mCRC: What to do after 1st line failure?

Clarinda Chua

National Cancer Centre Singapore

ESMO ASIA PRECEPTORSHIP PROGRAMME GASTROINTESTINAL TUMOURS

The armamentarium

1st line 2nd line ≥ 3rd line

Cytotoxics

5FUOxaliplatinIrinotecanTAS 102

BiologicsBevacizumabRamucirumabAfliberceptPanitumumabCetuximabRegorafenib

Outline

• 2nd line therapy

(a) Cytotoxics alone vs addition of biologics

(b) Which biologic? Anti-VEGF vs anti-EGFR

(c) Continuation of biologics beyond PD

(d) Ongoing studies

• ≥3rd line therapy

(a) Regorafenib and TAS-102

(b) HER2 targeting agents

(c) Immune-therapy in MSS

(c) Ongoing studies

Outline

• 2nd line therapy

(a) Cytotoxics alone vs addition of biologics

(b) Which biologic? Anti-VEGF vs anti-EGFR

(c) Continuation of biologics beyond PD

(d) Ongoing studies

• ≥3rd line therapy

(a) Regorafenib and TAS102

(b) HER2 targeting agents

(c) Immune-therapy in MSS

(c) Ongoing studies

2nd line cytotoxics

• 2nd line Oxaliplatin and Irinotecan > BSC1-2

• Change backbone cytotoxic

• 5FU -> 5FU/Ox or 5FU/Iri

• 5FU/Ox -> 5FU/Iri and vice versa3-5

• Exposure to all 3 chemotherapeutic agents improves outcomes6

1Cunningham D, Pyrhonen S, James RD et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998; 352: 1413–1418.2Rougier P, Lepille D, Bennouna J et al. Antitumour activity of three second-line treatment combinations in patients with metastatic colorectal cancer after optimal 5-FU regimen failure: a randomised, multicentre phase II study. Ann Oncol 2002;13: 1558–1567.3Koopman M, Antonini NF, Douma J et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 2007;370: 135–142.4Seymour MT, Maughan TS, Ledermann JA et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 2007;370: 143–152.

5Tournigand C, Andre T, Achille E et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22: 229–237.6Grothey A, Sargent D. Overall survival of patients with advanced colorectal cancer correlates with availability of fluorouracil, irinotecan, and oxaliplatin regardless of whether doublet or single-agent therapy is used first line. J Clin Oncol 2005; 23:9441–9442

Trial Name Phase

Regimen

1st EP and ResultsControl Experimental

EPIC1 III irinotecan + cetuximab OS Negative

200501812 III FOLFIRI + panitumumabPFS Positive

OS Negative

SPIRITT3

II

FOLFIRI+

bevacizumab

FOLFIRI+ panitumumab

PFS Negative

WJOG6210G4 OS Negative

PRODIGE185

FOLFIRI+

bevacizumab

FOLFIRI+ cetuximab

PFS Negative

E32006 III FOLFOX + bevacizumab OS Positive

VELOUR7 III FOLFIRI + ziv-aflibercept OS Positive

ML181478 III SOC + bevacizumab OS Positive

RAISE9 III FOLFIRI + ramucirumab OS Positive

An

ti-E

GFR

mA

bA

nti

-VEG

F m

Ab

1. Sobrero AF, et al. J Clin Oncol. 2008;26(14):2311-2319; 2. Peeters M, et al. J Clin Oncol. 2010;28(31):4706-4713; 3. Hecht JR, et al. Clin Colorectal Cancer. 2015;14(2):72-80; 4. Shitara K, et al. J Clin Oncol. 2016;34(suppl): Abstract 3567; Hiret S, et al. J Clin Oncol. 2016;34(suppl): Abstract 3514; 6. Giantonio BL, et al. J Clin Oncol. 2007;25(12):1539-1544, 2007; 7. Van Cutsem E, et al: J Clin Oncol. 2012;30(28):3499-3506; 8. Kubicka, et al. Ann Oncol. 2013;24(9):2342–2349; 9. Tabernero J, et al. Lancet Oncol. 2015;16(5):499-508

