New kids on the block: Immunotherapy in melanoma and GI Malignancies. Ralph P.W. Wong, MD FRCPC

Transcription

1 New kids on the block: Immunotherapy in melanoma and GI Malignancies Ralph P.W. Wong, MD FRCPC

2 "Cry 'Havoc!', and let slip the dogs of war Julius Caesar Act iii. Sc. 1 UPCON Primary Care Conference Ralph P.W. Wong MD FRCPC May 5, 217

3 Disclosures Faculty / Speaker s name: Ralph Wong Relationships with commercial interests: Grants/Research Support: None Speakers Bureau/Honoraria: None Consulting Fees: None Other: None

4 Mitigating Potential Bias Not Applicable

5 Objectives At the end of the presentation the learner will be able to: 1. To review the basic principles of how the immune system interacts with malignancy 2. To understand the concept of Checkpoint inhibition and it use in the management of GI malignancies and Melanoma

6 Breakthrough of the Year; Science 213 This year marks a turning point in cancer, as longsought efforts to unleash the immune system against tumours are paying off even if the future remains a question mark Couzin-Frankel J. Science 213;342:

7 Immuno-Oncology

8 The Immune System is Comprised of Two Arms : Innate and Adaptive 1 Immediate First line of immune defense Not antigenspecific response Innate Immunity 2,3 Adaptive Immunity Slow response Antigen-specific response Memory External threats: viruses, parasites, protozoa, fungi, bacteria, toxins Internal threats: cancer 1. Abbas AK, et al. Cellular and Molecular Immunology. 7th ed. Philadelphia, PA: Elsevier Saunders; Figure reprinted by permission from Macmillan Publishers Ltd: Nature Reviews Cancer. Dranoff G. Nat Rev Cancer. 24;4: Vesely MD, et al. Annu Rev Immunol. 211;29:

9 T-cell Activation: Tumour-associated Antigens Tumour-associated antigens can trigger a tumour-specific immune cell response: Antigen Inactive T cell APC matures 4 1 Tumours express a multitude of proteins, known as tumour-associated antigens 1,2,3,4 2 Antigen presenting cell ((APC) captures tumour-associated antigens 2 3 Activated APC can interact with T cells 4 1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 212;11: Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 211;48: Heemskerk B, Kvistborg P, Schumacher TNM. The cancer antigenome. EMBO J. 213;32(2): Boudreau JE, Bonehill A, Thielemans K, Wan Y. Engineering dendritic cells to enhance cancer immunotherapy. Mol Ther. 211;19(5);841-8

10 Activated APC presents the tumour-associated antigen to the T cell along with a co-stimulatory signal 1 Inactive T cell Activates 1 T-cell Activation: Cytotoxic T cells Activated T cell T cells proliferate Active, cytotoxic (killer) T cells Antigen recognition Antigen Tumour cell Activated APC Co-stimulatory signal Cytotoxic T cell induces apoptosis in tumour cell 1 1. Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6th ed. New York, NY: Garland Science; 24

11 The Cancer Immunity Cycle 9 1.Schumacher TN et al. Cancer Cell 215;27: Chen DS, Mellman I. Immunity 213;39:1-1

12 Mechanisms for Cancer to Evade the Immune System

13 Immune System Pathways Normal conditions: There are a number of immune activation and inhibition pathways that modulate the immune response and protect healthy tissues from collateral damage 1,7 Tumour evasion of the immune system may be associated with an imbalance in immune activation and inhibition. 1-5 Tumours may down-regulate co-stimulatory pathways. 2-3 Co-stimulatory receptors include: CD28 CD4 OX4 CD137 GITR Tumours may up-regulate immune checkpoints (inhibitory signaling pathways). 2,3,5,6 Checkpoint pathway molecules include: LAG-3 CTLA-4 B7-H3 PD-1 TIM-3 1. Baruah P, et al. Immunobiology. 212;217(7): Hemon P, et al. J Immunol. 211,186: Pardoll DM. Nat Rev Cancer. 212;12: Kirkwood JM, et al. CA Cancer J Clin. 212;62: Zang X, et al. PNAS. 27;14(49): Leitner J. Eur J Immunol. 29;39: Janeway CA, et al. Immunobiology: The Immune System in Health and Disease. 6 th ed. New York, NY: Garland Science; 24

