Immunoterapia e carcinoma del colon retto

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Immunoterapia

e carcinoma del colon retto

Alberto Zaniboni

Oncologia Medica

Fondazione Poliambulanza - Brescia

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Le et al, Science 2017

PD-1 blockade in MSI-H tumors

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TML is higher in MSI-H malignancies

Presented By Michael Morse at 2018 ASCO Annual Meeting

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11,6

9,0 8,3 9,2

7,4 7,2

5,4

9,9

5,7 6,7

5,0

6,4

0 5 10 15

Average of TML per MB

TMB per MB (Mean)

12% 11%

8% 6%

4% 3% 3% 3% 3% 2%

1% 0%

TMB ≥ 17 (%)

Percent With TMB ≥ 17

Mean TMB per MB

Salem ME, et al. ASCO GI 2017. Abstract 530. Slide credit: clinicaloptions.com

0 2 4 6 8 10 12 14

Tumor Mutation Burden Across GI Cancers

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Response rate to anti-PD1 and mutational load

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PDL1+ NOT a predictor of benefit for pembrolizumab in mCRC

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MSI Is Highly Correlated to TML in Patients With Colorectal Cancer

15

2

3 54

22

75

1 Colorectal

N = 1223 High TML

MSI-H High PD-L1

High TML and MSI-H MSI-H and high PDL-1 High TML and high PD-L1

High TML, MSI-H, and high PD-L1 TML

MSI

PD-L1 Slide credit: clinicaloptions.com Miglarese MR. PMWC 2018.

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Anti-PD1 antibody is inactive in pMMR/MSS CRC

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Pembrolizumab in MMRD CRC:

Duration of Disease Control

125

75 50 25 0 -25 -50 -75 -100

Change From Baseline (%)

-125 100

365 730

MMRP CRC MMRD CRC

• Complete and durable responses observed in > 50% of patients with MMRD CRC

Le DT, et al. ASCO 2016. Abstract 103. Slide credit: clinicaloptions.com

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Phase II CheckMate-142: Nivolumab

± Ipilimumab in MSI-H CRC

• Primary endpoint: ORR per investigator (RECIST 1.1)

• Secondary endpoint: ORR per BIRC

• Exploratory endpoints: safety, tolerability, PFS, OS, biomarkers

Nivo 3 mg/kg Q2W (n = 19) Monotherapy

Arm

MSI-H

CONTINUE Nivo 3 mg/kg Q2W

(n = 74)*

▪ Nivo 3 mg/kg + Ipi 1 mg/kg Q3W x 4

▪ Then Nivo 3 mg/kg Q2W (n = 19)

Second-line CRC MSI- H; ≥ 1 prior treatment for metastatic disease;

≥ 1 target lesion;

ECOG PS 0-1 (N = 120)

If ≥ 7/19 confirmed responses, continue

enrollment

▪ Nivo 3 mg/kg + Ipi 1 mg/kg Q3W x 4

▪ Then Nivo 3 mg/kg Q2W (n = 84)*

If ≥ 7/19 confirmed responses, continue

enrollment

Stage 1 Stage 2

*At time of this analysis, included all patients who received their first dose

≥ 6 mos prior to data cutoff (Monotherapy, September 2016;

Combination, January 2017).

Combination Arm

Overman M, et al. ASCO GI 2017. Abstract 519. Andre T, et al. ASCO 2017. Abstract 3531. Slide credit: clinicaloptions.com

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Provided by BMS in response to unsolicited requests only 62% of patients had a reduction in tumor burden

from baseline with NIVO monotherapy

15 100

Bestreductionin targetlesion (%)

75 50 25 0 -25 -50 -75 -100

• ORR (investigator-assessed): 31%

• DCR ≥ 12 weeks: 69%

• Median duration of response: not reached

• 73% of patients were alive at 12 months^a

100 75 50 25 0 - 25 -50 -75 -100

Bestreductionin targetlesion (%)

