INMUNOTERAPIA EN CANCER COLORRECTAL METASTASICO CCRm MSI-H NUEVO ESTANDAR EN PRIMERA LINEA Y/O PRETRATADOS? V. Alonso Servicio de Oncologia Medica H. U. Miguel Servet Zaragoza
MSI-H mcrc Clinical and Pathological characteristics Immune microenvironment Clinical trials with check-point inhibitors
CLASSIC MECHANISMS OF CARCINOGENESIS IN COLORECTAL CANCER Lee GH et al. EJSO 2015
MSI-H Microsatellites are tandem repeats of 1 to >10 nucleotides scattered throughout the genome Are particularly prone to DNA replication errors (DNA polymerases errors) Microsatellites sequences are fixed for life and the same in every tissue Insertion or deletions in microsatellites located in the DNA coding regions generate frameshift mutations leading to proteins truncations Evolution endowed eukaryotic cells with a dedicated system to repair mismatches in DNA The loss of mismatch repair system causes mutations (neoantigens) and ultimately cancer Vilar E et al. Nat rev Clin Oncol 2010
MSI CCR TUMORS PATHOLOGICAL FEATURES Poorly differentiated - Medullary pattern Mucinous component >50% with signet-ring cells Lack of dirty necrosis Increased tumor-infiltrating lymphocytes (mostly T cells CD8+) Prominent inflammatory reaction at the advanced edge of the tumor (Crohn-like reaction) Marginean CE et al. Arch Pathol Lab Med 2017
MSI CCR TUMORS CLINICAL FEATURES Older age Female Right-sided (proximal) tumors >70-75 years sporadic tumours <50 years Lynch Syndrome Stage MSI-H II 15-20% III 10-12% IV 4-5%
dmmr/msi-h as a Predictive Biomarker for Systemic Treatment in mcrc 1.0 0.8 0.6 0.4 0.2 0.0 PFS by MMR status 1 1.0 OS by MMR status 1 0.8 pmmr pmmr 0.6 0.4 dmmr dmmr 0.2 0.0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Months from randomization 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 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):266-73. 2. Venderbosch S et al. Clin Canc Res. 2014;20(20):5322-5330.
dmmr Testing Next-generation Sequencing Foundation Medicine: variance at 114 msi loci Immunohistochemistry Complete loss of expression in one of the MMR proteins = MSI-high Polymerase Chain Reaction Panel of 5 or more microsatellites with allelic shift in 2 (>30%) or more markers = MSI-high Intact expression Loss of expression
MOLECULAR PATHOLOGIC CLASSIFICATION COLORECTAL CANCER THE CANCER GENOME ATLAS PROJECT (TCGA) CONSENSUS MOLECULAR SUBTYPES CONSORTIUM (CMS)
TCGA CCR: Subtypes Hypermutated tumours (> 12 mut/10 6 bases): 16% TCGA. Nature 2012
Different types of CCR are correlated with different profiles genetic expression
Guinney J et al. Nat Med 2015
MSI-H mcrc High mutational burden High tumor neoatigen load High dense inmune infiltration
MUTATIONAL LOAD Lawrence MS, et al. Nature 2013;499:214 218
MUTATIONAL LOAD
Immune microenvironment of primary colorectal cancer Llosa NJ et al. Cancer Discover 2015
Immune microenvironment of primary colorectal cancer MSI represents a classic example of adaptive resistance in which an active immune Th1/CTL microenvironment results in compensatory induction of checkpoints that protect the tumor from killing Llosa NJ et al. Cancer Discover 2015
CLINICAL TRIALS
The Cancer-Immunity Cycle Chen, Immunity 2013
Le DT et al. ASCO 2015. Le DT et al. NEJM 2015
Type of response Patients (n=86) Complete Response 18 (21%) Partial Response 28 (33%) Stable Disease 20 (23%) Progressive Disease 12 (14%) Not Evaluable 8 (9%) Objective Response Rate 95% CI 53% (41-64%) 2-year OS 64% 2-year PFS 53% Le DT et al. Science 2017
Response, Disease Control and Durability ORR, n (%) [95% CI] Best overall response, n (%) CR PR SD PD Unable to determine Disease control, n (%) d [95% CI] All patients a N = 74 25 (34) [23.2, 45.7] 7 (9) 18 (24) 23 (31) 22 (30) 4 (5) 46 (62) [50.1, 73.2] Median DOR (range), months NR (1.4+ to 31.6+) Median duration of SD (range), months 8.3 (4.2, NE) Group A a,b n = 53 14 (26) [15.3, 40.3] 4 (8) 10 (19) 16 (30) 19 (36) 4 (8) 29 (55) [40.4, 68.4] Group B a,c n = 21 11 (52) [29.8, 74.3] 3 (14) 8 (38) 7 (33) 3 (14) 0 17 (81) [58.1, 94.6] NR (4.6+ to 27.2+) NR (1.4+ to 31.6+) 8.5 (4.1, NE) 5.3 (2.6, NE) Median time to response was approximately 2.8 months across all groups Clinical benefit was observed across all groups NE = not estimable; NR = not reached. a BICR data with a median follow-up of 21 months (range, 17-40). b Group A patients received 3 prior chemotherapies including a fluoropyrimidine, oxaliplatin, and irinotecan. c Group B patients did not receive prior treatment with all 3 of these chemotherapies (fluoropyrimidine, oxaliplatin and irinotecan). d Patients with a CR, PR, or SD for 12 weeks.
Median follow-up 14.8 m (2.6-23.7) Median duration of response was not reached Median PFS and OS were not reached Hochster H et al. ASCO GI 2017. Abst 673
PLANNED CLINICAL TRIALS
61 MSI-H pts Median follow-up 7.4 months Response Rate 26.6% Disease control 50.8% No data PFS, OS Diaz L et al. ASCO 2017
KEYNOTE 177 MSI-high mcrc N=270 MSI-h/dMMR Phase III CRC Trials Frontline Metastatic PI: Luis Diaz mfolfox6/bevacizumab R Pembrolizumab mfolfox6/bevacizumab NRG-CR1556/SWOG-1610 MSI-high mcrc N=311 R PI: James Lee and Michael Overman Atezolizumab mfolfox6/bevacizumab + Atezolizumab Stage III Adjuvant Alliance 021502 Resected Stage III N=700 PI: Frank Sinicrope R mfolfox6 + Atezolizumab (12 cycles) then Atezolizumab x 6 months mfolfox6 (12 cycles)
PRODIGE SAMCO TRIAL 2 nd line mcrc MSI-H Pretreated mcrc with MSI/dMMR R Arm A: Standard 2 nd line: mfolfox6, FOLFIRI, cetuximab, panitumumab, bevacizumab. Arm B: Avelumab Avelumab (anti-pd-l1 Ab); dose of 10 mg/kg IV q2 wk. Accrual goal: N= 116; HR 0.59 Primary endpoint: PFS (+5 months) PI: J Taieb, HEGP, Paris
CONCLUSIONS Test all metastatic CRC patients for MSI-high MSI-H prognostic factor in mcrc MSI-H biomarker for treatment with checkpoint inhibitors (predictive) Standard of Care for 2 nd line metastatic MSI-high CRC is now anti-pd1 therapy NCCN recommends either Pembrolizumab or Nivolumab (FDA approved)
CONCLUSIONS Phase III Trials for adjuvant and front-line metastatic MSI-H CRC are ongoing Combination with targeted agents: + chemotherapy, sequence? + radiotherapy? + targeted agents: anti-angiogenics; MEK? Other immuno modulating agents Biomarker selection MSI, Hypermutation, immune-infiltrated, gene expression signatures