Kolorektalni karcinom- novosti u liječenju

PANEL: Maja Banjin, Janja Ocvirk, Borislav Belev, Ivan Nikolić, Anes Pašić

Kolorektalni karcinom-novosti u liječenju

PANEL : Maja Banjin,Janja Ocvirk, Borislav Belev, Ivan Nikolić, Anes Pašić

– Pozicija primarnog tumora, prognostička i prediktivna vrednost za KRAS wt (“sidedness”) ?

– Nove terapijske opcije sa dopunom smernica

– Imunoterapija

– Biomarkeri i terapija

– Pozicija primarnog tumora, prognostička i prediktivna vrednost za KRAS wt (“sidedness”)

– Nove terapijske opcije i dopune smernice

– Imunoterapija

– Biomarkeri i terapija

Source: education.lego.com

Vučko 1984 Jure Franko-srebro

Olimpijski ski centar

Jahorina

Personalising treatment: what is state of the art?

915,103,765

How many ways can these six eight-stud building bricks be combined?

Personalising treatment: what is state of the art?

Multiple factors influence treatment choice

Patient characteristics

Patient preference

Tumourcharacteristics

Choice of chemotherapy

Choice of targeted therapy

Molecular characteristics

Definition of heterogeneity: clinical relevance

Molecular characteristics Tumour characteristics

Tumour locationRAS

BRAF

MSI status

HER2

Gene expression

Definition of heterogeneity: clinical relevance

Molecular characteristics Tumour characteristics

Tumour locationRAS

BRAF

MSI status

HER2

Gene expression

Distal and proximal colon cancers differ in terms of molecular, pathological and clinical features

Missiaglia et al. Ann Oncol 2014

BRAF MTMSIKRASPIK3CAMucinous differentiation

EREG expression18q loss20q gainEGFR gainHER2 gain

Right

Left

Right

Left

Enrichment of molecular characteristics by side

• Incidence: ~40% (increasing)

• Older patients• Microsatellite instability• BRAF mutations• KRAS mutations

Right-sided tumours• Incidence: ~60%• Younger patients• Predominantly WT• EGFR gain• HER2 gain• Better prognosis

Left-sided tumours

Bufill. Ann Intern Med 1990; Missiaglia et al. Ann Oncol 2014; Brule. ASCO 2013 Cancer Genome Atlas Network. Nature 2012;

Bendardaf. Anticancer Res 2008

• Phase III trial of cetuximab plus best supportive care (BSC) vs BSC alone in patients with EGFR+ refractory advanced CRC

NCIC CO.17 trial: effect of tumour location on PFS in KRAS WT patients

Brulé et al. Eur J Cancer 2015

Right-sided tumour (n=56)

Cetuximab + BSCBSC only

Prop

ortio

n al

ive

Time (months)0 5 10 15

1.0

0.8

0.6

0.4

0.2

0

Left-sided tumour (n=105)

Prop

ortio

n al

ive

Time (months)

1.0

0.8

0.6

0.4

0.2

00 5 10 15

Cetuximab + BSCBSC only

Cetuximab + BSC: 1.9 monthsBSC only: 1.9 months

HR=0.73 (0.42–1.27)p=0.26

Cetuximab + BSC: 5.4 monthsBSC only: 1.8 months

HR: 0.28 (0.18–0.45)p<0.0001

CALGB/SWOG 80405 Substudy: Tumor Location in KRAS wt mCRC

• CALGB/SWOG 80405 found no significant difference in OS or PFS between cetuximaband bevacizumab when added to first-line FOLFIRI or FOLFOX in pts with RAS wt mCRC[1]

• Primary tumor location may affect outcome in mCRC

• Retrospective analysis of data from CALGB/SWOG 80405 evaluated to determine effect of primary tumor location on outcomes in KRAS wt mCRC[5]

Clin Oncol. 2001;19: 2413-2421. 3. Brulé SY, et al. Eur J Cancer. 2015;51:1405-1414. 4. Loupakis F, et al. J NatlCancer Inst. 2015;107:dju427. 5. Venook AP, et al. ASCO 2016. Abstract 3504.’

Study N Molecular Selection Treatment Outcome

MosTumor Side

Right LeftO’Dwyer 2001[2] 1120 None 5-FU variations OS 10.9 15.8

Brulé 2015[3] 399 KRAS wt BSCBSC + CET PFS 1.9

1.91.85.4

Loupakis 2015[4] 2027 None

FOLFIRI/BEVFOLFOX4/XELOX/BEV

IFL/BEVOS

24.818.014.6

42.023.020.4

CALGB/SWOG 80405 Substudy: Baseline Population

Venook AP, et al. ASCO 2016. Abstract 3504.