2nd line treatmentCytotoxics alone vs addition of biologics; anti-VEGF vs anti-EGFR

Adapted from T Yoshino, APGCS 2017

ASCO GI Symposium 2005

E3200: + Bevacizumab

E3200: + Bevacizumab

Giantonio BJ, ASCO 2005

Giantonio et al . Journal of Clinical Oncology 2007 25:12, 1539-1544

ML18147: Bevacizumab beyond progression

D Arnold, ASCO 2012

VELOUR: + Aflibercept

ASCO 2012

RAISE: + Ramucirumab

J Tabernero, 2015 Gastrointestinal Cancers Symposium ASCO

2nd line anti-angiogenics

TrialE3200N=829

TML18147N=820

RAISEN=1072

VELOURN=373

RegimenFOLFOX-bevvs. FOLFOX

CT-bev vs. CTFOLFIRI-ram vs.

FOLFIRIFOLFIRI-AFL vs.

FOLFIRI

RR 23% vs 9% 5 % vs. 3 % 13.4 % vs. 12.5 %11.7 % vs.

8.4 %

PFS

7.3m vs. 4.7m

HR 0.61P<0.0001

5.7m vs. 4.1m

HR 0.68P<0.0001

5.7m vs. 4.5mHR 0.79

P=0.0005

6.7m vs. 3.9m

HR 0.66

OS

12.9m vs. 10.8m

HR 0.75P=0.0011

11.2m vs. 9.8m

HR 0.81P=0.0062

13.3m vs. 11.7mHR 0.84P=0.022

12.5m vs. 11.7m

HR 0.86

bev, bevacizumab; CT, 5-FU+irinotecan/oxaliplatin; ram, ramucirumab; aflib, aflibercept

Bennouna et al. Lancet Oncol 2013, Kubicka et al. ASCO-GI 2014 #520., Tabernero et al. Lancet Oncol 2015., Tabernero et al. ESMO 2011

Outline

• 2nd line therapy

(a) Cytotoxics alone vs addition of biologics

(b) Which biologic? Anti-VEGF vs anti-EGFR

(c) Continuation of biologics beyond PD

(d) Ongoing studies

• ≥3rd line therapy

(a) Regorafenib and TAS102

(b) HER2 targeting agents

(c) Immune-therapy in MSS

(c) Ongoing studies

2nd line anti-EGFR: EPIC

OS: 10.7m (Cetux/Iri) vs 10m (Iri), HR 0.975, p=0.71

PFS: 4m (Cetux/Iri) vs 2.6m (Iri), HR 0.692, p <0.0001 Sobrero et al. Journal of Clinical Oncology 2008 26:14, 2311-2319

PICCOLO: Panitumumab and Iri vs Iri alone in KRAS WT 5FU-resistant CRC

Median OS: 10·9m (95% CI 9·5–12·5) [irinotecan]vs10·4m (8·9–12·2) [IrPan]HR 1.01, 95% CI 0·83–1·23; p=0·91)

PFS was longer in the IrPan group than in the irinotecan group (HR 0·78, 95% CI 0·64–0·95; p=0·015

RR: 12% (Irinotecan) vs 34% (IrPan)

Seymour, Matthew T et al. Lancet Oncology 2013, Volume 14 , Issue 8 , 749 - 759

181: + Panitumumab

PFS (central review) by (A) wild-type (WT) KRAS and (B) mutant (MT) KRAS. OS by (C) WT KRAS and (D) MT KRAS.

