Cancer Immunotherapy: an Emerging Paradigm

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1 Cancer Immunotherapy: an Emerging Paradigm Branimir I. Sikic, MD Professor of Medicine Stanford University Nevada Cancer Control Summit Reno, November 6, 217

2 T-Cell Response: Second Signals to Accelerate or Brake Activating Signals Inhibitory Signals (brakes) * CD28 OX4 GITR CD137 T cell CTLA-4 PD-1 TIM-3 Releasing these brakes activates T-cells against cancers CD27 BTLA HVEM VISTA LAG-3 T-Cell Stimulation T-Cell Inhibition Mellman I, et al. Nature. 211;48:

3 Mechanism of Action: Ipilimumab releases the CTLA-4 brake on T-cells Jim Allison M.D. Anderson 3

4 Mechanism of Action: PD-1 and PD-L1 antibodies release brakes on T-cells and enable antitumor cytotoxicity 4

5 FDA approval status of Immune CTLA-4 and PD-1 Checkpoint Inhibitors Ipilumumab (CTLA-4): Melanoma (211) Pembrolizumab (PD-1): Melanoma (214) Non-small Cell Lung (215) Head and Neck cancers (216) Microsatellite-Instability High (MSI) solid tumors (217) Bladder cancers (217) Hodgkin lymphoma (217) Nivolumab (PD-1): Melanoma (214) Non-small Cell Lung (215) Renal (215) Hodgkin Lymphoma (216) Head and Neck Squamous (216) Bladder cancers (217)

6 FDA approval status of PD-L1 Checkpoint Inhibitors Atezolizumab: Urothelial cancers (216) Non-small Cell Lung Cancers (NSCLC), (216) Avelumab: NSCLC (216) Merkel Cell cancers (217) Durvalumab: Urothelial cancers (217)

7 Melanoma

8 Nivolumab anti-pd-1 therapy in Metastatic Melanoma: Spider plot of tumor size over time in individuals Topalian et al., NEJM 366: , 212

9 Updated Results From a Phase III Trial of Nivolumab Combined With Ipilimumab in Treatment-naïve Patients With Advanced Melanoma (Checkmate 67) Jedd D. Wolchok, 1 Vanna Chiarion-Sileni, 2 Rene Gonzalez, 3 Piotr Rutkowski, 4 Jean-Jacques Grob, 5 C. Lance Cowey, 6 Christopher D. Lao, 7 Dirk Schadendorf, 8 Pier Francesco Ferrucci, 9 Michael Smylie, 1 Reinhard Dummer, 11 Andrew Hill, 12 John Haanen, 13 Michele Maio, 14 Grant McArthur, 15 Dana Walker, 16 Joel Jiang, 16 Christine Horak, 16 James Larkin, 17* F. Stephen Hodi 18* 1 Memorial Sloan Kettering Cancer Center, Ludwig Institute for Cancer Research and Weill Cornell Medical College, New York, NY, USA; 2 Oncology Institute of Veneto IRCCS, Padua, Italy; 3 University of Colorado Cancer Center, Denver, CO, USA; 4 Maria Sklodowska-Curie Memorial Cancer Center & Institute of Oncology, Warsaw, Poland; 5 Hospital de la Timone, Marseille, France; 6 Texas Oncology-Baylor Charles A. Sammons Cancer Center, US Oncology Research, Dallas, TX, USA; 7 University of Michigan, Ann Arbor, MI, USA; 8 Department of Dermatology, University of Essen, Essen, Germany; 9 European Institute of Oncology, Milan, Italy; 1 Cross Cancer Institute, Edmonton, Alberta, Canada; 11 Universitäts Spital, Zurich, Switzerland; 12 Tasman Oncology Research, QLD, Australia; 13 Netherlands Cancer Institute, Amsterdam, The Netherlands; 14 University Hospital of Siena, Siena, Italy; 15 Peter MacCallum Cancer Centre, Victoria, Australia; 16 Bristol-Myers Squibb, Princeton, NJ, USA; 17 Royal Marsden Hospital, London, UK; 18 Dana-Farber Cancer Institute, Boston, MA, USA. *Contributed equally to the study 9

10 CA29-67: Study Design Design Randomized, double-blind, phase III study to compare NIVO+IPI or NIVO alone to IPI alone N=314 NIVO 1 mg/kg + IPI 3 mg/kg Q3W for 4 doses then NIVO 3 mg/kg Q2W Unresectable or Metatastic Melanoma Previously untreated 945 patients Randomize 1:1:1 Stratify by: Tumor PD-L1 expression* BRAF mutation status AJCC M stage N=316 NIVO 3 mg/kg Q2W + IPI-matched placebo Treat until progression** or unacceptable toxicity N=315 IPI 3 mg/kg Q3W for 4 doses + NIVO-matched placebo *Verified PD-L1 assay with 5% expression level was used for the stratification of patients; validated PD-L1 assay was used for efficacy analyses. **Patients could have been treated beyond progression under protocol-defined circumstances. 1

