IMMUNOTHERAPY: WHO AND WHEN? Elena Elez MD, PhD Colon Cancer Program Vall d Hebron Institute of Oncology (VHIO) meelez@vhio.net
CHALLENGING IMMUNO IN CRC: Sometimes when you innovate, you make mistakes. It is best to admit them quickly, and get on improving your other innovations Steve Jobs (1955-2011)
Deficient Mistmatch Repair (MMRD) System 2017 PDL IHC assessment>1%
Deficient Mistmatch Repair (MMRD) System Microsatellites are repeats of 1 to 10 nucleotides variable in length (from 5 to 50 repeats). A A A A A A A -> 7 poly-a microsatellite GT GT GT GT -> 4 poly-gt microsatellite ACGTCC-ACGTCC-ACGTCC -> 3 poly ACGTCC Localized in coding or non-coding regions of DNA Microsatellites cause DNA polymerase slips in the replicative fork causing DNA mismatches and ultimately protein mutations. Vilar E, Nat Clin Oncol 2010
MMRD tumors A deficient mismatch repair system (dmmr) is present in 10 20% of patients with sporadic CRC Favorable prognosis in early stage disease. Data on patients with advanced disease are scarce CAIRO (820 Patients, 515 available samples): 18 dmmr (3.5%) Proximal poor differentiated tumors -> Trend to worse OS, PFS and DCR (83% vs 56%) Koopman et al. BJC 2009
Hypermutant CRC Tumor infiltrating lymphocytes (TIL) CD8 Significant infiltration of CD8 cells is present in MSI tumors compared to MSS patient TCGA. Nature 2012, Le et al NEJM 2015
Pembrolizumab MMRD Le et al. Science 2017
Le et al. ASCO 2018
Nivolumab in MMRD mcrc CHECKMATE-142 Overman et al ASCO GI 2018, J Clin Oncol 2018
Nivolumab in MMRD mcrc Overman et al. Lancet Oncol 2017
Nivolumab/Ipilimumab Overman et al. J Clin Oncol 2018
Nivolumab/Ipilimumab PFS OS (mfup 13.4 months) PFS rates were 76% (9 months) and 71% (12 months); respectively OS rates were 87% and 85%. Not only SS but clinically significant with meaningful improvements in patient-reported outcomes (functioning, symptoms, and QoL). Overman et al. J Clin Oncol 2018
Clinical Case 2 70 years old male Relevant past medical history: HTA, DLP, DM II 1st sympthom: Perception subcutaneous indurations both arms and legs 1st diagnosis: Punch dermatologic lesion: M1 ADK colorectal origin. Work-up: Lab test (CEA, CA 19.9 -), T/A CT, PET/CT, FCS: Final diagnosis of right colon adenocarcinoma with liver and cutaneous M1.
Clinical Case 2 Molecular Profile: Amplicon: APC MT BRAF V600E MT P53 MT SMAD4 MT AKT MT IHQ: MSS 1st line: FOLFOX-BV 2nd line:?
HYPERMUTANT CRC GENOMICS, TRANSCRIPTOMICS AND STROMA MATTER
MOLECULAR SUBTYPES Guinney J, Dienstmann R, Tabernero J et al. Nat Med. 2015 Nov;21(11):1350-1356
MoTriColor
Clinical Case 2 Molecular Profile: Amplicon: APC MT BRAF V600E MT P53 MT SMAD4 MT AKT MT IHQ: MSS 1st line: FOLFOX-BV 2nd line: PDL1 inh/bv (PHII trial) CR skin (C1) PR at liver (C3)
ROLE OF STROMA Immune characterization of colorectal cancer in light of genomic and transcriptomic subtypes Dienstmann et al. Nature Med 2017
ROLE OF STROMA Increased TGFβ levels predict adverse outcomes in mcrc MSS like mcrc mice models: low mutational burden, T-cell exclusion and TGFβ-activated stroma Inhibition of TGFβ induced cytotoxic T- cell response against tumour cells that prevented metastasis Blockade of TGFβ signalling rendered tumours susceptible to anti-pd-1 PD- L1 therapy. Tauriello et al. Science 2018