KRAS WT:PFS: 5.9m vs 3.9m HR 0.73; 95% CI, 0.59 to 0.90; P = .004OS: 14.5m vs 12.5m HR 0.85, 95% CI, 0.70 to 1.04; P = .12RR: 35% vs 10%

Peeters et al. Journal of Clinical Oncology 2010 28:31, 4706-4713

2nd line anti-EGFR

Trial Control Experimental OS (control/exp)

PFS(control/exp)

RR

EPIC Irinotecan Irinotecan + Cetuximab

10m vs 10.7m

2.6m vs 4m 4.2% vs 16.4%

PICCOLO Irinotecan Irinotecan + Panitumumab

10.9m vs 10.4m

HR 0·7895% CI 0·64–0·95; p=0·015

12% vs 34%

181 FOLFIRI FOLFIRI +Panitumumab

12.5m vs 14.5m

3.9m vs 5.9m 10% vs 35%

• Trials may have included RAS MT patients• 2nd line anti-EGFR generally paired with Irinotecan backbone• No OS benefit to addition of anti-EFGR in 2nd line• PFS benefit• RR improvement

Outline

• 2nd line therapy

(a) Cytotoxics alone vs addition of biologics

(b) Which biologic? Anti-VEGF vs anti-EGFR

(c) Continuation of biologics beyond PD

(d) Ongoing studies

• ≥3rd line therapy

(a) Regorafenib and TAS102

(b) HER2 targeting agents

(c) Immune-therapy in MSS

(c) Ongoing studies

Continuation of antiangiogenics post PD

Median OS rates were 12.6, 19.9, and 31.8 months in the no post-PD treatment, no-BBP, and BBP groups

Grothey et al. JCO 2008 26:33, 5326-5334D Arnold, ASCO 2012

BRiTE observational studyARIES Observational study

TML study

anti-EGFR beyond PD? RP2 CAPRI-GOIM

Ciardiello et al. Annals of Oncology, Volume 27, Issue 6, 1 June 2016, Pages 1055–1061

PFS* wrtKRAS/NRAS/BRAF/PIK3CA status（n = 117）

KRAS/NRAS/BRAF/PIK3CA mt (n = 51) KRAS/NRAS/BRAF/PIK3CA wt (n = 66)

1.0

0.0

0 405

Months

Arm A（n = 19） Arm B （n = 32）

Median PFS, months

2.7 4.4

HR（95% CI）

1.70（0.94-3.05）

P = .07

Arm A（FOLFOX + cetuximab）

Arm B（FOLFOX）

*From randomization at start of second-line treatmentmt, mutated; wt, wild-type

2010

0.8

0.4

0.6

0.2

Pro

gre

ssio

n-F

ree

Su

rviv

al

Arm A （n = 31） Arm B （n = 32）

Median PFS, months

6.9 5.3

HR（95% CI）

0.56（0.33-0.94）

P = .025

Arm B

Arm A

N at risk:

3015

19

32

3525

1.0

0.0

0 405

Months

Arm A（FOLFOX + cetuximab）

Arm B（FOLFOX）

2010

0.8

0.4

0.6

0.2

Arm B

Arm A

N at risk:

3015

34

32

3525

06 02 01 00 023 210 24 02

014 28 24 12 017 05 01 00

Ciardiello F, et al. Ann Oncol. 2016;27(6):1055-1061.

Pro

gre

ssio

n-F

ree

Su

rviv

al

OS* wrtKRAS/NRAS/BRAF/PIK3CA（n = 117）

1.0

0.0

0 6018126

Months

Arm A（n = 19） Arm B（n = 32）

Median OS, months

11.6 14.0

HR（95% CI）

1.60（0.89-2.96）

P = .10

Arm A（FOLFOX + cetuximab）

Arm B（FOLFOX）

*From randomization at start of second-line treatment

3624

0.8

0.4

0.6

0.2

Arm A (n = 34） Arm B（n = 32）

Median OS, months

23.7 19.8

HR（95% CI）

0.57（0.32-1.02）

P = .056

Arm B

Arm A

N at risk:

4830

19

32

5442

05716 01 00 00

091927 36 04 01

1.0

0.0

0 6018126

Months

Arm A（FOLFOX + cetuximab）

Arm B（FOLFOX）

3624

0.8

0.4

0.6

0.2O

vera

ll Su

rviv

al

Arm B

Arm A

N at risk:

4830

34

32

5442

0222632 215 25 12

0152125 16 01 00

Ciardiello F, et al. Ann Oncol. 2016;27(6):1055-1061.

