Immunology and Immunotherapy. Ulrich Keilholz Charité Comprehensive Cancer Center

Transcription

1 Immunology and Immunotherapy Ulrich Keilholz Charité Comprehensive Cancer Center

2 DISCLOSURE SLIDE Advisory boards, speaker bureau, trial support, research collaboration Amgen AstraZeneca BMS Boehringer Ingelheim Glycotope Innate Lilly Medimmune MerckSerono MSD/Merck Novartis Pfizer Roche/Genentech U N I V E R S I T Ä T S M E D I Z I N B E R L I N 2

3 DISCLOSURE SLIDE Advisory boards, speaker bureau, trial support, research collaboration Amgen AstraZeneca BMS Boehringer Ingelheim Glycotope Innate Lilly Medimmune MerckSerono MSD/Merck Novartis Pfizer Roche/Genentech Unfortunately, there are still a few companies without head and neck cancer programs U N I V E R S I T Ä T S M E D I Z I N B E R L I N 3

4 Current situation of SCCHN drug treatment Induction chemotherapy ( TPF ) Radiochemotherapy Radioimmunotherapy First line rec/met Second line rec/met

5 Cetuximab in 1 st -line r/m SCCHN EXTREME: Phase III study design r/m SCCHN Stratified by Prior CT KPS (<80 vs 80) N=442 Cetuximab until PD CT CT CT Cisplatin (100 mg/m 2 IV, day 1) or Carboplatin (AUC 5, day 1) + 5-FU (1000 mg/m 2 /day IV, days 1 4) Every 3 weeks, up to 6 cycles Cetuximab Initial dose 400 mg/m 2 then 250 mg/m 2 weekly until PD Primary endpoint: OS Secondary endpoints include: PFS, RR, safety Vermorken JB, et al. N Engl J Med 2008;359:

6 RR and platin agent Cisplatin-based CT p= PD rate 19% Carboplatin-based CT p= PD rate 40% Cisplatin/ 5-FU (n=135) Cisplatin/ 5-FU + Erbitux (n=149) Carboplatin/ 5-FU (n=80) Carboplatin/ 5-FU + Erbitux (n=69) Data on file

7 PFS results Progression-free survival (%) month s 5.6 months CT (n=220) Cetuximab + CT (n=222) HR=0.54 (95% CI: ) p< months Months Vermorken JB, et al. N Engl J Med 2008;359:

8 OS results Overall survival (%) months 10.1 months CT (n=220) Cetuximab + CT (n=222) HR=0.80 (95% CI: ) p= months Months Vermorken JB, et al. N Engl J Med 2008;359:

9 ADCC: Antibody-dependent cell-mediated cytotoxicity Lysis of antibody-coated cell Namboodiri AM & Pandey JP. Clin Exp Immunol 2011;166:361-5

10 New components 2016 PD1 inhibitors 10 Title of Presentation DD.MM.YYYY

11 Failure of Immunesurveillance T-cell T- cell Tumor Tumor Tumor Tumor no Antigen no AG-specific blockade of Immunoevasisve T cell response AG-specific Microenvironment T cells

12

13 Development of autoimmunity effector cell Execution of immunity Antigen TCR TCR Antigen Antigen presenting cell Tumor cell Apoptosis Chemotherapy Radiotherapy Necrosis

14 Antibody to CTLA4 effector cell Antibody to PD1/PDL1 Development of autoimmunity CTLA4 CD28 PD1 Execution of immunity B7 B7 PD-L1 Antigen presenting cell Tumor cell Immune - checkpoint - blockade

