Inmunoncología en cáncer de colon Estado del arte. Dra. García Alfonso Jefe de Sección de Oncología Médica HGU Gregorio Marañón

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1 Inmunoncología en cáncer de colon Estado del arte Dra. García Alfonso Jefe de Sección de Oncología Médica HGU Gregorio Marañón

2 Cáncer Colorrectal No es sensible Inmunoterapia

3 Cáncer Colorrectal Inmunoterapia MSI 3%

4 Rhabdoid tumour Ewing sarcoma Thyroid Acute myeloid leukaemia Medulloblastoma Carcinoid Neuroblastoma Prostatre Chronic lymphocytic leukaemia Low-grade glioma Breast Pancreas Multiple myeloma Kidney clear cell Kidney papillary cell Ovarian Glioblastoma multiforme Cervical Diffuse large B-cell lymphoma Head and neck Colorectal Esophageal adenocarcinoma Stomach Bladder Lung adeno-carcinoma Lung squamous cell carcinoma Melanoma Somatic mutation frequency (/Mb) Frequency of genetic somatic mutations in cancer No at Risk MSI No MSI 0.01 C T C A C G T C T A T G Altered proteins contain new epitopes for immune recognition, providing a common denominator for cancer immunotherapy Lawrence Nature 2013

5 TCGA CCR: Subtipos Hipermutado (> 12 mut/10 6 bases): 16% 3/4 MSI, generalmente por hipermetilación del promotor del gen MLH1 1/4 mutaciones somáticas MMR y mutaciones POLE TCGA. Nature 2012

6 Diferentes tipos de CCR se correlacionan con distintos perfiles de expresión génica

7 Características de los subgrupos moleculares Nat Med Nov;21(11):1350-6

8 Overall Survival (n=2,796) Overall logrank p= * CMS4 vs. CMS2 HR = 1.7 ( ) p = * * Adjusted for stage, MSI, BRAF mut, adjuvant chemotherapy, and stratified by dataset. N at risk 2,796 2,253 1,991 1,778 1,526 1, All follow-up times censored at 72 months

9 El CSM4 (Mesenquimal) es el de peor pronóstico globalmente El CSM1 (MSI inmune) es el de peor pronóstico tras la recaida El CSM2 (Canónico) es el de mejor pronóstico tras la recaida RFS OS Survival after relaps Nat Med Nov;21(11):1350-6

10 MSI

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12 Slide 5 Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

13 MSI Orienta al Consejo Genético Marcador pronóstico en estadio II Marcador predictivo a la inmunoterapia (Categoría IIB) Incidencia Estadio II (15%); III: 12%; IV: 3% *NCCN guidelines validate testing for MSI-H 1. Sargent DJ et al. J Clin Oncol. 2010; 28(20): NCCN Guidelines V Venderbosch S et al. Clin Cancer Res. 2014; 20(20): Richman S. Int J Oncol. 2015; 47(4): Van Cutsem E et al. Ann Oncol. 2016; 27(8):

14 Consejo Genético Slide 6 Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

15 Slide 12 Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

16 Slide 13 Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

17 PFS probability OS probability The Value of dmmr/msi-h as a Predictive Biomarker for Chemotherapies in mcrc Is Under Investigation PFS by MMR status OS by MMR status 1 pmmr dmmr Months from randomization 0.8 pmmr dmmr Months from randomization dmmr Status: Prevalence 2 dmmr, n (%) pmmr, n (%) Total, N CAIRO* 18 (5.6%) 304 (94.4%) 322 CAIRO2* 29 (5.6%) 487 (94.4%) 516 COIN 65 (4.4%) 1396 (95.6%) 1461 FOCUS 41 (5.4%) 723 (94.6%) 764 Pooled data set 153 (5.0%) 2910 (95.0%) 3063 *dmmr testing assessed by IHC with PCR in the absence of MMR protein expression. dmmr testing assessed by PCR. dmmr testing assessed by IHC. dmmr, deficient mismatch repair; IHC, immunohistochemistry; mcrc, metastatic colorectal cancer; OS, overall survival; PCR, polymerase chain reaction; PFS, progression-free survival; pmmr, proficient mismatch repair. 1. Koopman M et al. Br J Cancer. 2009;100(2): Venderbosch S et al. Clin Canc Res. 2014;20(20):