14 T-cell Checkpoint Regulation Activating receptors CD28 OX4 CD137 Agonistic antibodies T-cell stimulation Inhibitory receptors CTLA-4 PD-1 TIM-3 LAG-3 Antagonistic (blocking) antibodies T-cell responses are regulated though a complex balance of inhibitory ( checkpoint ) and activating signals Tumours can dysregulate these pathways and consequently, the immune response Targeting these pathways is an evolving approach to cancer therapy Adapted from Mellman I, et al. Nature 211; 48(7378):48-9; Pardoll DM. Nat Rev Cancer 212; 12(4):

15 Mechanisms for Cancer to Evade the Immune System

16 Immune Escape in Cancer Many tumours escape the immune response by creating an immunosuppressive microenvironment that prevents an effective antitumour response 1,2 Recruitment of immunosuppressive cells Release of immunosuppressive factors Tregs MDSCs Factors/enzymes directly or indirectly suppress immune response Ineffective presentation of tumour antigens to the immune system Downregulation of MHC Expression Tumour Cell Suppression of APC APC Tumour Cells Tumour Microenvironment T-cell checkpoint dysregulation The mechanisms tumours use to escape the immune system provide a range of potential therapeutic targets for cancer CTLA-4 PD-1 B7-1 APC=antigen-presenting cell; MDSC=myeloid-derived suppressor cell; MHC=major histocompatibility complex; Treg=regulatory T cell. 1. Bremnes RM et al. J Thorac Oncol. 211;6: Jadus MR et al. Clin Dev Immunol. 212: CD28 OX4 GITR CD137 CD27 HVEM Costimulatory receptors T cell TIM-3 BTLA VISTA LAG-3 Coinhibitory receptors

17 Checkpoint inhibition as a way to awaken the immune system

18 Multiple Potential I-O Targets to Activate the Immune System Antitumour response is a net balance of complex inhibitory and stimulatory interactions between APC, T cell, and tumour 1-6 Multiple potential I-O targets, such as: T-cell co-stimulatory receptors T-cell checkpoint/inhibitory receptors APC Microenvironment Modulation of these targets by I-O therapies may activate the immune system to eliminate the tumour 1. Baruah P, et al. Immunobiology. 212;217(7): ; 2. Hemon P, et al. J Immunol. 211,186: ; 3. Pardoll DM. Nat Rev Cancer. 212;12: ; 4. Kirkwood JM, et al. CA Cancer J Clin. 212;62:39-335; 5. Zang X, et al. PNAS. 27;14(49): ; 6. Leitner J. Eur J Immunol. 29;39:

19 Priming Phase Periphery Immuno-oncology: Blocking CTLA-4 and PD-1 Pathways with Monoclonal Antibodies Effector Phase Tumour microenvironment T-cell activation (cytokines, lysis, proliferation, migration to tumour) Dendritic TCR MHC cell T cell T cell B7 B7 CD28 CTLA Anti-CTLA TCR MHC PD-1 PD-L1 Anti-PD-1/PD-L1 PD-1 PD-L2 Anti-PD-1 Tumour cell CTLA-4 pathway blockade PD-1 pathway blockade CTLA-4=cytotoxic T-lymphocyte antigen-4; PD-1=programmed cell death 1; PD-L1/2=PD ligand 1/2; TCR=T cell receptor. Adapted from Wolchock J, et al. Oral presentation at ASCO 213 (Abstract 912).