15 T-cell-Targets for immunoregulatory antibodies I Mellman et al. Nature 480, (2011)

16 PD1 / PD-L1 agents in clinical testing (as of June 2016)

17 Example: Pembrolizumab Antitumor Activity (execution of immunity) Melanoma 1 (N=655) KEYNOTE NSCLC 2 (N=262) KEYNOTE-001 H&N 3 (N=132) KEYNOTE-012 Urothelial 4 (N=33) KEYNOTE-012 Gastric 5 (N=39) KEYNOTE TNBC 6 (N=32) KEYNOTE-012 chl 7 (N=29) KEYNOTE-013 Mesothelioma 8 (N=25) KEYNOTE-028 Ovarian 9 (N=26) KEYNOTE-028 SCLC 10 (N=20) KEYNOTE-028 Esophageal 11 (N=23) KEYNOTE-028 Change From Baseline in Tumor Size, % chl = classical Hodgkin s lymphoma; H&N = head and neck; NSCLC = non-small cell lung cancer; TNBC = triple-negative breast cancer. 1. Daud A et al ASCO; 2. Garon EB et al. ESMO 2014; 3. Seiwert T et al ASCO; 4. Plimack E et al ASCO; 5. Bang YJ et al ASCO; 6. Nanda R et al. 17 SABCS 2014; 7. Moskowitz C et al ASH Annual Meeting; 8. Alley EA et al AACR; 9. Varga A et al ASCO; 10. Ott PA et al ASCO; 11. Doi T et al ASCO.

18

19 Efficacy and Safety Results From a Phase III Trial of Nivolumab Alone or Combined With Ipilimumab vs. Ipilimumab Alone in Treatment-naïve Patients With Advanced Melanoma (CheckMate 067) Presented By Jedd Wolchok at 2015 ASCO Annual Meeting

20 Slide 12 Presented By Jedd Wolchok at 2015 ASCO Annual Meeting

21 CheckMate 141 and KEYNOTE-055 (ASCO 2016) Inclusion criteria Nivolumab: CheckMate Pembrolizumab: KEYNOTE-055 2,3 Age 18 years PS 1 R/M SCCHN not amenable to curative local therapy Tumor progression or recurrence within 6 months of last dose of platinum therapy in the adjuvant, recurrent or metastatic setting Measurable disease by CT or MRI Age 18 years PS 1 R/M SCCHN not amenable to curative local therapy Tumor progression or recurrence within 6 months of any number of platinum-bases and cetuximab therapy lines in the adjuvant, recurrent or metastatic setting Must be resistant (not responding) to both platinum and cetuximab Measurable disease by CT or MRI 1. Ferris RL, et al. ASCO 2016 (Abstract No. 6009); 2. Bauml J, et al. ASCO 2016 (Abstract No. 6011); 3. (Accessed May 29, 2016).

22 New potential options in 2nd line R/M SCCHN (ASCO 2016) Nivolumab 1 Pembrolizumab 2 Nivolumab CheckMate vs IC n=240 ORR, % 13.3 vs 5.8 (NS) CR, % 2.5 vs 0.8 PR, % 10.8 vs 5.0 SD, % 22.9 vs 35.5 PD, % 41.7 vs 34.7 Not determined mpfs (mo) ORR, overall response rate; CR complete response; PD, progressive disease; PR, partial 22.1 vs vs 2.3 (NS) KEYNOTE n=92 ORR, % 17 PR, % 17 SD, % 19 PD, % 55 Not applicable 9 Patients with 6 months follow-up 1. Ferris RL, et al. ASCO 2016 (Abstract No. 6009); 2. Bauml J, et al. ASCO 2016 (Abstract No. 6011).

23 PEMBROLIZUMAB AFTER PROGRESSION ON PLATINUM AND CETUXIMAB IN HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC): RESULTS FROM KEYNOTE-055 Robert Haddad, 1 Tanguy Seiwert, 2 David G. Pfister, 3 Francis Worden, 4 Stephen V. Liu, 5 Jill Gilbert, 6 Nabil F. Saba, 7 Jared Weiss, 8 Lori Wirth, 9 Ammar Sukari, 10 Hyunseok Kang, 11 Michael K. Gibson, 12 Erminia Massarelli, 13 Steven Powell, 14 Amy Meister, 15 Xinxin Shu, 15 Jonathan Cheng, 15 Joshua Bauml 16 1 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; 2 University of Chicago, Chicago, IL, USA; 3 Memorial Sloan Kettering Cancer Center, New York, NY, USA; 4 University of Michigan Comprehensive Cancer Center, Ann Arbor, MI, USA; 5 Georgetown University Hospital, Washington, DC, USA; 6 Vanderbilt University School of Medicine, Nashville, TN, USA; 7 Winship Cancer Institute/Emory University, Atlanta, GA, USA; 8 Lineberger Comprehensive Cancer Center at the University of North Carolina, Chapel Hill, NC, USA; 9 Massachusetts General Hospital, Boston, MA, USA; 10 Karmanos Cancer Institute, Wayne State University, Detroit, MI, USA; 11 Johns Hopkins University School of Medicine, Baltimore, MD, USA; 12 University Hospitals Case Medical Center, Cleveland, OH, USA; 13 The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 14 Sanford Health, Sioux Falls, SD, USA; 15 Merck & Co., Inc., Kenilworth, NJ, USA; 16 University of Pennsylvania, Philadelphia, PA, USA J Clin Oncol, Sep 2016 esmo.org