18 Pathologic Features of dmmr CRCs

19 Microambiente en CCR con MSI TIL (linfocitos infiltrantes del tumor) productores de Interferon Gamma PD-1 Células mieloides infiltrantes del tumor PDL-1 + Cancer Discovery 2015 Doi: / CD

20 Essential role of pre-existing immunity: The Immune contexture The nature, functional orientation, density and location of adaptive immune cells within distinct tumor regions influence the risk of relapse Pages et al, NEJM 2005; Galon et al, Science 2006; Tosolini et al, Cancer Res 2011

21 Slide 29 Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

22 Therapeutic strategies according to immune contexture Kim and Chen 2016 Ann Oncol; Hedge et al 2016 Clin Cancer Res

23 Ensayos Clínicos

24 Ensayos de Inmunoterapia en CCRm

25 <br />Study Design: KEYNOTE-164

26 Pembrolizumab in digestive tumors: dmmr N Engl J Med 2015;372: DOI: /NEJMoa

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28 Keynote 177<br />first line mcrc MSI-H Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

29 Nivolumab +/- Ipilimumab (Checkmate 142)Study Design Stage 1 a Stage 2 b Patients Histologically confirmed metastatic/recurrent CRC dmmr/msi-h per local laboratory 1 prior line of therapy Nivolumab 3 mg/kg Q2W Stage 1 c Nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses Then nivolumab 3 mg/kg Q2W Nivolumab 3 mg/kg Q2W Stage 2 d Nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses Then nivolumab 3 mg/kg Q2W Primary endpoint: ORR per investigator assessment Secondary endpoint: ORR per blinded independent central review (BICR) Other endpoints: PFS, OS, biomarkers, safety and tolerability Q2W, every 2 weeks; Q3W, every 3 weeks. a Enrollment complete; b Opened based on an adequate ORR (CR + PR) in patients with centrally confirmed MSI-H CRC treated in mstage 1; c Opened despite an adequate ORR in mstage 1 to proceed to mstage2; d Opened based on an adequate ORR in cstage 1. Modified form Overman MJ, et al. ASCO-GI Poster oral #519

30 Phase 2 CheckMate 142 Study Design: Microsatellite Stable (MSS) Cohort Presented By Michael Overman at 2016 ASCO Annual Meeting "Uso experimental no autorizado"

31 Checkmate 142 (phase II)<br />Anti-PD1 +/- Anti CTLA-4 in MSI-H mcrc Presented By Heinz-Josef Lenz at 2017 ASCO Annual Meeting

32 NIVOLUMAB en monoterapia Response and Disease Control Patients, n (%) ORR, n (%) 95% CI Best overall response, n (%) CR PR SD PD Unable to determine Disease control for 12 weeks, n (%) a dmmr/msi-h per Local Laboratory (N = 74) dmmr/msi-h per Central Laboratory (n = 53) Investigator BICR Investigator BICR 23 (31.1) 20.8, (31.1) 29 (39.2) 18 (24.3) 4 (5.4) 20 (27.0) 17.4, (2.7) 18 (24.3) 28 (37.8) 20 (27.0) 6 (11.1) 19 (35.8) 23.1, (35.8) 21 (39.6) 10 (18.9) 3 (5.7) 17 (32.1) 19.9, (1.9) 16 (30.2) 21 (39.6) 12 (22.6) 3 (5.7) 51 (68.9) 46 (62.2) 39 (73.6) 37 (69.8) BICR, blinded independent central review. a Patients with CR, PR, or SD for 12 weeks. Overman MJ, et al. ASCO-GI Poster oral #519

33 CheckMate 142: MMR-D pts treated with Nivo (74 pts) Overman ASCO-GI 2017

34 Better Better Mean Change From Baseline Mean Change From Baseline Mean Change From Baseline Worse Worse Worse Worse Mean Change From Baseline Mean Change From Baseline Better Better Patient Reported Outcomes: EORTC QLQ-C Global Health Status/ QOL Role Functioning Clinically meaningful ( 10-point change) 1 improvements were reported in QOL, functioning, and symptoms as early as week Weeks Weeks 30 Fatigue 30 Appetite Loss 30 Pain Better Worse Weeks Patients Weeks Patients Weeks Patients QOL, quality of life. 1. Osoba D et al. J Clin Oncol. 1998;16: Overman MJ, et al. ASCO-GI Poster oral #519