Efficacy and safety results from IMblaze370, a randomised Phase III study comparing atezolizumab + cobimetinib and atezolizumab monotherapy vs regorafenib in chemotherapyrefractory metastatic colorectal cancer Johanna Bendell, 1 Fortunato Ciardiello, 2 Josep Tabernero, 3 Niall Tebbutt, 4 Cathy Eng, 5 Maria Di Bartolomeo, 6 Alfredo Falcone, 7 Marwan Fakih, 8 Mark Kozloff, 9 Neil H Segal, 10 Alberto Sobrero, 11 Yi Shi, 12 Louise Roberts, 12 Yibing Yan, 12 Ilsung Chang, 12 Anne Uyei, 12 Tae Won Kim 13 1 Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN, USA; 2 Università degli Studi della Campania Luigi Vanvitelli, Napoli, Italy; 3 Vall d'hebron Institute of Oncology, VHIO, Barcelona, Spain; 4 Medical Oncology, Austin Health, Heidelberg, VIC, Australia; 5 M. D. Anderson Cancer Center, Houston, TX, USA; 6 Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; 7 University Hospital of Pisa, Pisa, Italy; 8 City of Hope, Duarte, CA, USA; 9 University of Chicago, Chicago, IL, USA; 10 Memorial Sloan Kettering Cancer Center, New York, NY, USA; 11 IRCCS Ospedale San Martino IST, Genova, Italy; 12 Genentech, Inc., South San Francisco, CA, USA; 13 Asan Medical Center, University of Ulsan, Seoul, South Korea
Colorectal cancer (CRC) Patients with chemorefractory, locally advanced or metastatic CRC (mcrc) have a poor survival prognosis of 6-8 months 1,2 MSS mcrc is considered immune excluded as the tumours generally lack TILs 95% of patients have mcrc that is mismatch-repair proficient and MSS 3 Single-agent PD-L1/PD-1 inhibitors have demonstrated minimal activity in MSS mcrc 3 Preclinical evidence suggests that combining atezolizumab and cobimetinib augments antitumour T-cell responses 4 Atezolizumab (anti PD-L1) prevents PD-L1 from binding its receptors PD-1 and B7.1, thus restoring tumor-specific immunity 5,6 Cobimetinib (MEK1/2 inhibitor) may improve tumour immune recognition by increasing MHC-I expression, promoting T-cell accumulation in tumours, and limiting T-cell exhaustion 4 In a Phase Ib study of heavily pretreated patients with mcrc (n = 84), atezolizumab + cobimetinib was well tolerated and demonstrated promising clinical activity ORR of 8%, median OS of 9.8 months and 12-month OS of 43% 7 MEK1/2, mitogen activated protein kinase kinase 1 and 2; MSS, microsatellite stable; TIL, tumour-infiltrating lymphocyte. References: 1. Grothey A, et al. Lancet 2013; 2. Mayer RJ, et al. N Engl J Med 2015; 3. Le D, et al. N Engl J Med 2015; 4. Ebert P, et al. Immunity 2016; 5. Herbst RS, et al. Nature 2014; 6. Chen DS, et al. Clin Cancer Res 2012. 7. Bendell J, et al. ASCO-GI 2018. 22
IMblaze370: randomised, Phase III, multicentre, open-label study in mcrc Loss of clinical benefit Unresectable locally advanced or metastatic CRC Received 2 prior regimens of cytotoxic chemotherapy for metastatic disease ECOG PS 0-1 MSI-H capped at 5% R 2:1:1 Atezolizumab 840 mg IV q2w + cobimetinib 60 mg oral 21/7 days Atezolizumab 1200 mg IV q3w Regorafenib 160 mg oral 21/7 days Stratification Extended RAS mutation status ( 50% patients in each arm) Time since diagnosis of first metastasis (< 18 months vs 18 months) Primary endpoint OS a Atezo + cobi vs rego Atezo vs rego Data cutoff date: March 9, 2018 INV-assessed key secondary endpoints PFS ORR DOR Atezo, atezolizumab; cobi, cobimetinib; INV, investigator; rego, regorafenib. a Two-sided type I error rate of 0.05 was controlled by hierarchical testing (testing atezo vs rego only if atezo + cobi vs rego was positive). NCT02788279. 23
