Immunoterapia en Cáncer colorrectal. Manuel Benavides

Transcription

1 Immunoterapia en Cáncer colorrectal Manuel Benavides

2 Agenda - Cáncer colorrectal / MSI - MSI-H / MSI-L o MSI-S - Inhibidores de Checkpoints

3 Molecular Pathways in Colorectal Cancer tability or MSI (15%) Microsatellite instability or MSI (I-IV: 15%) -DNA MMR deficiency: MMR-D (MLH1, MSH2, MSH6, PMS2) e

4 MMR-d across 12,019 tumors. Venderbosch S et al. Clin Canc Res d-mmr Prevalence (%) CAIRO 5.6% CAIRO2 5.6% COIN 4.4% FOCUS 5.4% Pooled data set 5.0% D.T. Le et al. Science 2017

5 Genomic Landscape of CRC The Cancer Genome Atlas Network Nature 487, (2012)

6 Left-sided - Rectal / Sigmoid - MSS - KRAS mut - CIN+ Right-sided - MSI-H - Hypermethylated - BRAF mut - Chromosomal stability

7 Proportion of positive cases (%) Molecular characteristics vary across colorectal cancer subsites CIMP-high MSI-high BRAF mutation Caecum (n = 243) Ascending colon (n = 295) Hepatic flexure (n = 46) Transverse colon (n = 91) Splenic flexure (n = 33) Descending colon (n = 83) Sigmoid colon (n = 314) Rectosigmoid (n = 106) Rectum (n = 232) Yamauchi M. et al. Gut 2012

8 Mutations per Mb COLORECTAL CANCERS WITH MICR Hipermutados Portan más neo-antígenos, capaces de estimular una intensa respuesta inmune contra el tumor 1. dmmr CRC represent 12% of CRC and are associa (DMMR CR PolE MSI-H MSS N/A 1 0, samples 2. High expression of PD-1 ans PD-L1 in dmmr CR

9 Díaz LA. ASCO GI 2017

10 TMB per MB TMB 17 (%) Tumor Mutation Burden across GI Cancers 14% 12% 10% 8% 8 6% 6 4% 4 2% 2 Percent With TMB 17 Average of TML per MB 12% 11% 8% 6% 4% 3% 3% 3% 3% 2% 1% 0% 0 Tumor Mutation Burden and MSI A 0% Salem ME, e Tumor Mutation Burden and MSI: High Correlation in GI Cancers P <.0001 (t-test) MSI High FA MSI MSI Stable Salem ME, et al. ASCO GI 2017

11 Immune microenvironment of primary colorectal N.J. Llosa et al. Cancer Discovery 2015

12 as Immune mieloides microenvironment infiltrantes of primary del colorectal tumor PDL-1 + trantes del tumor) productores de Interferon Gamma PD-1 infiltrantes del tumor PDL-1 + MSI classic example of adaptive resistance active immune Th1/ CTL microenvironment results in compensatory induction of Cancer Discovery 2015 Doi: / CD checkpoints that protect the tumor from killing Cancer Discovery 2015 Doi: / C N.J. Llosa et al. Cancer Discovery 2015

13 J. Guinney et al. Nature Medicine 2015

14 Agenda - Cáncer colorrectal / MSI - MSI-H / MSI-L o MSI-S - Inhibidores de Checkpoints

15 Immunotherapy in colorectal cancer D. Lynch et al. Ann Transl Med 2016

16

17 Published online, March 9, 2017 Assay comparisons and not clinical concordance - SP142 assay is an outlier - Pathologists are much better at scoring the TPS than the ICPS - IHC may be a good method for assessment of PD-L1 in tumor cells but probably inadequate for immune cell expression independent of which assay is selected.

18 CheckMate 142 Stage 1 a Stage 2 b Patients Nivolumab 3 mg/kg Q2W 74 pts Histologically confirmed metastatic/recurrent CRC dmmr/msi-h per local laboratory Nivolumab 3 mg/kg Q2W Stage 1 c Stage 2 d 1 prior line of therapy Nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses Then nivolumab 3 mg/kg Q2W 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 Presented by: Dr Michael J. Overman

19 CheckMate 142 Main Baseline Characteristics - 3 previous regimens received: 54% - Both BRAF and KRAS wild type 29 (39%) BRAF mut.: 16% KRAS mut. 35% - Tumor-associated immune cells expressing PD-L1 at baseline 1% 21 (28%) <1% 47 (64%) - Clinical history of Lynch syndrome Yes 27 (36%) Unknown 19 (26%) Presented by: Dr Michael J. Overman M.J. Overman et al. Lancet Oncol 2017