20 CLTA-4 Monoclonal Antibodies

21 Tumor CTLA-4: Mechanism of Action (MoA) Attenuated or Terminated Proliferation Unrestrained Proliferation IL-2 APC APC Tumor-specific Antigenic Peptides Can Lead to Anti-Cancer Immune Responses TCR Peptide/MHC CD28 B7-1,2 CTLA-4 ipilimumab Adapted from Chambers CA, et al. Annu Rev Immunol. 21;19:

22 Anti-PD-1/L1

23 PD-1 and PD-L1 Antibodies PD-1 inhibitory receptor found on activated lymphocytes and monocytes and is associated with tumour immune escape Binds with PD-L1 on tumour cells Interaction between PD-1 and PD-L1 suppresses the cytotoxic T-cell response Adapted from N Engl Med. 212;366(26):2517

24 Potential Clinical Response Patterns with I-O Therapeutic Approaches

25 Response to I-O Therapy is a Multi-step Process that May Impact Response Kinetics Therapies that affect the immune system may not induce a measurable impact on tumour growth immediately after administration 1 I-O Start 2 Immune cell activation and proliferation Effect on tumour Effect on survival Day 1 Days to Weeks Several Weeks Several Months Initial I-O therapy administration Immune activation and T-cell proliferation start early on after initial I-O administration Clinically measurable immune-mediated antitumour effects occur over weeks to months Potential effect on survival may occur several months after initial I-O administration 1. Hoos A, Britten CM. OncoImmunology. 212;1: ; 2. Hoos A, et al. J Natl Cancer Inst. 21;12:

26 Tumour change from baseline (%) Tumour change from baseline (%) Potential Tumour Response Patterns to Therapy Response in baseline lesions typically seen with chemotherapy, but also I-O therapies and targeted therapies. Captured by existing RECIST and WHO criteria Stable disease : Slow, steady decline in tumour volume seen with chemotherapy, targeted and I-O therapies. Captured by existing RECIST and WHO criteria Therapy start Thresholds for response or progressive disease (RECIST) Graphs for illustrative purposes showing responses to ipilimumab in advanced melanoma Therapy start 125 Time 125 Time Adapted from Wolchok JD, et al. Clin Cancer Res 29;15: ; Hoos A, et al. Annals of Oncology 212;23(suppl 8): viii47 viii52.

27 Tumour change from baseline (%) Potential Tumour Response Patterns to Therapy Adapted from Wolchok JD, et al. Clin Cancer Res 29;15: ; Hoos A, et al. Annals of Oncology 212;23(suppl 8): viii47 viii52. Tumour change from baseline (%) Response after initial increase in tumour volume; novel and specific to I-O therapy RECIST or WHO criteria may not be appropriate to assess Reduction in tumour burden after appearance of new lesions; novel and specific to I-O therapy, RECIST or WHO criteria may not be appropriate to assess Therapy start Some vaccines may not follow similar patterns of response as other I-O therapies Therapy start Total Baseline New lesions 125 Time 125 Time

28 Example of Evolution of Response to CTLA-4 Inhibition Screening Week 12: Initial increase in total tumour burden (mwho PD) Week 96: Durable and ongoing response without signs of iraes Week 16: Responding AE = immune-realted adverse events Harmankaya K, et al. Presented at the World Meeting of Interdisciplinary Melanoma/Skin Cancer Centers: November 19-21, 29; Berlin, Germany.

29 Pseudo-progression: Inflammation Causes Swelling, May Appear as Tumour Growth or New Lesions Upon Imaging 1 Considerations when evaluating true progression vs. pseudo-progression May indicate progression May indicate pseudo-progression Performance status Deterioration of performance Remains stable or improves Systemic symptoms Worsen May or may not improve Symptoms of tumour enlargement Tumour burden Baseline New lesions Present Increase Appear and increase in size May or may not be present Increase followed by response Appear then remain stable and/or subsequently respond Biopsy may reveal Evidence of tumour growth Evidence of T-cell infiltration 1. Wolchok JD, et al. Clin Cancer Res. 29;15: ; 2. Topalian SL, et al. N Engl J Med. 212;366: ; 3. Eisenhauer EA, et al. Eur J Cancer. 29;45: ; 4. Chow LQ. Am Soc Clin Oncol Educ Book. 213:28-285; 5. American Cancer Society. Lung Cancer.