KRAS/NRAS/BRAF/PIK3CA mt (n = 51) KRAS/NRAS/BRAF/PIK3CA wt (n = 66)

Ove

rall

Surv

ival

Outline

• 2nd line therapy

(a) Cytotoxics alone vs addition of biologics

(b) Which biologic? Anti-VEGF vs anti-EGFR

(c) Continuation of biologics beyond PD

(d) Ongoing studies

• ≥3rd line therapy

(a) Regorafenib and TAS102

(b) HER2 targeting agents

(c) Immune-therapy in MSS

(c) Ongoing studies

FOLFIRI + Panitumumab(n= 91)

FOLFIRI + Bevacizumab(n = 91)

R

SPIRITT Trial1 (n = 182)

FOLFIRI + Panitumumab(n = 60)

FOLFIRI + Bevacizumab (n = 60)

R

WJOG6210G Trial3 (n = 120)

1st line BEV

mFOLFOX6/FOLFIRI + Cetuximab(n = 65)

mFOLFOX6/FOLFIRI + Bevacizumab (n = 65)

R

PRODIGE18 Trial2 (n = 130)

1st line BEV

1st line BEV

1. Hecht JR, et al. Clin Colorecal Cancer. 2015;14(2):72-80. 2. Hiret S, et al. J Clin Oncol. 2016;34(suppl): Abstract 3514.3. Shitara K, et al. J Clin Oncol. 2016;34(suppl): Abstract 3567.

Anti-VEGF vs Anti-EGFR in 2nd line

Adapted from T Yoshino, APGCS 2017

Bmab 9.2 months

Pmab 7.7monthss

（n = 91）

（n = 91）

HR = 1.01, P = .97Bmab 5.9 months

Pmab 6.0 months

（n = 58）

（n = 59）

HR = 1.14, P = .498

SPIRITT1 (n = 182)

WJOG6210G3 (n = 120)

PRODIGE182 (n = 130)

PFS: Anti-VEGF vs anti-EGFR in 2nd line

1. Hecht JR, et al. Clin Colorecal Cancer. 2015;14(2):72-80.2. Bennouna et al. ESMO 20173. Shitara K, et al. J Clin Oncol. 2016;34(suppl): Abstract 3567.

Adapted from T Yoshino, APGCS 2017

Bmab 21.4 months

Pmab 18.0 months

（n = 91）

（n = 91）

HR = 1.06, P = .75

Bmab 13.4 months

Pmab 16.2 months

（n = 58）

（n = 59）

HR = 1.16, P = .499

SPIRITT1 (n = 182)

WJOG6210G3 (n = 120)

PRODIGE182 (n = 130)

1. Hecht JR, et al. Clin Colorecal Cancer. 2015;14(2):72-80.2. Bennouna et al. ESMO 20173. Shitara K, et al. J Clin Oncol. 2016;34(suppl): Abstract 3567.