35 3531 Combination of nivolumab (NIVO) + ipilimumab (IPI) in the treatment of patients (pts) with deficient DNA mismatch repair (dmmr)/high microsatellite instability (MSI-H) metastatic colorectal cancer (mcrc): CheckMate 142 Study Thierry Andre, 1 Sara Lonardi, 2 Ka Yeung Mark Wong, 3 Michael Morse, 4 Ray McDermott, 5 Andrew Hill, 6 Alain Hendlisz, 7 Heinz-Josef Lenz, 8 Joseph Leach, 9 Rebecca A. Moss, 10 Z. Alexander Cao, 10 Jean-Marie Ledeine, 11 Scott Kopetz, 12 Michael Overman 12 1Hopital Saint Antoine, Paris, France; 2 Istituto Oncologico Veneto IOV-IRCSS, Padova, Italy; 3 The University of Sydney, Sydney Medical School, Sydney, Australia; 4 Duke University Office of Research Administration, Durham, NC, USA; 5 St Vincent s University Hospital, Dublin, Ireland; 6 Tasman Oncology Research Pty Ltd, Southport, Queensland, Australia; 7 Institut Jules Bordet, Brussels, Belgium; 8 University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA, USA; 9 Allina Health System, Minneapolis, MN, USA; 10 Bristol-Myers Squibb, Princeton, NJ, USA; 11Bristol-Myers Squibb, Braine-l Alleud, Belgium; 12 MD Anderson Cancer Center, Houston, TX, USA Andre T., et al. ASCO Poster oral #3531

36 Efficacy Investigator-assessed response was achieved in 55% of patients and the disease control rate was 79% dmmr/msi-h (N = 84) ORR, n (%) [95% CI] Best overall response, n (%) CR PR SD PD Not determined/reported Disease control for 12 weeks, a n (%) [95% CI] 46 (55) [43.5, 65.7] 2 (2) 44 (52) 26 (31) 9 (11) 3 (4) 66 (79) [68.3, 86.8] Median TTR, months (range) 2.8 ( ) Median DOR, months, [95% CI] NR [NE, NE] DOR, duration of response; NE, not estimable; NR, not reached; TTR, time to response. a Defined as patients with complete response, partial response, or stable disease for 12 weeks.. Andre T., et al. ASCO Poster oral #3531

37 Probability of Progression- Free Survival PFS per Investigator Assessment with NIVO + IPI Median time from first dose to death or last known alive date: 8.7 months (range, 0.1 to 20.1) The 9 month rates of PFS and OS were 77% and 88%, respectively Medians for PFS and OS had not yet been reached PFS rate (95% CI), % 6 months 77 (66.5, 85.1) 9 months 77 (66.5, 85.1) Median PFS (95% CI), months NR (11.5, NE) No. at Risk Time (months) NE = not estimable; NR = not reached. Andre T., et al. ASCO Poster oral #3531

38 Probability of Overall Survival OS per Investigator Assessment with NIVO + IPI Time (months) No. at Risk NE = not estimable; NR = not reached. Andre T., et al. ASCO Poster oral #3531

39 Safety: Summary of TRAEs with NIVO + IPI AEs were manageable, with Grade 3/4 TRAEs reported in 29% of patients dmmr/msi-h (N = 84) No treatment-related deaths were reported Patients, n (%) Any Grade Grade 3 or 4 Any TRAE 57 (68) 24 (29) Serious TRAEs 15 (18) 14 (17) Discontinuation due to TRAEs a 11 (13) 8 (9) TRAEs reported in 10% of patients Diarrhea 20 (24) 1 (1) Fatigue 14 (17) 1 (1) Aspartate aminotransferase increase 14 (17) 8 (9) Pyrexia 13 (16) 0 Pruritus 13 (16) 2 (2) Alanine aminotransferase increase 12 (14) 7 (8) Nausea 12 (14) 0 Hyperthyroidism 11 (13) 0 Hypothyroidism 11 (13) 0 a All events (ALT level increase, autoimmune hepatitis, colitis, dyspnea, necrotizing myositis, pneumonitis, immune sarcoidosis, transaminase increase, thrombocytopenia) occurred in one patient each with the exception of acute kidney injury, which was reported in 2 patients. Andre T., et al. ASCO Poster oral #3531