11 Study Endpoints: NIVO+IPI or NIVO vs IPI Co-primary endpoints: Progression-free survival (PFS) and overall survival (OS) Secondary and exploratory endpoints: Objective response rate (ORR) by RECIST v1.1 Efficacy by tumor PD-L1 expression level Safety profile (in patients who received 1 dose of study drug) Current analysis: Efficacy and safety update with follow-up of at least 18 months OS remains immature 11

12 Progression-Free Survival Median PFS, months (95% CI) HR (99.5% CI) vs. IPI NIVO + IPI (N=314) NIVO (N=316) IPI (N=315) 11.5 ( ) 6.9 ( ) 2.9 ( ).42 (.31.57)*.55 (.43.76)* -- Progression-free Percentage Survival of PFS (%) HR (95% CI) vs. NIVO 49% 42%.76 (.6.92)** 46% 39% *Stratified log-rank P<.1 vs. IPI **Exploratory endpoint 2 1 NIVO+IPI NIVO IPI 18% % PFS per Investigator (months) Number of patients at risk: Nivolumab + Ipilimumab Nivolumab Ipilimumab Database lock Nov

13 Response To Treatment NIVO + IPI (N=314) NIVO (N=316) IPI (N=315) ORR, % (95% CI)* Two-sided P value vs IPI <.1 <.1 -- Best overall response % Complete response Partial response Stable disease Progressive disease Unknown Median duration of response, months (95% CI) NR Ongoing response among responders, % *By RECIST v1.1. NR = not reached. Database lock Nov

14 Progression-free Survival by Tumor PD-L1 Expression Tumor PD-L1 Expression Level <5% Tumor PD-L1 Expression Level 5% Median PFS, months (95% CI) HR (95% CI) vs NIVO NIVO + IPI (N=21) 11.1 ( ).74 (.58.96)* NIVO (N=28) 5.3 ( ) IPI (N=22) 2.8 ( ) Median PFS, months (95% CI) HR (95% CI) vs. NIVO NIVO + IPI (N=212) NR (9.7 NR).87 ( )* NIVO (N=218) 22. (8.9 NR) IPI (N=215) 3.9 ( ) Percentage of PFS Percentage of PFS NIVO + IPI 2 NIVO + IPI 1 NIVO IPI 1 NIVO IPI PFS (months) PFS (months) Number of patients at risk: NIVO + IPI Number of patients at risk: NIVO + IPI NIVO NIVO IPI IPI For the original PD-L1 PFS analysis, the descriptive hazard ratio comparing NIVO+IPI vs NIVO was.96, with a similar median PFS in both groups (14 months) Database lock Nov

15 Response to Treatment by Tumor PD-L1 Expression* NIVO+IPI NIVO IPI PD-L1 ( 5%) PD-L1 (<5%) ORR, % (95% CI) Median Duration of Response (months) ORR, % (95% CI) Median Duration of Response (months) NR 2.7 NR NR *Pre-treatment tumor specimens were centrally assessed by PD-L1 immunohistochemistry (using a validated BMS/Dako assay). Database lock Nov

16 Safety Summary Patients reporting event, % Treatment-related adverse event (AE) Any Grade NIVO+IPI (N=313) Grade 3-4 Any Grade NIVO (N=313) Grade 3-4 Any Grade IPI (N=311) Grade Treatment-related AE 68.8% leading of to patients who discontinued 39 NIVO+IPI 31 due 11 to treatment-related 7 15AEs achieved 14 a response discontinuation Treatment-related.3.3 death* *One reported in the NIVO group (neutropenia) and one in the IPI group (colon perforation) Database lock Nov

17 Most Common Treatment-related Select AEs Any Grade NIVO+IPI (N=313) Grade 3-4 Any Grade NIVO (N=313) Grade 3-4 Any Grade IPI (N=311) Grade 3-4 Skin AEs, % Rash Pruritus Gastrointestinal AEs, % Diarrhea Colitis Endocrine AEs, % Hypothyroidism Hyperthyroidism Hepatic AEs, % Elevated ALT Elevated AST Pulmonary AEs, % Pneumonitis Renal AEs, % Elevated creatinine Immune-modulating medicines were used to manage adverse events and led to resolution rates of immune mediated AEs in the vast majority (>85%) of patients Database lock Nov