Characteristic Overall*(N = 1137)

Tumor SideP ValueRight

(n = 293)Left

(n = 732)Mean age, yrs 58.4 61.2 57.3 < .0001Male, % 62.1 54.9 65.0 .002Synchronous stage IV, % 79.3 86.9 76.0 .0009Previous adjuvant therapy, % 14.2 10.6 15.7 .03FOLFOX/FOLFIRI, % 73.4/26.6 74.4/25.6 72.4/27.6 .51Primary in place, % 26.6 19.2 29.6 .0007Metastases pattern, % Liver only Liver metastases Extrahepatic

30.942.828.5

27.540.532.0

32.143.224.7

.02†

*Side totals excluding 66 pts with tumor in transverse colon and 46 pts with unknown location.†Any liver metastases vs extrahepatic.

CALGB/SWOG 80405 Substudy: Tumor Sidedness Prognostic for PFS

Venook AP, et al. ASCO 2016. Abstract 3504.

Median PFS, Mos(n = 1025)

Primary Tumor SideHR (95% CI) P Value*Right

(n = 293)Left

(n = 732)

All pts 8.9 11.7 1.03 (1.11-1.50) .0006

Cetuximab 7.8 12.4 1.56 (1.26-1.94) < .0001

Bevacizumab 9.6 11.2 1.06 (0.86-1.31) .55

*Adjusted for biologic, protocol chemotherapy, previous adjuvant therapy, previous radiotherapy, age, sex, synchronous disease, in place primary, liver metastases.

CALGB/SWOG 80405 Substudy: Tumor Sidedness Prognostic for overall survival

• OS prolonged for left-sided vs right-sided tumors

Venook AP, et al. ASCO 2016. Abstract 3504.

Mos

OS (%

)

100

80

60

40

20

00 12 24 36 48 60 72 84 96 108

Side N (Events)Median(95% CI)

HR(95% CI) P Value

Left

Right

732 (550)

293 (242)

33.3(31.4-35.7)

19.4(16.7-23.6)

1.55(1.32-1.82) < .0001

Left

Right

CALGB 80405: effect of tumour location on OS in all RAS WT patients

100

80

604020

0

Even

t fre

e (%

)

Months from study entry

Left: 32.7 monthsRight: 29.2 months

100

80

604020

0Ev

ent f

ree

(%)

Months from study entry

Left: 39.3 monthsRight: 13.7 months

Bevacizumab Cetuximab

0 24 48 72 84603612 0 24 48 72 84603612

Lenz et al. ESMO 2016

HR=0.55 (95% CI: 0.39–0.79)Adjusted p=0.001

HR=0.88 (95% CI: 0.62–1.25)Adjusted p=0.50

CALGB/SWOG 80405 Substudy: Conclusions

• Location of primary tumor prognostic in KRAS wt mCRC

– PFS, OS longer in pts with left- vs right-sided tumors

• Tumor sidedness predictive of response to biologics

– Markedly longer OS in pts with left-sided tumors treated with first-line chemotherapy + cetuximab vs bevacizumab

– Pts with right-sided tumors showed greater benefit with first-line chemotherapy + bevacizumab vs cetuximab

• Investigator conclusions:

– Sidedness is a surrogate marker for tumor biology

– Identification of other biomarkers may replace sidedness, help individualize care

– Pts should be stratified by sidedness in clinical trials

Venook AP, et al. ASCO 2016. Abstract 3504.

PRIME/PEAK/181

Different level of evidence to Erbitux: No Phase III data with pani

versus bev No significant difference in OS

Differences in CT backbone used: No Phase III trial with 1st

line pani + FOLFIRI

Significant increase in OS only shown in

PRIME!

FIRE-3 study

Erbitux + FOLFIRI> 38 months mOS in LS tumors

10 month benefit vs bev in LS tumors!

CRYSTAL-study

Erbitux + FOLFIRI> 28 months OS in LS tumors

7 month benefit vs CT alone in LS tumors!

Current insight from meta-analysis: overall survival

Clear OS benefit of anti-EGFR + CT therapy over bev + CT or CT alone in

LS tumors

1. Loupakis et al. J Natl Cancer Inst 2015 2. Barras. Biomark Cancer 2015

3. Missiaglia et al. Ann Oncol 2014 4. Hainsworth et al. ASCO 2016

5. Sartore-Bianchi et al. Lancet Oncol 20166. Siena. ESMO 2016

Summary: implementing biomarker knowledge into clinical decisions

BRAF mutations are more frequent in right-sided tumours,2

as is MSI-high status3

HER2: new emerging target in mCRC, predominantly in left-sided tumours3

Compelling evidence for pertuzumab + trastuzumab;4

other HER2-targeted combinations are being explored5,6

Primary tumour location is a surrogate marker of molecular alterations;

it has prognostic and possibly predictive implications1

– Pozicija primarnog tumora, prognostička i prediktivna vrijednost za KRAS wt (“sidedness”)

– Nove terapijske opcije i dopune smjernice

– Imunoterapija

– Biomarkeri i terapija