24 KEYNOTE-055: Single Arm, Phase 2 Trial in R/M HNSCC After Progression on Platinum/Cetuximab Patients Recurrent/ metastatic HNSCC Resistant to platinum and cetuximab Measurable disease (RECIST v1.1) ECOG PS 0-1 Pembrolizumab 200 mg Q3W Flat Dose Continue until: 24 months of treatment Progressive Disease Intolerable toxicity Investigator/patient decision Safety and Survival Follow-up Response assessment: Every 6-9 weeks Primary end points: ORR (RECIST v1.1, central imaging vendor) in all patients and PD-L1+ patients, safety Secondary end points: ORR in HPV+ patients, PFS, OS, duration of response ORR, overall response rate; Q3W, every three weeks. Defined as tumor progression/recurrence within 6 months of last platinum and cetuximab dose.

25 Efficacy of pembrolizumab on the basis of RECIST (v1.1; Response Evaluation Criteria in Solid Tumors) by central imaging vendor review. Laura Q.M. Chow et al. JCO doi: /jco by American Society of Clinical Oncology

26 (A) Association of efficacy and programmed death-ligand 1 (PD-L1) expression by American Society of Clinical Oncology Laura Q.M. Chow et al. JCO

27 27 ESMO Pres. Symp and New Engl J Med Oct 2016

28 28 ESMO Pres. Symp and New Engl J Med Oct 2016

29 29 ESMO Pres. Symp and New Engl J Med Oct 2016

30 30 ESMO Pres. Symp and New Engl J Med Oct 2016

31 A Comparative Study of PD-L1 Diagnostic Assays in Head and Neck Squamous Cell Carcinoma 955PD M.J. Ratcliffe 1, A. Sharpe 2, M.C. Rebelatto 3, M. Scott 2, C. Barker 2, P. Scorer 2, J. Walker 2 1 AstraZeneca, Alderley Park, UK; 2 AstraZeneca, Cambridge, UK; 3 MedImmune, Gaithersburg, MD, USA ESMO 2016

32 How reliable is the PD-L1 immunohistology? Multiple PD-L1 IHC diagnostic assays have been and are being developed for use with individual therapies Dako PD-L1 IHC 22C3 pharmdx is approved as an IVD companion diagnostic for use with pembrolizumab Dako PD-L1 IHC 28-8 pharmdx is approved as an IVD complementary diagnostic for use with nivolumab The VENTANA PD-L1 (SP142) Assay is approved as an IVD complementary diagnostic for use with atezolizumab The VENTANA PD-L1 (SP263) Assay is in development for use with durvalumab The four assays have been developed independently 1 4 Within the next 2 years, it is likely that multiple PD-L1 assays will be available It is vital to compare the analytical performance of PD-L1 diagnostic assays Methods 501 archival clinical HNSCC (Stage I IV) tumour samples were obtained from a commercial source Testing was performed on consecutive tissue sections by one of three pathologists trained by the manufacturer, in a CLIA programme-certified laboratory CLIA, Clinical Laboratory Improvement Amendments; HNSCC, head and neck squamous cell carcinoma; IHC, immunohistochemistry; IVD, in vitro diagnostic; PD-L1, programmed cell death ligand-1 1. Roach C, et al. Appl Immunohistochem Mol Morphol 2016;24: Phillips T, et al. Appl Immunohistochem Mol Morphol 2015;23: Boyd ZS, et al. Cancer Immunol Res 2016;4(1 Suppl.):B001 (abstr) 4. Rebelatto M, et al. J Clin Oncol 2015;33(15_Suppl.):8033 (abstr)