30 Clinical Efficacy of Immunooncology Treatment

31 Somatic mutation frequencies observed in exomes from 3,83 tumour normal pairs. Mutational heterogeneity in cancer-altered proteins contain neoepitopes for immune recognition MS Lawrence et al. Nature, 1-5 (213) doi:1.138/nature12213

32 Melanoma

33 Chemotherapy ( )

34 Landmark Meta-analysis: Overall Survival (OS) in Metastatic Stage IV Melanoma Median OS: 6.2 months 25.5% alive at 1 year Only ~1% alive at 24 months Survival data from 42 phase II trials with over 21 stage IV patients 1 yr. survival 25% Median survival 6.2 mo. Korn EL, et al. J Clin Oncol. 28;26(4):

35 Proportion Alive Ipilimumab: Pooled Survival Analysis from Phase II/III Trials in Advanced Melanoma Patients at Risk Ipilimumab CENSORED N = 1861 Median OS (95% CI): 11.4 mo ( ) 3-year OS Rate (95% CI): 22% (2% to 24%) Months Ipilimumab Schadendorf et al. J Clin Oncol 215; 33(17):

36 OS Relative to Historical Data Historical controls Phase II: 1278 patients in 42 cooperative group trials from 1975 to 25 Phase III: 3739 patients in 1 trials from 1999 to 211

37 OS (%) OS (%) 1. Robert C, et al. N Engl J Med. 215;372: Robert C, et al. N Engl J Med. 215;372(28): CHECKMATE 66 and KEYNOTE 6: Overall survival 1 Nivolumab vs DTIC in BRAFnegative, previously untreated melanoma [1 ] HR for death:.42 (99.79% CI: ; P <.1) Pembrolizumab vs Ipilimumab in Advanced Melanoma [2] 1 Pembrolizumab q3w 8 Nivolumab 8 Pembrolizumab q2w 6 Dacarbazine Ipilimumab 2 Nivolumab Dacarbazine mos (95% CI) Not reached 1.8 mos ( ) Mos Mos

38 CTLA 4/PD-1 combination

39 Case Presentation 56 yr. old female 4.9 mm ulcerated (T4b, Nx M) BRAF wild type, NRAS mutated melanoma right upper arm resected April 216 declined adjuvant interferon

40 Case Presentation October 216, presents to clinic with increasingly severe axillary pain, hoarse voice Exam confirmed large mass in right axilla, right arm swelling and inability to abduct arm Pain syndrome consistent with brachial plexopathy

41 Case Presentation October 3, 216

42 Case Presentation Offered clinical trial with nivolumab/ipilimumab Commenced therapy November 24, 216 Noted decreased mass and pain after one cycle, hoarse voice resolved Developed Grade 1 rash after third cycle Jan 6, 217

43 Case Presentation October 3, 216 April 27, 217

44 CHECKMATE 67: Phase III Trial of Nivolumab + Ipilimumab vs. Nivolumab vs. Ipilimumab for First-line Treatment of Melanoma Stratified by PD-L1 expression (< 5% vs 5%), BRAF status, and AJCC M stage Previously untreated pts with unresectable stage III/IV melanoma and ECOG PS -1 (N = 945) Nivo 1 mg/kg + Ipi 3 mg/kg q3w for 4 doses, then Nivo 3 mg/kg q2w (n = 314) Nivo 3 mg/kg q2w + Placebo (n = 316) Ipi 3 mg/kg q3w for 4 doses + Placebo (n = 315) Until disease progression or unacceptable toxicity Coprimary endpoints: PFS, OS Secondary endpoints: ORR, tumor PD-L1 expression and efficacy, safety Larkin, et al. NEJM epub May 31, 215.

