The left versus right colon cancer storyWhat is the truth?

Prof. V. HeinemannCCCLMU, Klinikum GrosshadernLudwig-Maximilian-University of Munich, Germany

Three stages of truth (Schopenhauer)• Ridicule• Violent opposition• Acceptance for granted

Conflicts of Interest

● Advisory Boards: Merck, Amgen, Roche, Servier, Sanofi, Bayer, Novartis, Boehringer-Ingelheim, SIRTEX, MSD, BMS

● Honorary fees: Merck, Amgen, Roche, Servier, SIRTEX, MSD, BMS, Servier

● Scientific grants:Merck, Amgen, Roche, Servier, Boehringer-Ingelheim, SIRTEX, MSD, BMS, Pfizer, Shire

Molecular Profile

CT doublet+ moAb

Combination CT + bevacizumab

CT triplet+ bevacizumab

RAS mtRAS wt BRAF mt

Right-sided Left-sided

Sidedness affects treatment decisions

most of the evidence

60-80%

20-40%

Prognostic Relevance of Primary Tumour Sidedness in Clinical Studies

Holch et al. Eur J Cancer 2017Clearly better outcome in LPT: HR 1.5favors RC favors LC

Study Regimen Right-sided location

CRYSTAL FOLFIRI + CetuximabFOLFIRI

19%27%

PRIME FOLFOX + PanitumumabFOLFOX

19%24%

FIRE-3 FOLFIRI + CetuximabFOLFIRI + Bev

19%25%

PEAK FOLFOX + PanitumumabFOLFOX + Bev

29%21%

CALGB Chemo + CetuximabChemo + Bev

30%34%

Prevalence of right-sided tumors in clinical studies

Range: 19-34%

BevacizumabEffect of sidedness on survival

Pooled Analysis: NO16966 and AVF2107

Sidedness was determined in 1590 (72%) of 2214 pts

• 27% right • 73% left

Conclusions:• Incomplete analysis

• Bevacizumab comparably improvesOS in LSP and RSP

• Effect not significant in RSP

Loupakis BJC 2018

Left side

Right side

Cremolini C, et al. Ann Oncol 2018

TRIBE: Impact of Sidedness on OS

Unselected ptsLSP: HR 0.99RSP: HR 0.56

Unselected pts Right-sided Left-sided

FOLFOXIRI + Bev FOLFIRI + Bev FOLFOXIRI + Bev FOLFIRI + Bev

ORR 63.9% 54.6% 64.6% 56.6%

RAS/BRAF-wtLSP: HR 0.88RSP: HR 0.50

FOLFOXIRI + Bev

FOLFIRI + Bev

Cremolini C, et al. Ann Oncol 2018

TRIBE: Impact of Sidedness on OS

Unselected ptsLSP: HR 0.99RSP: HR 0.56

Unselected pts Right-sided Left-sided

FOLFOXIRI + Bev FOLFIRI + Bev FOLFOXIRI + Bev FOLFIRI + Bev

ORR 63.9% 54.6% 64.6% 56.6%

RAS/BRAF-wtLSP: HR 0.88RSP: HR 0.50

FOLFOXIRI + Bev

FOLFIRI + Bev

RSP: FOLFOXIRI plus bevacizumab may be regarded as a preferred option in pts fit for combination and independent of their molecular statusLSP: Doublet plus bevacizumab remains the preferred option

Anti-EGFR agentsEffect of sidedness on survival

• Meta-analysis: chemo doublet +/- EGFR-i (PRIME, CRYSTAL)

• Meta-analysis: head-to-head comparisons: EGFR-i versus bevacizumab(CALGB, FIRE-3, PEAK)

PRIME (FOLFOX +/- Panitumumab): Effect of Sidedness

Boeckx N, et al. Ann Oncol 2017

Clear benefit from Pmab

No benefit from Pmab

Left-sided mCRC

right-sided mCRC

Meta-analysis: addition of an anti-EGFR agent to chemoOverall Survival

Left-sided primaryClear benefit fromanti-EGFR therapy

Right-sided primaryNo benefit fromanti-EGFR therapy

Holch J, Eur J Cancer

PRIME

CRYSTAL

PRIME

CRYSTAL

Head to head comparisonsanti-EGFR agents versus bevacizumab

FIRE-3(FOLFIRI + Cetuximab versus FOLFIRI + Bevacizumab) Effect of Sidedness

Tejpar S, et al. JAMA Oncopl 2016

No significantdifference Cetuximab

superior: Δ=10mo

Meta-Analysis of Head to Head ComparisonsOverall survival

Holch J, Eur J Cancer. 2017

Left-sided primaryClear benefit fromanti-EGFR agentscompared to bevacizumab

Right-sided primaryStrong trend in favor of bevacizumab

Left-sided mCRC

right-sided mCRC

CALGB/SWOG 80405

FIRE-3

PEAK

CALGB/SWOG 80405

FIRE-3

PEAK

Meta-Analysis of Head to Head ComparisonsProgression-free survival

Left-sided mCRC

right-sided mCRC

CommentComparable effectsof sidedness on PFS and OS

H-to-H Comparisons: FIRE-3, PEAK, CALGBOverall Survival according to sidedness

Study

FIRE-3(n=394)

CALGB(n=474)

PEAK(n=234)

Left-Sided Primary Tumours

Chemo +anti-EGFR

Chemo + Bevacizumab

HRP

38.3 mo 28.0 mo 0.630.002

39.2 mo 32.6 mo 0.770.04

43.4 mo 32.0 mo 0.84na

Right-Sided Primary Tumours

Chemo +anti-EGFR

Chemo + Bevacizumab

HRP

18.3 mo 23.0 mo 1.30.28

13.7 mo 29.2 mo 1.360.10

17.5 mo 21.0 mo

Bevacizumab works in LSP

EGFR-i workeven better in LSP

Very poor survival in EGFR-i treated RPT

Anti-EGFR agentsEffect of sidedness on ORR

Holch J....Heinemann V, Eur J Cancer. 2017 Jan;70:87-98.

