IMMUNOTHERAPY: WHO AND WHEN?

Elena Elez MD, PhD

Colon Cancer Program

Vall d’Hebron Institute of Oncology (VHIO)

meelez@vhio.net

“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)

CHALLENGING IMMUNO IN CRC:

2017

Deficient Mistmatch Repair (MMRD)

System

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

TCGA. Nature 2012, Le et al NEJM 2015

Hypermutant CRC

Significant infiltration of CD8 cells is present in MSI tumors compared to MSS patient

Tumor infiltrating lymphocytes (TIL) CD8

Pembrolizumab MMRD

Le et al. Science 2017

Le et al. ASCO 2018

Nivolumab in MMRD mCRC

Overman et al ASCO GI 2018, J Clin Oncol 2018

CHECKMATE-142

Overman et al. Lancet Oncol 2017

Nivolumab in MMRD mCRC

Nivolumab/Ipilimumab

Overman et al. J Clin Oncol 2018

• 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).

PFS – OS (mFUP 13.4 months)

Overman et al. J Clin Oncol 2018

Nivolumab/Ipilimumab

• 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 ofright 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: ?

Clinical Case 2

HYPERMUTANT CRC

GENOMICS,

TRANSCRIPTOMICS AND

STROMA MATTER…

Guinney J, Dienstmann R, Tabernero J et al. Nat Med. 2015 Nov;21(11):1350-1356

MOLECULAR SUBTYPES

MoTriColor

• 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)

Clinical Case 2

Immune characterization of colorectal cancer in light of genomic and

transcriptomic subtypes

ROLE OF STROMA

Dienstmann et al. Nature Med 2017

Tauriello et al. Science 2018

• 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.

ROLE OF STROMA

Efficacy and safety results from IMblaze370,

a randomised Phase III study comparing

atezolizumab + cobimetinib and atezolizumab

monotherapy vs regorafenib in chemotherapy-

refractory 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 Kim13

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 months1,2

• MSS mCRC is considered immune excluded as the tumours generally lack TILs

– 95% of patients have mCRC that is mismatch-repair proficient and MSS3

– Single-agent PD-L1/PD-1 inhibitors have demonstrated minimal activity in MSS mCRC3

• Preclinical evidence suggests that combining atezolizumab and cobimetinib augments antitumour T-cell responses4

– Atezolizumab (anti‒PD-L1) prevents PD-L1 from binding its receptors PD-1 and B7.1, thus restoring tumor-specific immunity5,6

– Cobimetinib (MEK1/2 inhibitor) may improve tumour immune recognition by increasing MHC-I expression, promoting T-cell accumulation in tumours, and limiting T-cell exhaustion4

• 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

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

• 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%Regorafenib 160 mg oral 21/7 days

Atezolizumab 840 mg IV q2w

+ cobimetinib 60 mg oral 21/7 days

Atezolizumab 1200 mg IV q3wR

2:1:1

Lo

ss o

f

clin

ical

ben

efi

t

Primary endpoint

• OSa

– Atezo + cobi vs rego

– Atezo vs rego

INV-assessed key secondary endpoints

• PFS

• ORR

• DOR

Stratification

• Extended RAS mutation status (≥ 50% patients in each arm)

• Time since diagnosis of first metastasis (< 18 months vs ≥ 18 months)

• Data cutoff date: March 9, 2018

Safety summary

Atezo + cobi

n = 179

Atezo

n = 90

Rego

n = 80

Dose intensity

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

ANTI-CEA TCB MoAB

Argiles et al. ESMO WCGI 2017

New Agents

CEA-TCB at doses of ≥ 60 mga demonstrated clinical activity in mCRC

26

Study 1: CEA-TCB monotherapy(n = 31, 60-600 mg)

Study 2: CEA-TCB + atezolizumab(n = 25, 5-160 mg)

-100

-50

0

50

100

300 mg90 mg

60 mg

100 mg

135 mg

200 mg

400 mg

600 mg

Bes

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ha

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targ

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b

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, %

No clear correlation betweenCEA-TCB dose and response

Correlation between CEA-TCB dose and response

Bes

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b

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, %

-100

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^

^160 mg20 mg

40 mg

80 mg10 mg

5 mg

MSI ^MMR unknown *

**

*

Argilés G, et al. CEA-TCB in CRC. ESMO WGI 2017.

Data reported by investigators, cutoff: March 3, 2017. a Radiological signs of tumor inflammation seen at ≥ 60 mg (safety data cutoff is ≥ 40 mg).

Therapy Antigen Enhancer Phase Study population Trial ID

Anti-tumor vaccines

Autologous tumor cells

BCG

II Adjuvant CRC PMID: 8445413

III Adjuvant CRC PMID: 15755632

III Adjuvant Stage II CRC NCT02448173

Newcastle Disease Virus

IICRC Liver M1

resectedPMID: 18488223

Dendritic cell vaccines

CEA Dendritic cells IAdjuvant Stage III

CRC NCT01890213

MUC 1 Dendritic cells IICRC Liver or lung M1

resectedNCT00103142

Pubmed - Clinicaltrials.gov

Vaccines for

Immune stimulation

Therapy Target Enhancer Phase Trial Design Trial ID

TILsAutologous tumor cells

IL-2 Pembrolizumab

II GI tumors NCT01174121

CAR T Cells

CEA ITumors expressing

CEANCT02349724

CEA Yttrium 90 ITumors expressing

CEANCT02416466

EGFR I/IITumors expressing

EGFRNCT01869166

Cytokine-induced-killer

cells

Autologous tumor cells

IIAdjuvant CRC in

combination with XELOX

NCT01929499

Clinicaltrials.gov

AdoptiveT-cell therapy for

inmune stimulation

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