45 Select Treatment-Related AEs, % Treatment-Related AEs Associated With Nivolumab/Ipilimumab combination Nivo + Ipi (n = 313) Nivo (n = 313) Ipi (n = 311) All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 Any reported AE Leading to discontinuation Skin Pruritus Rash Maculopapular rash < 1 < < 1 2 < 1 Gastrointestinal Diarrhea Colitis < Hepatic ALT increase AST increase < 1 Endocrine Hypothyroidism < <

46 Updated Response To Treatment NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) ORR, % (95% CI)* 58.9 ( ) 44.6 ( ) 19. ( ) Best overall response % Complete response Partial response Stable disease Progressive disease Unknown Median duration of response, months (95% CI) NR (NR NR) 31.1 (31.1 NR) 18.2 (8.3 NR) *By RECIST v1.1; NR = not reached. At the 18-month DBL, the CR rate for NIVO+IPI, NIVO and IPI was 12.1%, 9.8% and 2.2%, respectively Database lock: Sept 13, 216, minimum f/u of 28 months AACR April 6, 217

47 Progression-free Survival (%) Updated Progression-Free Survival Nivo + Ipi (n = 314) Nivo (n = 316) Ipi (n = 315) 1 Median PFS, mos (95% CI) 11.7 ( ) 6.9 ( ) 2.9 ( ) HR (99.5% CI) vs Ipi.42 ( )* HR (95% CI) vs Nivo.76 (.6-.94).54 ( )* _ % 43% 43% 37% 2 1 NIVO+IPI NIVO 18% IPI 12% Months Patients at risk: NIVO+ IPI NIVO IPI Database lock: Sept 13, 216, minimum f/u of 28 months AACR Presentation April 3, 217

48 Overall Survival (%) Overall Survival NIVO+IPI NIVO IPI 73% 74% 67% Median OS, mo (95% CI) HR (98% CI) vs. IPI HR (95% CI) vs. NIVO Months Patients at risk: NIVO+IPI NIVO IPI % 59% 45% NIVO+IPI (N=314) NIVO (N=316) IPI (N=315) NR.55 (.42.72)*.88 ( ) NR (29.1 NR).63 (.48.81)* 2. ( ) *P<.1 Database lock: Sept 13, 216, minimum f/u of 28 months AACR April 6, 217

49 GI Malignancies

50 Le et al NEJM 215; 372(26):

51 PD-1 Blockade in MMR-Deficient Tumors: Patient Population Baseline Characteristics MMR-Deficient CRC (n = 13) MMR-Proficient CRC (n = 25) MMR-Deficient Other Tumors (n = 1) Median age, yrs Diagnosis, % CRC Ampullary/biliary Endometrial Small bowel Prostate Gastric 1 2 prior therapies, % Lynch syndrome, % Le et al NEJM 215; 372(26):

52 PD-1 Blockade in MMR-Deficient Tumors: Efficacy Efficacy Outcome (RECIST), % MMR-Deficient CRC (n = 13) MMR-Proficient CRC (n = 25) MMR-Deficient Other tumors (n = 1) ORR 62 6 Disease control rate To date, responses > 1 yr. observed, and 13 or 14 responding pts continue to maintain response Other efficacy outcomes in MMR-deficient vs MMR-proficient tumors Median PFS: not yet reached vs 2.3 mos Median OS: not yet reached vs 5 mos Biochemical response (eg, CEA, CA-19) declined early with treatment in pts with MMR-deficient cancers and correlated with ORR, PFS, OS Le et al NEJM 215; 372(26):

53 Clinical Responses to Pembrolizumab Treatment. Le et al NEJM 215; 372(26):

54 Anal cancer

55 Morris et al. Lancet Oncol epub Feb 217

56

57 Change From Baseline in Tumor Size, % Pembrolizumab Activity 1 Melanoma1 1 NSCLC 2 1 H&N3 Urothelial 4 TNBC Gastric 6 1 chl NHL PMBCL 8 Mesothelioma Ovarian 1 1 SCLC 11 1 Esophageal 12 1 NPC 13 1 Anal Biliary Tract 15 1 Colorectal 16 ER + /HER2 BC 17 Thyroid 19 Salivary Daud A et al. ASCO 215; 2. Garon EB et al. ESMO 214; 3. Seiwert T et al. ASCO 215; 4. Plimack E et al. ASCO 215; 5. Nanda R et al. SABCS 214; 6. Bang YJ et al. ASCO 215 ; 7. Moskowitz C et al. ASH 214; 8. Zinzani PL et al. ASH 215; 9. Alley EA et al. AACR 215; 1. Varga A et al. ASCO 215; 11. Ott PA et al. 215 ASCO; 12. Doi T et al. ASCO 215; 13. Hsu C et al. ECC 215; 14. Ott PA et al. ECC 215; 15. Bang Y-J et al. ECC 215; 16. O Neil B et al. ECC 215; 17. Rugo HS et al. SABCS 215; 18. Frenel JS et al. ASCO 216; 19. Mehnert JM et al. ASCO 216; 2. Cohen R et al. ASCO 216.