18 Conclusions NIVO+IPI and NIVO alone significantly improved PFS and ORR versus IPI alone, in patients with untreated advanced melanoma The combination resulted in greater PFS and ORR than NIVO alone, including patients with poor prognostic factors Majority of treatment-related AEs resolved with immunemodulating medications 18

19 Squamous Cell Carcinomas of the Head and Neck

20 Nivolumab in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck After Platinum Therapy: Overall Survival 1 Median OS, mo (95% CI) HR (97.73% CI) P-value Overall Survival (% of patients) Nivolumab (n = 24) 7.5 (5.5, 9.1) Investigator s Choice (121) 5.1 (4., 6.).7 (.51,.96) 1-year OS rate (95% CI) 36.% (28.5, 43.4) Months 16.6% (8.6, 26.8) No. at Risk Nivolumab Investigator s Choice

21 Nivolumab in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck After Platinum Therapy Overall Survival by Tumor PD-L1 Expression 1 1 PD-L1 1% PD-L1 < 1% HR (95% CI) 8 HR (95% CI) Overall Survival (% of patients) Investigator s Choice (n = 61).55 (.36,.83) Nivolumab (n = 88) Overall Survival (% of patients) (.54, 1.45) Nivolumab (n = 73) Investigator s Choice (n = 38) No. at Risk Months Months Nivolumab Investigator s Choice

22 Treatment-Related Adverse Events Nivolumab in R/M SCCHN After Platinum Therapy Event Any grade n (%) Nivolumab (n = 236) Grade 3 4 n (%) Any grade n (%) Investigator s Choice (n = 111) Grade 3 4 n (%) Any treatment-related AE 139 (58.9) 31 (13.1) 86 (77.5) 39 (35.1) Fatigue 33 (14.) 5 (2.1) 19 (17.1) 3 (2.7) Nausea 2 (8.5) 23 (2.7) 1 (.9) Diarrhea 16 (6.8) 15 (13.5) 2 (1.8) Anemia 12 (5.1) 3 (1.3) 18 (16.2) 5 (4.5) Asthenia 1 (4.2) 1 (.4) 16 (14.4) 2 (1.8) Mucosal inflammation 3 (1.3) 14 (12.6) 2 (1.8) Alopecia 14 (12.6) 3 (2.7) Skin 37 (15.7) 14 (12.6) 2 (1.8) Endocrine 18 (7.6) 1 (.4) 1 (.9) Gastrointestinal 16 (6.8) 16 (14.4) 2 (1.8) Hepatic 5 (2.1) 2 (.8) 4 (3.6) 1 (.9) Pulmonary 5 (2.1) 2 (.8) 1 (.9) Hypersensitivity/infusion reaction 3 (1.3) 2 (1.8) 1 (.9) Renal 1 (.4) 2 (1.8) 1 (.9)

23 Nivolumab in Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck After Platinum Therapy: Conclusions Nivolumab is the first agent to demonstrate a significant improvement in survival in patients with SCCHN who progress after platinum-based therapy Nivolumab doubled the 1-year survival rate: 36% with nivolumab compared to 17% for investigator s choice therapy Nivolumab demonstrated survival benefit regardless of PD-L1 expression or p16 status There were fewer treatment-related adverse events with nivolumab vs investigator s choice therapy Nivolumab is a new standard-of-care option for patients with R/M SCCHN after platinum-based therapy

24 Non-Small Cell Lung Cancers

25 Nivolumab is superior to docetaxel in previously treated patients with NSCLC NEJM 373: , 215

26 Failure of first-line immunotherapy with nivolumab versus chemotherapy in NSCLC ( CheckMate-26 ) Primary endpoint: Progression free survival 4.2 m for nivo and 5.9 m for chemotherapy 423 patients PD-L1 expression > 5% Carbone et al., NEJM 217; 376:

27 Pembrolizumab versus platinum-based chemotherapy first line in 35 NSCLC patients with high PD-L1 expression ( Keynote-24) Subset (25-3%) of patients with very high (> 5%) PD-L-1 expression PFS 1.3 m for pembrolizumab vs. 6. m for chemotherapy HR for survival.6 in favor of pembro vs chemo NEJM 216; 375:

28 Reck ESMO 216

29 Pembrolizumab versus platinum-based chemotherapy first line in NSCLC patients with high PD-L1 expression ( Keynote-24 )

30 Keynote 24 Take Home First major change in treatment of first line since megfr inhibitors Establishes mono-immunotherapy as initial treatment Applies to about 3% of first line NSCLC patients (very high PDL-1) Caveat: 5% of control pts did not cross over, so Overall Survival (OS) might not reflect real world Leaves many unanswered questions: Dose? Duration of therapy?

