Definizione, incidenza, decorso clinico, terapie

Carcinoma del colon-retto MSI+

Definizione, incidenza, decorso clinico, terapie

Sara Lonardi

2019: ONCOLOGIA DI PRECISIONE Roma, 24-25 maggio 2019

Regione del Veneto

USD Sperimentazioni Cliniche di Fase Precoce UOC Oncologia Medica 1

Dipartimento di Oncologia

Istituto Oncologico Veneto – IRCCS, Padova

NCCN Guidelines for dMMR/MSI-H Biomarker Testing

• Universal MMR or MSI testing is recommended in all patients with a personal history of colon or rectal cancer to identify individuals with Lynch Syndrome (LS)

• Stage II MSI-H patients may have a good prognosis and do not benefit from 5-FU adjuvant therapy

• Nivolumab and pembrolizumab recommended as second-line or third-line treatment options in patients with dMMR/MSI-H mCRC who are

appropriate for intensive therapy

• Nivolumab and pembrolizumab recommended as first-line options for dMMR/MSI-H mCRC patients who are not appropriate for intensive therapy

NCCN Guidelines® for Colon Cancer V.1.2017. 2016 Nov 23

Guinney et al, Nat Med ’15

Prognostic value of CMS and MSI in early stage CRC

Prognostic effect in FIRE-3/CALGB 80405

Stintzing et al, ASCO 2017; Lenz et al, ASCO 2017

A new piece on the puzzle of mCRC!

50%

RAS mutations

BRAF mutation

RAS/BRAF wild-type

40%

HER-2 3%

Rearrangem

MSI 5%

Courtesy C. Cremolini

IMMUNOHISTOCHEMISTRY (IHC)

Process of detecting antigens in cells of a tissue section through the use of an

antibody which specifically recognizes an antigen of the target protein

POLYMERASE CHAIN REACTION (PCR) An artificial method of replicating DNA in the laboratory, typically used to identify the presence or absence of a DNA mutation

Routine Biomarker Testing Methods: IHC and PCR

MLH- 1 Present MLH- 1 Absent

MMR Classification:

Proficient MMR (pMMR):

all proteins are intact

Deficient MMR (dMMR):

loss of at least one protein

MSI Status Classification:

MSI-High (MSI-H): Instability of >2 loci (or

>30% of loci if larger panel of markers) MSI-Low (MSI-L): Instability at 1 locus (or 10%–30% of loci if larger panel of markers) MSS: none of the markers show instability

And from the clinical point of view..

Microsatellite instability is associated with..

• Right primary tumor

• Mucinous histology

• Peritoneal and distant nodes metastasis

• BRAF mutations

Microsatellite instable cancers (MSI-H) have a defect in repairing DNA resulting in a very high mutation rate

Dienstmann R, et al. J Clin Oncol. 2014;32:Abstract 3511.

Strickland KC, et al. Oncotarget. 2016;7:13587–13598.

Microsatellite instability

MLH1 PMS2

MSH2

Errors generated during DNA replication¹

Proficient mismatch repair (pMMR):

Errors detected and fixed

MLH1 PMS2

MSH2 MSH6

Deficient mismatch repair (dMMR):

Errors not detected and accumulate

Heterodimer complexes:

MutS and MutL

MSH6

Complex mechanisms of immune-escape

Ineffective presentation of tumor

antigens (eg, downregulation of MHC I)

Recruitment of immunosuppressive cells with inactive T cells (eg, Tregs, MDSCs)

T-cell checkpoint dysregulation (eg, PD-1, CTLA-4)

Tumor release of immunosuppressive factors (eg, TGF-β, IDO, IL-10)

Active T cell Inactive T cell

Tumor-associated antigens

APC

Immunosuppressive factors

Treg

Tumor cells

Figure adapted from Vesely 2011

• Microsatellite instable cancers (MSI-H) have a defect in repairing DNA resulting in a very high mutation rate

• Higher number of neoantigens in MSI-H tumors attracts tumor-

infiltrating lymphocytes (TILs) and overexpression of programmed death- 1 (PD-1) and PD-1 ligand 1 (PD-L1) which inhibits tumor cell killing

MSI

T Cell T Cell

T Cell

T Cell

T Cell

NON-MSI Tumor Cell

Dienstmann R, et al. J Clin Oncol. 2014;32:Abstract 3511.

Strickland KC, et al. Oncotarget. 2016;7:13587–13598.