OS: Anti-VEGF vs anti-EGFR in 2nd line

Adapted from T Yoshino, APGCS 2017

Trial SPIRITT PRODIGE18 WJOG6210G

RR 19% vs 32% 25% vs 32% 6% vs 46%

Outline

• 2nd line therapy

(a) Cytotoxics alone vs addition of biologics

(b) Which biologic? Anti-VEGF vs anti-EGFR

(c) Continuation of biologics beyond PD

(d) Ongoing studies

• ≥3rd line therapy

(a) Regorafenib and TAS102

(b) HER2 targeting agents

(c) Immune-therapy in MSS

(c) Ongoing studies

Cancer Stem Cells (CSCs) or cancer cells with stemness phenotypes • self-renewal capability• highly malignant • thought to be fundamentally responsible for

malignant growth, recurrence, drug-resistance and metastasis

• highly resistant to chemotherapies and current targeted agents

Kim TI. World J Gastroenterol. 2014 Apr 14;20(14):3835-46

CCTG CO.23: Phase III Trial of BBI-608 (napabucasin) vs placebo in advanced CRC

R A N D O M I Z E

Pre-treated advanced colorectal carcinoma

napabucasin 480mg q12h

+ BSC

placebo q12h + BSC

Till toxicity or no benefit or death

1:1

Endpoints: Primary – overall survivalSecondary – progression-free survival, ORR (RECIST)

DCR, safety, QoL (EORTC QLQ C30), Health Utilities (HUI3), economics, biomarker (pSTAT3, b-catenin) effect on OS/PFS

Stratify: ▪ ECOG PS (0 vs 1)▪ KRAS status▪ Prior anti-VEGF therapy (y vs n)▪ Time from diagnosis metastases to

randomization (<18 vs >18 months)

Death

pSTAT3 is a predictive biomarker of OS benefit from napabucasin

pSTAT3 positive pSTAT3 negative

HR 0.24 [0.12-0.51], p=0.0002mOS 5.1 vs 3.0 months

HR 1.44 [1.06-1.95]mOS 4.0 vs 4.9 months

• BBI-608 monotherapy did not improve OS or PFS in unselected ACRC• While pSTAT3 positivity was a poor prognostic factor in untreated pts,

NAPA treatment in pts with positive pSTAT3 significantly improved OS.

Jonker, ESMO 2016Adapted from APGCS, T Yoshino

Ongoing study: Napabucasin (BBI-608) in Combination With FOLFIRI in Adult Patients With Previously Treated Metastatic

Colorectal Cancer (CanStem303C)

• BBI608: a first-in-class, orally-administered, cancer stem cell inhibitor, simultaneously inhibits multiple key cancer stemness pathways.

• BBI608: a first-in-class, orally-administered, cancer stem cell inhibitor, simultaneously inhibits multiple key cancer stemness pathways.

BBI608:• a first-in-class, orally-administered, cancer stem cell inhibitor, simultaneously inhibits

multiple key cancer stemness pathways. • inhibits both Stat3 and β-catenin pathways

Outline

• 2nd line therapy

(a) Cytotoxics alone vs addition of biologics

(b) Which biologic? Anti-VEGF vs anti-EGFR

(c) Continuation of biologics beyond PD

(d) Ongoing studies

• ≥3rd line therapy

(a) Regorafenib and TAS102

(b) HER2 targeting agents

(c) Immune-therapy in MSS

(c) Ongoing studies

Correct: Regorafenib vs BSC

OS: 6·4m (regorafenib) vs 5·0m (placebo)HR 0.77; 95% CI 0·64–0·94; one-sided p=0·0052)

PFS: 1.9m (regorafenib) vs 1.7m (placebo)HR 0.49; 95% CI 0·42–0·58; p<0·0001)

RR: 1·0% (regorafenib) and 0·4% (placebo)(p=0·19)

Grothey et al. Lancet 2013, Volume 381 , Issue 9863 , 303 - 312

Patients had to have received all available standard treatment options. 100% had prior Bev. ~40% had prior anti-EGFR

Regorafenib: Toxicities

Grothey et al. Lancet 2013, Volume 381 , Issue 9863 , 303 - 312

Concerns regarding toxicities particularly in real life practice

Tolerability of prescribed dose of 160mg/day 3 out of 4 weeks

CONCUR: Regorafenib in Asians

• At least 2 prior treatment lines or intolerance of standard rx• Preceding standard rx did not necessarily include targeted rx• 204 pts randomised 2:1• OS was significantly better with regorafenib than it was with placebo• Regorafenib: 97% had drug-related AE (vs 46%), SAE 9% vs 4%