40 Atezolizumab: molecule summary Compound Generic name Other names Molecule type Mechanism of action Ongoing clinical trials Drug Overview RG7446 Atezolizumab Development phase Phases I, II, III Tecentriq, anti PD-L1, RO , MPDL3280A Engineered IgG1 MAb to eliminate Fc-effector function to avoid killing of activated T cells Binds and inhibits PD-L1 to promote antitumor immune responses Lung, bladder, renal, prostate, breast, ovarian, GI, skin, other solid tumors and hematologic cancers Molecular Information Binds to PD-L1 on tumor cells and tumorinfiltrating immune cells References: 1. Herbst R, et al. Nature. 2014;515(7528): Powles T, et al. Nature. 2014;515(7528): McDermott DF, et al. J Clin Oncol. 2016;34(8): Emens L, et al. AACR [Oral presentation; abstract 6317]. 5. Gordon M, et al. Chicago Thoracic 2016 [Poster presentation; abstract 84]. 6. Petrylak D, et al. ASCO [Oral presentation; abstract 4501]. 7. Wakelee H, et al. Chicago Thoracic 2016 [Oral presentation; abstract Oral01.04]. 8. Fehrenbacher L, et al. Lancet. 2016;387(10030): Rosenberg J, et al. Lancet. 2016;387(10031): Desai J, et al. ESMO [Poster presentation; abstract 470P]. 11. Bellmunt J, et al. ESMO [Poster presentation; abstract 782PD]. 12. Rosenberg J, et al. ASCO [Oral presentation; abstract 104]. 13. Schmid P, et al. ASCO [Oral presentation; abstract 11506]. 14. Barlesi F, et al. ESMO [Oral presentation; abstract LBA44_PR]. 15. Wallin JJ, et al. Nat Commun. 2016;7: Sequist LV, et al. ESMO 2016 [Poster presentation; abstract 1425PD]. 17.

41 Cobimetinib + Atezolizumab PD-L1 and MEK inhibition: a rational combination

42 Cobimetinib + Atezolizumab KRAS MT CRC All CRC pts N=20 N=23 ORR 20% 17% CR 0 0 PR 20% 17% SD 20% 22% PD 50% 52% NE 10% 9% mpfs (mo) mos (mo) 2.3 (1.8-9,5) NE (6,5- NE) 2.3 (1.8-9,5) NE (6,5- NE) Bendell ASCO 2016

43 Estudio fase III multicéntrico, abierto, randomizado, con tres grupos de tratamiento para investigar la eficacia y seguridad de cobimetinib en combinación con atezolizumab y de atezolizumab en monoterapia, comparado con regorafenib, en pacientes con adenocarcinoma colorrectal localmente avanzado o metastásico no resecable tratado previamente Ongoing

44 Combined chemotherapy plus Bevacizumab may create a favourable microenvironment for immunotherapy Presented By Wallin et al at 2016 AACR Annual Meeting

45 Atezolizumab plus Bevacizumab and/or FOLFOX in mcrc: phase Ib Presented By Wallin et al at 2016 AACR Annual Meeting

46 Slide 32 Presented By Dirk Arnold at 2016 ASCO Annual Meeting

47 Otras modalidades de Inmunoterapia en CCRm.- Vacunas: Imprime PGG, GVAX, vacunas basadas en células dendríticas, vacunas dirigidas frente a diferentes antígenos como CEA, NY-ESO-1, HER-2.- Terapia Celular adoptiva dirigida frente a distintos antígenos: NY-ESO-1, MAGE-A3, MUC Virus oncolíticos: Enadenotucirev, Reolysin.- Adyuvantes para otras inmunoterapias: epacadostat, rintatolimod, motolimod.- Citokinas: IL-12, AM Lefitolimod (MGN1703): agonista del TLR-9 que estimula la respuesta inmune innata. En marcha el F III IMPALA que explora su papel como mantenimiento en CCRm

48 MGN1703 lefitolimod activates endosomal TLR-9 on plasmacytoid DCs and B cells Broad activation of the innate and adaptive immune system: 1) Antigen presenting cells (pdcs and B cells) 2) Subsequent activation of various pathways (CTL, NK-cells, ADCC) Adapted from: B. Wittig et al. / Critical Reviews in Oncology/Hematology 94 (2015) 31 44

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50 Tabernero; ASCO 2017

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55 Tratamiento de pacientes no subsidiarios de QT intensiva

56 Muchas gracias!