• ORR (investigator-assessed): 55%

• DCR ≥ 12 weeks: 79%

• Median duration of response: not reached

• 88% of patients were alive at 9 months^a 80% of patients had a reduction in

tumor burden

from baseline with NIVO + IPI

⃰ Confirmed CR or PR per investigator

% Change truncated at 100

aKaplan-Meier estimated

Summary of efficacy with NIVO ± IPI in CheckMate-142

^7,9

Background

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Rationale for Immunotherapy in

MSI-H Tumors

Ongoing Nivolumab Trials:

mCRC and Pan- Tumor

Nivolumab Monotherapy for

MSI-H mCRC

Ongoing I-O Competitor

Trials

A-Z

Local approval may be required before external use. Refer to local guidelines.

Immuno-Oncology in dMMR/MSI-H Cancers

Nivolumab + Ipilimumab Combination therapy for

MSI-H mCRC

Change in Target Lesions Over Time

1 6 Overman MJ, et al. Lancet Oncol. 2017;18(9):1182-1191.

Patients Treated With Nivolumab^a

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Rationale for Immunotherapy in

MSI-H Tumors

Ongoing Nivolumab Trials:

mCRC and Pan- Tumor

Nivolumab Monotherapy for

MSI-H mCRC

Ongoing I-O Competitor

Trials

A-Z

Local approval may be required before external use. Refer to local guidelines.

Immuno-Oncology in dMMR/MSI-H Cancers

Nivolumab + Ipilimumab Combination therapy for

MSI-H mCRC

Investigator-Assessed Response and Disease Control^1,2,3

• DCR^b was 80% (95% CI: 71.5, 86.6) with combination therapy and 69% (57.1, 79.2) with monotherapy^1,d

• Combination therapy provided a numerically higher ORR, including CRs, and DCR relative to monotherapy during a similar follow-up period^d

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aMedian follow-up was 13.4 months (range, 9–25). ^bDiseasecontrol was defined as patients with a CR, PR, or SD for ≥12 weeks. ^cMedian follow-up was 13.4 months (range, 10–32).

dCheckMate-142 monotherapy and combination therapy cohorts were not randomized or designed for a formal comparison.

1. Overman MJ, et al. J Clin Oncol. 2018 Jan 20:JCO2017769901. doi: 10.1200/JCO.2017.76.9901. [Epub ahead of print].2. André T, et al. Oral presentation at ASCO-GI 2018.

3. Overman MJ et al. Lancet Oncol 2017;18:1182–1191.

3 5

12

26 31

38 51,3

31 3,4

CR PR SD PD Unknown

Patients (%)

ORR(95% CI):

31% (20.8, 42.9)

Nivolumab N = 74^3,c Nivolumab + ipilimumab

N = 119^1,2,a

ORR (95% CI): 55% (45.2, 63.8)

20 40 60 80 100

0

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<br />No activity for Nivolumab + Ipilimumab in MSS mCRC

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Mek inhibitor plus anti-PDL1 did not provide a solution

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Segal NH, et al. ESMO 2017. Abstract 403P

CEA-TCB Overview

• CEA-TCB is the first investigational TCB antibody against CEA with a novel 2-to-1 format

• Simultaneously binds with 1 arm to the CD3 chain on T cells and with 2 arms to CEA on tumor cells, trapping T cells

– Increases the affinity for binding to CEA-expressing tumors

• Engages and activates T cells, causing potent killing of tumor cells

• Increases T-cell infiltration, resulting in a more inflamed tumor microenvironment

• CET-TCB is being investigated in 2 phase 1 studies: alone (NCT02324257) and combined with atezolizumab, an anti-PD-L1 (NCT02650713)

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Segal N, et al. ESMO 2017. Poster 403P.

CEA-TCB: Phase 1 Results

• CEA-TCB induced rapid tumor lesion inflammation in most patients, consistent with its mechanism of action (MOA)

– Adverse effects (AEs) related to tumor lesion inflammation were mostly transient and related to dose and number, size, and location of lesions

Reproduced from Segal N, et al. ESMO 2017. Poster 403P with permission.