OS: 8.8m vs 6.3m HR 0.5595% CI 0.40-0.77, one-sided p=0.00016

PFS: 3.2m vs 1.7m, HR 0.3195% CI 0·22–0·44; one-sided p<0·0001

Li, Jin et al. Lancet Oncology 2015, Volume 16 , Issue 6 , 619 - 629

Preliminary Analysis Suggests Greater Benefit with Regorafenib in CMS2 and CMS4

*Figure and table from Teufel, et al.2

1. Dienstmann R, et al. J Clin Oncol. 2014;32(5s): Abstract 3511. 2. Teufel M, et al. J Clin Oncol. 2015;33(15 suppl): Abstract 3558.

Molecularsubtype

Overall Survival Progression-Free Survival

n Hazard Ratio 95% CI Hazard Ratio 95% CI

CMS1 24 1.116 0.290-4.690 0.850 0.321-2.252

CMS2 140 0.779 0.486-1.249 0.571 0.387-0.842

CMS3 32 1.047 0.399-2.749 0.287 0.112-0.737

CMS4 85 0.672 0.358-1.261 0.483 0.286-0.814

All samples 281 0.797 0.572-1.12 0.528 0.401-0.698

RECOURSE: TAS-102

Mayer RJ et al. N Engl J Med 2015;372:1909-1919

RECOURSE: TAS-102

OS: 7.1m (TAS-102) vs 5.3mHR 0.68; 95% CI 0.58 to 0.81; P<0.001

PFS: 2.0m (TAS-102) vs 1.7mHR 0.48; 95% CI, 0.41 to 0.57; P<0.001

Benefit generally seen across all prespecified sub-groups including KRAS status, geographic region, primary tumour site etcRR 1.6% vs 0.4% (p=0.29)

TAS-102: Relationship Between Chemotherapy-InducedNeutropenia (CIN) and Outcome

Placebo

TAS-102, ANC G1/2 at cycle 1

TAS-102, ANC G3/4 at cycle 1

TAS-102, ANC G0 at cycle 1

0 3 6 9 12 15 18

00.5

1

OS for pts who Experienced Onset of Neutropenia in Cycle 1

Adapted from Nishina T, Yoshino T, et al. ASCO 2016 #254

• Neutropenia most common TAS-102 AE • Postulated to reflect high drug conc in pts• Of 112 pts given TAS-102, 31 (28%) developed Grade 3/4 neutropenia in treatment cycle 1, 19 (17%) in

cycle 2, and 8 (7%) in ≥ cycle 3• Onset of Grade 3/4 neutropenia at cycle 1 and 2 was associated with longer median OS compared to pts

without neutropenia• Grade 3/4 neutropenia occurrence might be an on-treatment predictive biomarker of TAS-102 • TAS-102 treatment should not be discontinued permanently due to the onset of Grade 3/4 neutropenia

CORRECT: Regorafenib RECOURSE: TAS-102

OS: 6·4m vs 5·0m

PFS: 1.9m vs 1.7m

OS: 7.1m vs 5.3m

PFS: 2.0m vs 1.7m

Grothey et al. Lancet 2013, Volume 381 , Issue 9863 , 303 - 312

Regorafenib and TAS-102 in the nth line setting

Regorafenib vs TAS-102

Grothey et al. Lancet 2013, Volume 381 , Issue 9863 , 303 - 312

Outline

• 2nd line therapy

(a) Cytotoxics alone vs addition of biologics

(b) Which biologic? Anti-VEGF vs anti-EGFR

(c) Continuation of biologics beyond PD

(d) Ongoing studies

• ≥3rd line therapy

(a) Regorafenib and TAS102

(b) HER2 targeting agents

(c) Immune-therapy in MSS

(c) Ongoing studies

Tras

HERACLES: Trastuzumab and Lapatinib in HER2-amplified mCRCPOC open label P2 Trial

trastuzumab at 4 mg/kg loading dose followed by 2 mg/kg once per weekoral lapatinib at 1000 mg per day