Microsatellite instability in mCRC

Where it all started

Le et al, N Eng J Med 2015

Type of response MSI

(n=10)

MSS (n=18)

Complete Response 0% 0%

Partial Response 40% 0%

Objective Response Rate 40% 0%

Disease Control Rate 90% 11%

NCCN Guidelines for dMMR/MSI-H Biomarker Testing

• Universal MMR or MSI testing is recommended in all patients with a personal history of colon or rectal cancer to identify individuals with Lynch Syndrome (LS)

• Stage II MSI-H patients may have a good prognosis and do not benefit from 5-FU adjuvant therapy

• Nivolumab and pembrolizumab recommended as second-line or third-line treatment options in patients with dMMR/MSI-H mCRC who are

appropriate for intensive therapy

• Nivolumab and pembrolizumab recommended as first-line options for dMMR/MSI-H mCRC patients who are not appropriate for intensive therapy

NCCN Guidelines® for Colon Cancer V.1.2017. 2016 Nov 23

, Tremelimumab

, PDR001

Immunotherapy: checkpoint blockade

The «Old» Story: CPI monotherapy

No. at Risk

0 3 6 9 12 15 18 21 24 27 30 33 36 39

Months

74 44 35 31 29 27 15 14 14 12 6 1 0 0

Overall survival (%)

100 90 80 70 60 50 40 30 20 10 0

All patients n = 74

Median OS (95% CI), months NR (19.6, NE) OS rate (95% CI), %

12 months 18 months

72 (60.0, 80.9) 67 (54.9, 76.9)

15

Overman et al, 2018 ASCO GI Symposium

T cell Tumor cell

TCR MHC

PD-L1 PD-1

- - -

T cell Dendritic

cell

MHC TCR

CD28 B7 CTLA-4

- - -

Activation

(cytokines, lysis, proliferation, migration to tumor)

B7 + + +

+ + +

CTLA-4 Blockade (ipilimumab) PD-1 Blockade (nivolumab)

anti-CTLA-4 anti-PD-1

+ + +

PD-L2 PD-1

anti-PD-1

- - -

Mechanism of action of Nivolumab and Ipilimumab

Tumor Microenvironment

Presented by: Prof Thierry André 18

• Median follow-up in the combination therapy cohort (N = 119) was 13.4 months (range, 9–25) Primary endpoint:

• ORR per investigator

assessment (RECIST v1.1)

Other key endpoints:

• ORR per BICR, DCR^b, DOR, PFS, OS, and safety

• Histologically

confirmed metastatic or recurrent CRC

• dMMR/MSI-H per local laboratory

• ≥ 1 prior line of therapy

Nivolumab 3 mg/kg + ipilimumab 1 mg/kg Q3W

(4 doses and then nivolumab 3 mg/kg Q2W)

Combination Cohort^a

Nivolumab 3 mg/kg Q2W

Monotherapy Cohort^a

Phase 2 Nonrandomized Study

• Results of the monotherapy cohort (N = 74) with a similar median follow-up of 13.4 months (range, 10–32) will also be presented

Overman et al, J Clin Oncol. 2018

The «New» Story: CPI combo!

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]

Nivolumab¹ N = 74^c Nivolumab + ipilimumab

N = 119^a

ORR [95% CI]: 55% [45.2, 63.8]

20 40 60 80 100

0

DCR: combo 80% [95% CI: 71.5-86.6]

mono: 69% [95% CI: 57.1-79.2]

Investigator-Assessed Response and Disease Control

19 Presented by: Prof Thierry André

Overman et al, 2018 ASCO GI Symposium

Progression-Free and Overall Survival

Nivolumab

Months 100

90 80 70 60 50 40 30 20 10 0

0 3 6 9 12 15 18 21 24

Progression-free survival (%)c

27 30

Nivolumab + ipilimumab

100 90 80 70 60 50 40 30 20 10 0

0 3 6 9 12 15 18 21 24

Overall Survival (%)

2 7 30 33 Months

Nivolumab + ipilimumab Nivolumab

Nivolumab +

ipilimumab^a,d Nivolumab^1,e,f

9-mo rate (95% CI), % 87 (80.0, 92.2) 78 [66.2, 85.7]

12-mo rate (95% CI), % 85 (77.0, 90.2) 73 [61.5, 82.1]

Nivolumab +

ipilimumab^a,b Nivolumab^1,e,f 9-mo rate (95% CI), % 76 (67.0, 82.7) 54 [41.5, 64.5]

12-mo rate (95% CI], % 71 (61.4, 78.7) 50 [38.1, 61.4]