20 CheckMate 142 Objective Response Rate 31% - 36% M.J. Overman et al. Lancet Oncol 2017

21 CheckMate 142 Stage 1 a Stage 2 b Patients Nivolumab 3 mg/kg Q2W Histologically confirmed metastatic/recurrent CRC dmmr/msi-h per local laboratory 1 prior line of therapy Nivolumab 3 mg/kg Q2W Stage 1 c Stage 2 d Nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W for 4 doses Then nivolumab 3 mg/kg Q2W 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 Presented by: Dr Michael J. Overman

22 Probability of Overall Survival CheckMate 142 Anti CTLA4 + anti-pd-1 en MSI-H mcrc Investigator-assessed response Responses regardless of PD-L1 tumor expression, BRAF or KRAS mut., or a clinical history of LS BRAF-mut.: ORR of 48% Clinical history of LS: ORR of 74% OS per Investigator Assessment with NIVO + IPI PFS OS No. at Risk 84 NE = not estimable; NR = not reached Time (months) Th. Andre et al. ASCO 2017, ESMO 2017

23 Safety Nivolumab Nivolumab + Ipilimumab All Patients (N = 74) Patients, n (%) Grade 3 4 Any TRAE 15 (20.3) TRAEs reported in 10% of patients Fatigue Diarrhea Pruritus Lipase increased Rash 1 (1.4) 1 (1.4) 0 6 (8.1) 0 No deaths reported due to study drug toxicity Presented by: Dr Michael J. Overman

24 D.T. Le et al. NEJM 2015 N: 11 N: 21

25 Updated results ORR: 54% Expression of CD8 and PD-L1 Not associated with PFS or OS D.T. Le et al. Science 2017

26 Pembrolizumab / Nivolumab NCCN Guidelines Colon cancer v March 13 Previous oxaliplatin Previous irinotecan Previous Folfoxiri Previous Fluoro-pyrimidines monotheraphy Patients not appropiate for intensive therapy

27 KEYNOTE-177 Pembrolizumab vs. Chemotherapy MSI-H or MMR-d Stage IV Colorectal Carcinoma (1st-line)

28 Estudio fase III multicéntrico, abierto, randomizado, con tres grupos de tratamiento para investiga eficacia y seguridad de cobimetinib en combinación MSI-H: con 0% atezolizumab y de atezolizumab en monotera comparado con regorafenib, en pacientes con adenocarcinoma colorrectal localmente avanzad metastásico no resecable tratado previamente 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 (m) 2.3 ( ) mos (m) NE (6.5-NE) 2.3 ( ) NE (6.5-NE) Ongoing Bendell J et al. ASCO GI 2017

29 Ph. N RR* (%) mpfs (m) MSI-H Atezolizumab + Bevacizumab Hochster ASCO GI 2017 Atezolizumab + Bevacizumab and/or Folfox Bendell ASCO GI 2015 Pembrolizumab + mfolfox6 S. Shahda. ASCO 2017 *Recist I % I ? II NR MSI 10% MSS 73% UK: 17%

30 MODUL V6 BIOMARKER-DRIVEN MAINTENANCE TREATMENT for 1st-line mcrc Multicentre Randomised Clinical Trial. Primary Object.: PFS in each maintenance cohort re 1: Study Design 5FU/LV Capecitabina Cetuximab Bevacizumab Vemurafenib Trastuzumab Pertuzumab Cobimetinib Atezolizumab

31 Primary endpoint: OS Maintenance treatment with MGN1703 Immunomodulatory molecule. Binding to TLR-9 in immune cells Innate and adaptive immune responses

32

33 J. Tabernero. ESMO 2017

34 CCRm: 1 a Línea... Daily practice 3 ESCENARIOS Resecable / Potencialmente resecable / Irresecable Edad PS Ctas del paciente 12 Variables Ctas. Del tumor Presentación clínica Carga tumoral CdV Ctas. del tratamiento Perfil de toxicidad Comorbilidades Localización F. Económicos Preferencias RAS Braf al menos 2 LOCALIZACIONES Derecho Izquierdo / Recto MSI MSS

35 Muchas gracias Manuel Benavides MD, PhD