolizumab Pidilizumab Ipilimumab and Tremelimumab MPDL3280A MEDI4736 MSB C Kyi and Postow FEBS Letters 2014

31 Antibodies that block CTLA-4
Tremelimumab Ipilimumab

32 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

33 Long-term results of 2nd 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

34 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

35 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

36 Blocking immunologic checkpoints
Nivolumab Pembrolizumab Pidilizumab Ipilimumab and Tremelimumab MPDL3280A MEDI4736 MSB C Kyi and Postow FEBS Letters 2014

37 Tumor Microenvironment
PD-1 Immune Checkpoints Dendritic Cell MHC and Antigen T-Cell Receptor T Cell PD-1 PD-L1 B7 Tumor CD28 PD-L1 PD-L1/PD-L2 PD-1 PD-1 PD-L1 Lymph Node Tumor Microenvironment Postow et al. JCO 2015

38 PD-1/PD-L1 Agents in Development
Target Agent Class PD-1 Nivolumab (MDX1106, BMS ) IgG4 fully human Ab Pembrolizumab (MK-3475) IgG4 engineered humanized Ab Pidilizumab (CT‑011) IgG1 humanized Ab AMP‑224 Fc of human IgG-PD-L2 fusion PD-L1 BMS (MDX‑1105) MPDL3280A IgG1 engineered fully human Ab MEDI4736 MSB C IgG1 fully human Ab

39 ARSS Question 3 Which of the following statements about anti-PD-1 therapy in melanoma is false? Nivolumab has improved overall survival compared to dacarbazine. Pembrolizumab has improved overall survival compared to ipilimumab. Pembrolizumab has a higher rate of significant toxicity than ipilimumab. Nivolumab and pembrolizumab are only available for patients who have progressed on ipilimumab and if relevant, a BRAF inhibitor.

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

41 Nivolumab vs. DTIC-- HR: 0.42
Nivolumab improves OS Nivolumab vs. DTIC-- HR: 0.42 Ipi + DTIC vs. DTIC-- HR: 0.72

42 Pembrolizumab: Clinical Activity
Baseline: April 13, 2012 April 9, 2013 HD, high-dose; IL-2, interleukin-2. 72-year-old male with symptomatic progression after bio-chemotherapy, HD IL-2, and ipilimumab Images courtesy of A. Ribas, UCLA.

43 Pembrolizumab improves OS compared to ipilimumab
HD, high-dose; IL-2, interleukin-2.

44 Efficacy of PD-1 Agents Drug Sponsor Target Disease Type Response (n)
Reference Nivolumab BMS PD-1 Solid Tumors 21% (42) Topalian et al. NEJM 2012 Melanoma 32% (44) Weber et al. JCO 2013 NSCLC 14% (63) Antonia et al. WCLC 2013 RCC 21% (168) Motzer et al. ASCO 2014 Ovarian 17% (18) Hamanishi ASCO 2014 Pembrolizumab Merck 40% (113) Daud et al. AACR 2014 19% (146) Gandhi et al. AACR 2014 34% (411) Ribas et al. ASCO 2014 26% (45) Rizvi et al. ASCO 2014 Head & Neck 18% (55) Selwert et al. ASCO 2014 CT-011 Curetech Hematologic Cancers 33% (17) Berger et al. Clin Cancer Res 2008 6% (101) Atkins et al. ASCO 2014 AMP-224 Amplimmune/GSK Solid tumors Response, SD (42) Infante et al. ASCO 2013

45 Efficacy of PD-1 Agents Drug Sponsor Target Disease Type Response (n)
Reference Nivolumab BMS PD-1 Solid Tumors 21% (42) Topalian et al. NEJM 2012 Melanoma 32% (44) Weber et al. JCO 2013 NSCLC 14% (63) Antonia et al. WCLC 2013 RCC 21% (168) Motzer et al. ASCO 2014 Ovarian 17% (18) Hamanishi et al. ASCO 2014 Pembrolizumab Merck 40% (113) Daud et al. AACR 2014 19% (146) Gandhi et al. AACR 2014 34% (411) Ribas ASCO 2014 26% (45) Rizvi et al. ASCO 2014 Head & Neck 18% (55) Selwert et al. ASCO 2014 CT-011 Curetech Hematologic Cancers 33% (17) Berger et al Clin Cancer Res 2008 6% (101) Atkins ASCO 2014 AMP-224 Amplimmune/GSK Solid tumors Response, SD (42) Infante et al. ASCO 2013