Safety summary Dose intensity Atezo + cobi n = 179 Atezo n = 90 Rego n = 80 Cycles of cobi or rego, median (range), n 2 (1-18) 2 (1-17) Doses of atezo, median (range), n 4 (1-34) 3 (1-23) Dose intensity cobi or rego (range), % 93% (19-100) 80% (25-100) Dose intensity atezo (range), % 98% (51-101) 100% (62-105) All cause AEs, n (%) 178 (99%) 83 (92%) 78 (98%) Grade 3-4 109 (61%) 28 (31%) 46 (58%) Grade 5 5 (3%) a 0 2 (3%) b Treatment-related AEs, n (%) 170 (95%) 49 (54%) 77 (96.3%) Grade 3-4 80 (45%) 9 (10%) 39 (49%) Grade 5 2 (1%) 0 1 (1%) Serious AEs, n (%) 71 (40%) 15 (17%) 18 (23%) Treatment-related serious AEs 46 (26%) 7 (8%) 9 (11%) AEs leading to withdrawal from any treatment, n (%) 37 (21%) 4 (4%) 7 (9%) AEs leading to dose interruption or modification, n (%) 109 (61%) 18 (20%) 55 (69%) a Cause of death: sepsis (n = 2), cerebrovascular accident (n = 1), acute kidney injury (n = 1) and general physical health deterioration (n = 1). b Cause of death: death (n = 1) and intestinal perforation (n = 1). Data cutoff: March 9, 2018. 24
New Agents ANTI-CEA TCB MoAB Argiles et al. ESMO WCGI 2017
Best change in target lesions from baseline, % Best change in target lesions from baseline, % CEA-TCB at doses of 60 mg a demonstrated clinical activity in mcrc Study 1: CEA-TCB monotherapy (n = 31, 60-600 mg) Study 2: CEA-TCB + atezolizumab (n = 25, 5-160 mg) 100 50 * 60 mg 200 mg 90 mg 300 mg 100 mg 400 mg 135 mg 600 mg MMR unknown 100 50 ^ 5 mg 10 mg 20 mg ^ MSI 40 mg 80 mg 160 mg 0 * * * 0-50 -50 ^ -100 No clear correlation between CEA-TCB dose and response -100 Correlation between CEA-TCB dose and response Data reported by investigators, cutoff: March 3, 2017. a Radiological signs of tumor inflammation seen at 60 mg (safety data cutoff is 40 mg). 26 Argilés G, et al. CEA-TCB in CRC. ESMO WGI 2017.
Vaccines for Immune stimulation Therapy Antigen Enhancer Phase Study population Trial ID II Adjuvant CRC PMID: 8445413 BCG III Adjuvant CRC PMID: 15755632 Anti-tumor vaccines Autologous tumor cells III Adjuvant Stage II CRC NCT02448173 Newcastle Disease Virus II CRC Liver M1 resected PMID: 18488223 Dendritic cell vaccines CEA Dendritic cells I MUC 1 Dendritic cells II Adjuvant Stage III CRC CRC Liver or lung M1 resected NCT01890213 NCT00103142 Pubmed - Clinicaltrials.gov
AdoptiveT-cell therapy for inmune stimulation Therapy Target Enhancer Phase Trial Design Trial ID TILs Autologous tumor cells IL-2 Pembrolizumab II GI tumors NCT01174121 CEA I Tumors expressing CEA NCT02349724 CAR T Cells CEA Yttrium 90 I Tumors expressing CEA NCT02416466 EGFR I/II Tumors expressing EGFR NCT01869166 Cytokineinduced-killer cells Autologous tumor cells II Adjuvant CRC in combination with XELOX NCT01929499 Clinicaltrials.gov
IMMUNOTHERAPY: WHO AND WHEN?
WHO MSI mcrc: FOR SURE, but Don t forget MSI patients also carry additional aberrations MSS mcrc: PDL1 alone: No, for sure PDL1-MEK: Good rational, must be further evaluated Could be: For selected population (CMS3?) To consider alternative combos (role of bev?) PDL1 with whatever is no a valid approach it must be based on CRC biology: Role of WNT, TGFB, CMSs. MSI/MSS: New agents / New targets
WHEN MSI mcrc: FOR SURE, along any moment of the disease when feasible From my point of view: It must be priorized (pending MK3475-177/164 trials) MSS mcrc: Now: just in a cinical trial scenario and in the refractory setting Lot of work towards patient selection, this question has not been already answered even for routinary biologicals.
IMMUNOTHERAPY: WHO AND WHEN? Elena Elez MD, PhD Colon Cancer Program Vall d Hebron Institute of Oncology (VHIO) meelez@vhio.net