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Increasing the frequency of T cells capable of cytolysis of tumor: CEA-TCB (T-Cell Bispecific Antibody) + Atezolizumab<br />

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a. Schoenfeld JD, et al. Hum Vaccin. 2011;7:976-981; b. Hodi FS, et al. Cancer Immunol Res. 2014;2:632-642.

Antiangiogenic Agents + Immunotherapy

Rationale: antiangiogenic immunotherapy enables more robust inhibition of tumor angiogenesis while simultaneously impacting the immune-inhibitory effects of the proangiogenic tumor milieu^[a]

•

Benefits of combining antiangiogenic agents with immunotherapy has been seen in patients metastatic melanoma receiving ipilimumab + bevacizumab

^[b]

– Effects on inflammation, lymphocyte trafficking, and immune regulation were observed

– Indicates dual roles of angiogenic factors in blood vessel formation and immune regulation

•

Trials combining immune augmentation with angiogenesis are currently ongoing for mCRC

•

Patients should be encouraged to enroll into clinical trials

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Clinical Trials with bevacizumab plus checkpoint blockade

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Vaccines plus checkpoint blockade in pMMR

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Slide 32

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P392

Provided by BMS in response to unsolicited requests only

Microbiome Analyses in Patients With Previously Treated, Deficient DNA Mismatch

Repair/Microsatellite Instability-High Metastatic Colorectal Cancer Treated With

Nivolumab ± Ipilimumab: CheckMate-142

Scott Kopetz,¹Vittorina Zagonel,²Michael J. Overman,¹ Ray McDermott,³Michael A. Morse,⁴ Franklin L. Chen,⁵ James Lee,⁶ Rebecca A. Moss,⁷Lilan Ling,⁸Alex Greenfield,⁷

Danielle Greenawalt,⁷Z. Alexander Cao⁷

1The University of Texas MD Anderson Cancer Center, Houston, TX; ²Istituto Oncologico Veneto IOV-IRCCS, Padova, Italy; ³St Vincent’s University Hospital, Dublin, Ireland; ⁴Duke University, Durham, NC; ⁵Novant Health Oncology Specialists, Winston-Salem, NC; ⁶University of Pittsburgh

Cancer Institute, Pittsburgh, PA; ⁷Bristol-Myers Squibb, Princeton, NJ; ⁸Memorial Sloan Kettering Cancer Center, New York, NY

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Provided by BMS in response to unsolicited requests only ³¹

Methods

Adapted from Eckburg PB, et al. Science. 2005;308(5728):1635-1638. Reprinted with permission from AAAS.

Figure 2. Representative phylogenetic tree of human intestinal bacteria

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Critical Reviews in Oncology / Hematology (2018), https://doi.org/10.1016/j.critrevonc.2018.07.001

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GRAZIE per l’attenzione

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a. Ebert PJR, et al. Immunity. 2016;44:609-621; b. Bendell JC, et al. J Clin Oncol. 2016;34(suppl). Abstract 3502.

Cobimetinib + Atezolizumab Overview

• Cobimetinib is a reversible, potent, highly selective MEK1/2 inhibitor

MOA Preclinical Evidence^[a]

• Increased number of effector-phenotype antigen-specific CD8(+) T cells within

tumors

• Increased expression of class I MHC within tumors

Benefits of Combination Treatment^[b]

• Adding atezolizumab shows synergistic effect, generating antitumor T-cell

responses

• Phase 1b study (N=23): 17% ORR and 72%

6-month OS; higher response than either

agent alone Reproduced from Bendell JC, et al. J Clin Oncol.

2016;34(suppl). Abstract 3502 with permission.

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Critical Reviews in Oncology / Hematology (2018), https://doi.org/10.1016/j.critrevonc.2018.07.001