46 Efficacy of PD-L1 Agents
Drug Sponsor Target Disease Type Response (n) Reference MPDL3280a Genentech 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 MEDI4736 MedImmune 11% (179) Segal et al. ASCO 2014 16% (58) Brahmer et al ASCO 2014 Head & Neck 14% (22) Gastric 19% (16) MSB C EMD Serono Solid tumors Response (27) Heery et al. ASCO 2014 MDX BMS 17% (135) Brahmer et al. NEJM 2012

47 Efficacy of PD-L1 Agents
Drug Sponsor Target Disease Type Response (n) Reference MPDL3280a Genentech 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 MEDI4736 MedImmune 11% (179) Segal et al. ASCO 2014 16% (58) Brahmer et al ASCO 2014 Head & Neck 14% (22) Gastric 19% (16) MSB C EMD Serono Solid tumors Response (27) Heery et al. ASCO 2014 MDX BMS 17% (135) Brahmer et al. NEJM 2012

48 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

49 MPDL3280A: Urothelial Bladder Cancer
Speaker notes: Single-arm, multicenter, open-label study 68 pts with previously treated metastatic bladder cancer (n = 30 PD-L1 positive) ORR – 43% by RECIST in PD-L1+ pts; 11% by RECIST in PD-L1 neg pts Median time to first response was 42 days (range, 38 to 85 days) Median duration of response has not been reached Powles T, et al. ASCO 2014

50 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 1 (0.7) Diarrhea 27 (20.0) Myalgia 16 (11.9) Headache 14 (10.4) Increased AST 13 (9.6) Asthenia Nausea Vitiligo 12 (8.9) Hypothyroidism 11 (8.1) Increased ALT Cough Pyrexia 10 (7.4) Chills 9 (6.7) Abdominal pain 7 (5.2) ALT, alanine aminotransferase; AST, aspartate aminotransferase. Notes for speaker Most treatment-related AEs were of grade 1-2 severity and were managed by treatment discontinuation, supportive care, and, occasionally, glucocorticoids Rate of immune-related or other toxicities was not increased in IPI-refractory patients Ribas A, et al. ASCO 2013

51 Immunohistochemistry for PD-L1 expression
PD-L1 tumor cell membrane staining: 5%, heterogeneous 80%, homogeneous 3%, focal PD-L1 Negative PD-L1 Positive Slide courtesy of Margaret Callahan

52 ARSS Question 4 Which of the following statements about PD-L1 is true?
PD-L1 is required to benefit from anti-PD1 therapy. PD-L1 is required to benefit from ipilimumab. PD-L1 is tested using similar methodology across clinical trials. PD-L1 may reflect an immunologically active tumor

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

54 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

55 Pretreatment immunologic biomarkers
Square peg into a round hole?

56 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) Radiotherapy Postow et al. NEJM 2013

57 Ipilimumab + Nivolumab
All patients in concurrent cohorts 300 250 250 First occurrence of new lesion 200 200 150 Cohort 2: 1 mg/kg nivolumab + 3 mg/kg ipilimumab 150 100 50 100 Change in target lesions from baseline (%) Change in target lesions from baseline -20 50 -40 -60 -80 -50 -100 ORR, overall response rate. -100 10 20 30 40 50 60 70 80 90 100 110 120 Patients Weeks since treatment initiation Therapy, % ORR Ipilimumab 7 Nivolumab 28 Combination 42 Wolchok et al., NEJM 2013

58 Summary Proof-of-concept for the promise of immune checkpoint blocking antibodies Durable responses in melanoma and other cancers Biomarkers inform biology but not yet treatment selection Combinations may be better than single agent

59 Future Questions How should we target the next T cell co-regulatory receptors? Mellman et al. Nature 2011

60 Future Questions How should we target the next T cell co-regulatory receptors? What endpoints should the FDA consider for regulatory approval?

61 Future Questions How should we target the next T cell co-regulatory receptors? What endpoints should the FDA consider for regulatory approval? Can targeting T-cells enhance other cancer therapeutics?

62 1891 to 2015

63 1891 to 2015

64 Case reports of the abscopal effect
Postow M, et al. New Engl J Med 2012

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