31 Combing Two Different Checkpoint Inhibitors in NSCLC CheckMate 12: Safety and Efficacy of First line Nivolumab and Ipilimumab in Advanced NSCLC Presented By Matthew Hellmann at 216 ASCO Annual Meeting

32 Pilot Study Results Nivolumab Plus Ipilimumab in First-line NSCLC:<br />Kinetics of Response Presented By Matthew Hellmann at 216 ASCO Annual Meeting

33 Nivolumab Plus Ipilimumab in First-line NSCLC: Conclusions Presented By Matthew Hellmann at 216 ASCO Annual Meeting

34 Nivolumab Antitumor Activity Waterfall plots of tumor regression Max Change in Target Lesions From BL (%) Max Change in Tumor Burden From BL (%) Melanoma (n = 272) [1] Pts Advanced RCC (N = 34) [3] Pts 1 mg/kg nivolumab 1 mg/kg nivolumab Max Change in Target Lesions From BL (%) Max Change in Tumor Burden From BL (%) Stable Disease Advanced NSCLC (N = 117) [2] Pts Hodgkin s Lymphoma (N = 23) [4] Partial Response Pts Alive Dead Confirmed responders Complete Response 1. Weber JS, et al. Lancet Oncol. 215;16: Rizvi NA, et al. Lancet Oncol. 215;16: McDermott DF, et al. J Clin Oncol. 215;[Epub ahead of print]. 4.Ansell SM, et al. N Engl J Med. 215;372:

35 Pembrolizumab Antitumor Activity Waterfall plots of tumor regression Change From Baseline in Sum of Largest Diameter of Target Lesions (%) Melanoma [1] (N = 411) KEYNOTE NSCLC [2] (N = 262) KEYNOTE HNSCC [3] (N = 61) KEYNOTE-12 Change From Baseline in Sum of Largest Diameter of Target Lesions (%) Urothelial Cancer [4] (N = 33) KEYNOTE Gastric Cancer [5] (N = 39) KEYNOTE TNBC [6] (N = 32) KEYNOTE chl [7] (N = 29) KEYNOTE Robert C, et al. Lancet. 214;384: Garon EB, et al. ESMO 214. LBA Chow LQ, et al. ESMO 214. LBA O Donnell P, et al. ASCO GU 215. Abstract Muro K, et al. ASCO GI 215. Abstract Nanda R, et al. SABCS 214. Abstract S Moskowitz C, et al. ASH 214. Abstract 29.

36 Summary of Activity of PD-1/PDL-1 inhibitors Survival: Melanoma, Lung, Renal, SCCHN RR or PFS: Hodgkin s, Merkel, MSI-H Colorectal > 1% RR: Anal, Bladder, Biliary, Breast, DBLCL, Esophageal, Gastric, HCC Mesothelioma, Myeloma, NPC, Ovarian, SCLC Not active: Colorectal (MSI-L), Pancreas, Prostate 36

38 Immunotherapy Adverse Events Onset: Average is 6-12 weeks after initiation of therapy Can occur within days of the first dose, after several months of treatment, and after discontinuation of therapy Patient complaints are autoimmune and drugrelated until proven otherwise Rule out infections, metabolic causes, tumor effects, etc. Early recognition, evaluation, and treatment are critical Slide courtesy of Joel Neal MD/PHD

39 General Principles of Immune-related Toxicity Management Generally based on severity of symptoms Grade 1: Supportive care; +/- withhold drug Grade 2: Withhold drug, consider redosing if toxicity resolves to grade 1; low-dose corticosteroids (prednisone.5 mg/kg/day or equivalent) if symptoms do not resolve within a week Grade 3-4: Discontinue drug; high-dose corticosteroids (prednisone 1-2 mg/kg/day or equivalent) tapered over 1 month once toxicity resolves to grade 1 Slide courtesy of Joel Neal MD/PHD

40 Management of Immune Checkpoint Toxicity A Multidisciplinary Approach Dermatologist Endocrinologist Gastroenterologist Medical oncologist Pulmonologist Neurologist Slide courtesy of Jeffrey Crawford MD

41 Future Directions More than 8 trials of PD-1 inhibitors in many types of cancer Combinations with other immunotherapies, such as vaccines and other antibodies Utility in minimal disease settings, such as adjuvant therapies and consolidation for patients in clinical complete remission Predictive markers for response (PD-1, PDL-1, MSI)

43 Thanks to Dr. Daniel Hoth for insights and slides

44 The Future of Oncology is Bright!

45 Thank you! Questions?

Índice. Melanoma Cáncer de Pulmón Otros tumores

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