• Progressed on fluoropyrimidines, oxaliplatin, irinotecan, cetuximab, or panitumumab containing regimens; with or without anti-angiogenic regimens

• ECOG 0-1

• HER2 +ve tumors: tumours with 3+ HER2 score in more than 50% of cells by immunohistochemistry or with 2+ HER2 score and a HER2:CEP17 ratio higher than two in more than 50% of cells by FISH

HERACLES

screened 914 patients with KRAS exon 2 (codons 12 and 13) wild-type mCRC and identified 48 (5%) patients with HER2-positive tumours

Sartore-Bianchi, Andrea et al. Lancet Oncology 2016, Volume 17 , Issue 6 , 738 - 746

Her2 amplification as a clinically relevant genetic alteration in mCRC

Median TTP: 5.5m TTP 7.3m (Her2 3+) vs 4.2m (Her2 2+)Median DOR: 38 weeksMedian PFS: 21 weeks (95% CI 16–32) Median OS calculated post hoc: 46 weeks (95% CI 33–68)12 (45%) of 27 patients were alive at 1 year

Main toxicities: diarrhoea, rash, fatigue, paronychia, conjunctivitis (predominantly G1-2)

Seven (88%) of eight patients who achieved an objective response had tumours with a HER2 score of 3+ on IHC which was paralleled by a high HER2 gene copy number as assessed by FISH and qPCR

Outline

• 2nd line therapy

(a) Cytotoxics alone vs addition of biologics

(b) Which biologic? Anti-VEGF vs anti-EGFR

(c) Continuation of biologics beyond PD

(d) Ongoing studies

• ≥3rd line therapy

(a) Regorafenib and TAS102

(b) HER2 targeting agents

(c) Immune-therapy in MSS

(c) Ongoing studies

Cobimetinib + Atezolizumab in MSS mCRC

MEK inhibition:• upregulation of major

histocompatibility complex class I (MHC I) on tumor cells

• induces intratumoral T-cell infiltration

• enhances anti-PD-L1 activity

serial biopsy cohort showed enhanced PD-L1 upregulation, CD8 T-cell infiltration and MHC I expression on treatment, providing mechanistic rationale for the combination

MSS CRC can be converted to inflammed phenotype by MEK inhib?

Further analysis and RP3 (Atezolizumab vs Cobi+Atezo vs Regorafenib in chemo-refractory mCRC) ongoing

23 CRC patients

ORR: 17% (4/23)

SD: 22% (5/23)

By NGS scoring, 3/4 responders were MMR proficient1/4 MSI status unknown

Bendell, ASCO 2016

• 2nd line therapy– Dependent on 1st line therapy

– Cytotoxics alone vs addition of biologic: Anti-angiogenics generally demonstrated OS benefit, anti-EGFR mAb generally showed higher RR and PFS benefit

– Anti-VEGF mAb vs. Anti-EGFR mAb: Mainly phase 2 trials with no clear difference except RR favoring anti-EGFR mAb over Anti-VEGF mAb

– Continuation of biologics beyond PD: Yes for anti-angiogenics, No for anti-EGFR

– Ongoing Trials: CanStem 303 (BBI608 with FOLFIRI)

• ≥ 3rd line therapy– TAS-102 and Regorafenib: gen similar magnitude of benefit. Toxicities/availability.

Potential role of CIN in TAS-102 and CMS/other biomarkers

– Her2 amplification: clinically relevant genetic alteration that can be targeted

– Cobimetinib and Atezolizumab: possible conversion of MSS to immune-responsive tumor

Summary & Conclusion

Thank you