58 Phase III trials are underway in gastric cancer and hepatoma where PD-1 inhibition has shown activity Stay tuned

59 FDA Approvals Nivolumab/ ipilimumab Melanoma Oct 215 Dec 214 Sept 214 Nivolumab Pembrolizumab Atezolizumab Avelumab NSCLC 1 st line NSCLC 2 nd line Renal Cancer 2 nd line Hodgkins (Refractory) SCCHN 2 nd line Oct 216 PD-L1 +ve Oct 215 Oct 215 PD-L1 +ve Nov 215 May 216 Nov 216 Aug 216 Oct 216 Bladder Ca 2 nd line Feb 217 May 216 Merkel Cell > 1 st line March 217

60 Health Canada Approvals Melanoma (1 st and 2 nd line) Nivolumab/ipilimumab Nivolumab Pembrolizumab Lung Cancer (2 nd line) Nivolumab Pembrolizumab (PD-L1 +ve) Renal Cancer (2 nd line) Nivolumab

61 Unanswered questions

62 Quo Vadis?

63 Combining anticancer agents with Immunotherapy Apetoh et al Ann Oncol. 215;26(9):

64 The landscape of T cell activating and inhibitory receptors TIGIT

65 Turning a cold tumour hot ; Colon cancer Open-label phase Ib dose escalation and expansion study Dose Escalation Pts with chemo-refractory solid tumors, ECOG PS - 1, measurable disease per RECIST v1.1 Cobimetinib* 2, 4, or 6 mg PO QD + Atezolizumab 8 mg IV Q2W *Dosed in cycles of 21 days on/7 days off. 1 KRAS mutant pt, 1 KRAS WT pt. 1 KRAS mutant pt. Dose-escalation: 3 mcrc pts (2 KRAS mutant, 1 KRAS WT); 28-day DLT window for MTD determination Dose-expansion: 2 mcrc pts (all KRAS mutant); other cohorts included NSCLC, metastatic melanoma, solid tumors serial biopsy Primary objectives: safety, clinical activity Bendell J, et al. ASCO 216. Abstract 352.

66 Efficacy Response/tumor volume reduction not associated with PD-L1 status Outcome KRAS-Mutant CRC (n = 2) All CRC (n=23) 4 pts had PRs, 3 of which were mismatch repair proficient (1 not evaluable) Median time to first response: 3.7 mos (range: 1.8 to 4.1) Median DOR: NR (range: 5.4 to 11.1 mos) 2 pts with ongoing responses ORR, % PR SD PD NE PFS Median, mos (95% CI) 6-mo, % (95% CI) ( ) 39 ( ) ( ) 35( ) Increased intratumoral CD8 T-cell infiltration over BL in the mcrc cohort OS Median, mos (95% CI) 6-mo, % (95% CI) NE (6.5-NE) 77 ( ) NE(6.5-NE) 72( ) Bendell J, et al. ASCO 216. Abstract 352.

67 Issues

68

69 Case Presentation Oct 22, 215 December 3, 215

70 Case Presentation May 26, 216 February 8, 217

71 The NEW Tsunami I/O therapy PAYERS

72 Conclusion This is an exciting time to be in Medical Oncology The new I-O drugs are changing the way we look at managing patient with advanced cancer Previously untreatable Stage IV melanoma patients are now experiencing long term survival

73 Conclusion Checkpoint inhibitors have yet to have a defined role in GI malignancies but would expect that to change in the near future especially for SCC anus Phase III trial underway in gastric cancer and hepatoma

74 We have only scratched the surface of what the immune system can potentially be harnessed to do in treating cancer patients

75

76 QUESTIONS?