Overman et al, J Clin Oncol 2018

12m-OS rate Regorafenib: 24%

TAS-102: 27%

CheckMate 142: TRAEs With Nivo + Ipi in mSI-H mCRC

Overman M et al, J Clin Oncol 2018

* Reported in > 10% of patients

Mean change from baseline per three-level five-dimensional EuroQol instrument visual analog scale

Patient-Reported Outcomes: EQ-5D

Patients who continued treatment for 19 weeks achieved a level of health per the EQ-5D VAS that would be regarded as equal to or exceeding the general health of many populations, p=0.01 Overman M et al, J Clin Oncol 2018

• Median follow-up was 13.8 months (range, 9–19 months)^c

• Histologically confirmed metastatic or recurrent CRC

• MSI-H/dMMR per local laboratory

• No prior treatment in metastatic setting

Nivolumab 3 mg/kg Q2W +

Ipilimumab 1 mg/kg Q6W^a

Primary endpoint: ORR per investigator assessment (RECIST v1.1) Other key endpoints: ORR per BICR, DCR^b, DOR, PFS, OS, and safety

Nivolumab + Ipilimumab First-line Cohort

Durable Clinical Benefit With Nivolumab Plus Low-Dose Ipilimumab as First-Line Therapy in Microsatellite Instability-High/Mismatch

Repair Deficient Metastatic Colorectal Cancer

Heinz-Josef Lenz,¹ Eric Van Cutsem,² Maria Luisa Limon,³ Ka Yeung Mark Wong,⁴ Alain Hendlisz,⁵ Massimo Aglietta,⁶ Pilar García- Alfonso,⁷ Bart Neyns,⁸ Gabriele Luppi,⁹ Dana B. Cardin,¹⁰ Tomislav Dragovich,¹¹ Usman Shah,¹² Ajlan Atasoy,¹³ Roelien Postema,¹³ Zachary Boyd,¹³ Jean-Marie Ledeine,¹³ Michael James Overman,¹⁴ Sara Lonardi¹⁵

Investigator-assessed

Nivolumab + ipilimumab N = 45

ORR^a, n (%) [95% CI]

27 (60) [44.3–74.3]

Best overall response, n (%) CR

PR SD PD

Not determined

3 (7) 24 (53) 11 (24) 6 (13)

1 (2) DCR^b, n (%)

[95% CI]

38 (84) [70.5–93.5]

RECIST Response and Best Reduction in Target Lesions

Best reduction from baseline in target lesion (%)

Patients 75

100

50

*

*

* *

*

* *

*

* *

* *

* *

* *

* *

*

* *

* *

* *

* *

25 0 –25 –50 –75 –100

–30%

28 Apr 2017 09 Jun 2017 19 Jul 2017

17 Aug 2017 06 Oct 2017

Radiologic Response

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

0 3 6 9 12 15 18

Probability of progression-free survival

Progression-free survival (months)

No. at risk 45 37 34 24 15 7 7

0 3 6 9 12 15 18 21

Probability of overall survival

Overall survival (months)

45 42 40 38 24 13 1 0

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0

Progression-free and Overall Survival

PFS Nivolumab+Ipilimumab

N=45

Median PFS, months (95% CI) NR (14.1–NE) 9-mo rate, % (95% CI) 77 (62.0–87.2) 12-mo rate, % (95% CI) 77 (62.0–87.2)

OFS Nivolumab+Ipilimumab

N=45

Median OS, months (95% CI) NR (NE) 9-mo rate, % (95% CI) 89 (74.9–95.1) 12-mo rate, % (95% CI) 83 (67.6–91.7)

23.5.2017

31.7.2017

10.7.2018

Beyond MSI

TMB

MSI-H specimens are a subset of high TMB specimens

Fabrizio, ESMO Annual Meeting 2016

Correlation between TMB and RR with Checkpoint inhibitors

Yarchoan et al, NEJM 2017

Vanderwalde et al, Cancer Med 2018

Colorectal Cancer NSCLC

Relationships between high TMB, MSI-H, and high PD-L1

We need to search for something else..

Pol E

TCGA Nature 2012 Giannakis et al, Cell Reports 2016 4% POLE-mutant

“Ultramutated”

Microsatellite stable

TCGA colorectal cancers Recurrent heterozygous

missense mutations in exonuclease domain (P286R, V411L, S459F)

POLE proofreading domain mutations

Extremely rare, extremely sensitive

Gong et al. JNCCN ‘17

Conclusions

• MSI is the most validate biomarker for checkpoint inhibitors

• MSI should be routinely tested at least in GI cancers

• Immune-Checkpoint are highly effective in MSI-H metastatic colorectal cancer

• Other biomarkers are looming on the horizon

sara.lonardi@iov.veneto.it