33 28-8 and Dako 22C3 assays in HNSCC Intrinsic inter-assay agreement 3 assays scored by a single pathologist (n=114) Tumour cells* Cutof f Dako 22C3 Dako 28-8 Ventana 1% 89.5 (83.5) 92.1 (86.6) SP263 5% 90.4 (84.5) 91.2 (85.6) (83.5) 91.2 (85.6) % (89.9) 94.7 (89.9) Immune Cutof % cells* f 50 Dako 98.3 (94.6) 22C Dako (92.2) 28-8 Ventana 1% % 91.2 (85.6) 95.6 (91.0) SP263 5% 91.2 (85.6) 95.6 (91.0) 10 % 85.1 (78.5) 88.6 (82.5) (92.2) 95.6 (91.0) = OPA >85% % 50 % (97.4) 99.1 (95.9) Dako 22C3 and Dako 28-8 showed good agreement with Ventana SP263 across the assay range for tumour cell staining and immune cell staining Intrinsic assay OPA >85% across multiple cutoffs for both tumour cells and immune cells 33

34 Overall percentage agreement (OPA) between assays (multiple pathologists) Tumour cells* Ventana SP263 Immune cells* Ventana SP263 Cutof f Dako 22C3 Dako 28-8 Ventana SP142 1% 81.8 (78.6) 86.3 (83.5) 56.1 (52.3) 5% 84.7 (81.7) 88.0 (85.3) 70.2 (66.6) 10 % 89.2 (86.6) 89.0 (86.4) 77.4 (74.1) 25 % 92.8 (90.5) 93.0 (90.7) 86.8 (83.9) 50 Cutof 95.7 Dako (93.8) 94.8 (92.8) 92.1 (89.8) % Dako 28-8 Ventana f 22C3 SP142 1% 83.2 (80.2) 89.0 (86.4) 68.5 (64.9) 5% 82.0 (78.9) 87.0 (84.2) 56.9 (53.1) 10 % 80.5 (77.3) 82.2 (79.1) 67.7 (64.0) 25 % 96.7 (95.0) 94.8 (92.8) 95.2 (93.3) 50 % 99.2 (98.1) 98.1 (96.8) 99.2 (98.1) = OPA >85% = OPA >80% <85% = OPA <80% With the inclusion of multiple readers, OPA was still high for three of the four assays tested Concordance with Ventana SP142 was less strong, particularly at lower cutoffs Ventana SP142 sensitivity appears lower than the other three assays Severe disparaties around cutoff level

35 PERSONAL COMMENT Problem of the heterogeneity observed Largest inhomogeneity around frequently used cutoff levels Use cases for PD-L1 assays Enrichment of patient cohorts, stratification Assays potentially interchangeably, but not within one study Decision on treatment allocation (PD1 / PD-L1 agent yes or no) We are not there, assay concordance needs to be much better Decision on license / reimbursement Emerging, but different assays and cutoffs for different histologies Excellent study, but this is only the beginning

36 Biomarkers Presented By Tanguy Seiwert at 2015 ASCO Annual Meeting

37 Approximate proportion of patients (%) PD-1 Blockade: Kinetics of iraes in Melanoma Skin Time (weeks) Gastrointestina Endocrine Hepatic Pulmonary Renal Weber JS, et al. ASCO

38 08. June 2016 New SOB

39 29. July wks predisolone

40 07. Oct wks predisolone

41 Charité Head and Neck Cancer Study Group Radiooncoogy Inge Tinhofer-Keilholz Carmen Stromberger Volker Budach ENT Surgery Veit Hoffmann Andreas Albers Steffen Dommerich Katharina Stölzel Pathology Korinna Jöhrens Medical Oncoogy Konrad Klinghammer Damian Rieke Sebastian Ochsenreither Ulrich Keilholz Maxilofacial Srugery Jan-Dirk Raguse Thomas Plath Andreas Erwens U N I V E R S I T Ä T S M E D I Z I N B E R L I N 41