Meta-analysis: addition of an anti-EGFR agent to chemoORR: Left- and right-sided mCRC

Left-sided mCRC

right-sided mCRC

Left-sided primaryClearly favorsanti-EGFR treatment

Right-sided primaryTrend in favor of anti-EGFR treatment

PRIME

CRYSTAL

PRIME

CRYSTAL

Holch J....Heinemann V, Eur J Cancer. 2017 Jan;70:87-98.

Meta-analysis: Head to head comparisonsORR: Left- and right-sided mCRC

Left-sided primaryClearly favorsanti-EGFR treatment

Right-sided primaryTrend in favor of anti-EGFR treatment

CALGB/SWOG 80405

FIRE-3

PEAK

CALGB/SWOG 80405

FIRE-3

PEAK

Left-sided mCRC

right-sided mCRC

ORR (primary objective)

N FOLFOXIRI + Pmab

FOLFOXIRI P

Full analysis set 96 87.3% 60.6% 0.004

Left 78 90.6% 68.0% 0.02

Right 18 70.0% 37.5% 0.34

VOLFI(FOLFOXIRI + Panitumumab versus FOLFOXIRI)

Effect of intensified treatment in RPT vs LPT

ConclusionIn RPT there is a discordant effect of Pmab on ORR and PFS

Geissler M, et al. ASCO #3509, 2018

Later treatment linesEffect of sidedness on OS

Brulé SY, et al. Eur J Cancer 2015

NCIC CO.17: Relevance of sidedness in pretreated patients**KRAS wild-type

Conclusions• Highly selected patient

population

• BRAF V600 mutation RC 4.7% LC 0.8%

• Cetuximab is effective compared to BSC

• Effects smaller in right-sided than left-sided mCRC

*Patients who had previously been treated with a fluoropyrimidine, irinotecan, and oxaliplatinor had contraindications to treatment with these drugs

HR = 0.66p=0.18

HR = 0.73p=0.26

HR = 0.49p=0.002

HR = 0.28p <0.0001

What is the truth?

Continuum of DNA Alterations

According to Yamauchi M. et al., Gut 2012;61:847-54*CIMP: CPG-island methylation phenotype; MSI, microsatellite instability

50

40

30

20

10

0Caecum

(n = 243)Colon

ascendens(n = 295)

Hepatic flexur

(n = 46)

Colon transversum

(n = 91)

Splenic flexur

(n = 33)

Colon descendens

(n = 83)

Colon sigmoideum(n = 314)

Recto-sigmoid

(n = 106)

Rectum(n = 232)

CIMP-high MSI-high BRAF MutationAnt

eilp

ositiv

e Fä

lle(%

)

right-sided left-sided

Prevalence of CMS According to Sidedness

Loree JM, et al. Clin Cancer Res 2018;

608 patients with stage I-IV CRCFIRE-3

FIRE-3

HR for OS According to Primary Tumor Location

Loree JM,.... Kopetz S; Clin Cancer Res 2018

FIRE-3: Greater DpR correlates with longer OS

Stintzing S, et al. Lancet Oncology 2016

Depth of response correlated significantly with OS (two-sided Bravais Pearson test)

FOLFIRI + Cetuximab

FOLFIRI + BevacizumabR

N = 400

Prim. Endpoint = ORR

Δ = 8.1 months

DpR is predictor of OSin left-sided mCRC

Sidedness differentially affects the relation betweenEGFR-i induced ORR and OS

Discordance of ORR and OSin right-sided mCRC

?

T + EGFR-i

if ORR is a primary goal

D + Bev

if EGFR-i are not accepted/tolerated

RAS wt

Left-sided

Left versus right colon cancer story: My Take

D + EGFR-i

if OS is a primary goal

Right-sided

D/T + Bev

if OS is a primary goal

default recommendation

default recommendationD: chemo doublet

T: chemo triplet

Clinical Practice Recommendation:LPT RAS-wt mCRC:

● Define RAS- and BRAF mutation status upfront

● Prefer an anti-EGFR agent in 1st-line treatmentif prolongation of OS is a primary goal (most patients)

● If anti-EGFR agents are not accepted or toleratedswitch to a doublet plus bevacizumab

● Focus on exploration of family history● Define BRAF mutation and MSI status upfront

● Prefered 1st-line treatment option: triplet plus bevacizumab

● Alternative option: triplet plus anti-EGFR agent if tumor reduction or conversion therapy is a primary goal

if you are willing to evaluate early tumor response(e.g. after 6-8 weeks)

in case of insufficient response: immediately switch to bev-based therapy

Clinical Practice Recommendation:RPT RAS-wt mCRC: