actualización en el abordaje terapéutico ante un cáncer colorrectal metastásico

Actualización en el abordaje terapéutico ante un cáncer colorrectal metastásico

Mauricio Lema Medina MDClínica de Oncología Astorga / Clínica SOMA, Medellín, Colombia

VII Congreso Internacional de coloproctologíaBogotá, 18.08.2016

Disclaimer

“Esta presentación ha sido creada por el autor de la charla y es de su propiedad. La información, conceptos y opiniones aquí expresados son responsabilidad del autor y no comprometen a Productos Roche S.A., sus colaboradores o compañías vinculadas.”

Mauricio Lema: Conflicto de interés

Roche

@onconerd

FULV

Capec

Iri

Bev

Cet

Pan

TKI

Surgery

Ablative Rx

OxOther anti

VEGF

Advances in the Treatment of Colorectal Cancer[1,2]

2000 2005 2008 2012

Capecitabine Oxaliplatin

Cetuximab

Irinotecan

5-FU

Panitumumab

Targeted therapies

Bevacizumab

KRAS

1. National Cancer Institute. Colon cancer treatment (PDQ). 2013. 2. National Cancer Institute. Cancer drug information. 2013.

Regorafenib

Access to Chemotherapy Improves Survival

Grothey A, et al. J Clin Oncol. 2005;23:9441-9442.

22

20

18

16

14

12

Med

ian

OS

(Mos

)

0 20 40 60 80Patients With 3 Drugs (%)

LV5FU2Bolus 5-FU/LV

Infusional 5-FU/LV+ irinotecanInfusional 5-FU/LV+ oxaliplatinBolus 5-FU/LV+ irinotecanIrinotecan+ oxaliplatin

First-line therapy

0102030405060708090

100

0 1 2Years

% A

live

IFL (med 15.0 mo)FOLFOX4 (med 19.5 mo)IROX (med 17.4 mo)

FOLFOX4 vs IFL (P=.0001; HR=0.66) IROX vs IFL (P=.04)

N9741: Overall Survival

Goldberg et al. J Clin Oncol. 2004;22:23.

Median Overall Survival in First-Line mCRC

BSC

0 6 12 18 24Median OS (Mos)

~ 4-6 mos

12-14 mos

~ 15-16 mos

19-20 mos

5-FU/LV

FOLFOX4 or CAPEOX

IFL or FOLFIRI

21.5 mosFOLFOX6

Gallagher DJ, et al. Oncology. 2010;78:237-248.

Hanrahan V, Currie MJ, Gunningham SP, et al. J Pathol 2003;200:183-194.

1997: humanization of A4.6.1 produces bevacizumab

• Recombinant humanized monoclonal anti-VEGF antibody developed from murine anti-VEGF mAb A4.6.11

• 93% human, 7% murine

• recognizes all major isoforms of human VEGF, Kd = 8 x 10–10M

• terminal half-life 17–21 days

1. Presta, et al. Cancer Res 1997

CRC: Biologic Subsets That Respond Differently to EGFR-Targeted Agents

BRAF

KRAS

EREG or AREG

PI3K PTEN

EGFR

PIP1

PIP3

Signaling to the nucleus

Low expression of EGFR ligands → decreased response to EGFR-targeted agents

PTEN loss of expression → decreased response to EGFR-targeted agents

Siena S, et al. J Natl Cancer Inst. 2009;101:1308-1324. Rizzo S, et al. Cancer Treat Rev. 2010;36 Suppl 3:S56-61.

CRC: Biologic Subsets That Respond Differently to EGFR-Targeted Agents

BRAF

KRAS

EREG or AREG

PI3K PTEN

EGFR

PIP1

PIP3

Signaling to the nucleus

Low expression of EGFR ligands → decreased response to EGFR-targeted agents

Mutant BRAF → decreased response to EGFR-targeted agents

PTEN loss of expression → decreased response to EGFR-targeted agents

Mutant KRAS → decreased response to EGFR-targeted agents

Siena S, et al. J Natl Cancer Inst. 2009;101:1308-1324. Rizzo S, et al. Cancer Treat Rev. 2010;36 Suppl 3:S56-61.

Mutations in KRAS, NRAS, and BRAF Distribution and Prognostic Significance

BRAF mutation All patientsAny mutationKRAS mutation

KRAS WTAll WT

Mutation Status

0

6

12

Med

ian

PFS

(Mos

)

Arm A Arm B

0

6

12

18

Med

ian

OS

(Mos

)

57 340

268

815

367

289

45 366

297

815

362

2920

10

20

30

40

2-Yr

OS

(%)

Prognostic Effect of Mutational Status

“All WT”n = 581 (44%)

KRAS MTn = 565 (43%)

NRAS MTn = 50 (4%)

BRAF MTn = 102 (8%)

TotalN = 1316 (81%)

554

1139

102

Population n (%) Arm A Arm B

ITT 1630 815 815

Assessed for mutations 1316 648 668

KRAS mutation NRAS mutation BRAF mutation

565 (43)50 (4)102 (8)

2681857

2973245

KRAS WT 729 (55) 367 362

KRAS/NRAS/BRAF WT“All WT”

581 (44) 289 292

Maughan TS, et al. ASCO 2010. Abstract 3502.

Phase III 80405 Trial: First-line CT + Either Cetux or Bev in KRAS-WT mCRC

Primary endpoint: OS

Secondary endpoints: ORR, PFS, TTF, duration of response

Patients with mCRC

and KRAS WT (codons 12, 13),

ECOG PS 0/1(N = 1137)

FOLFOX or FOLFIRI + Bevacizumab q2w

(n = 559)

ClinicalTrials.gov. NCT00265850. Venook AP, et al. ASCO 2014. LBA3..

FOLFOX or FOLFIRI + Cetuximab q1w

(N = 578)

A third arm with CT + bevacizumab + cetuximab was closed to accrual in September 2009

CALGB/SWOG 80405: OS in the ITT Population

mOS (95% CI), mosCT + Cetux 29.9 (27.0-32.9)CT + Bev 29.0 (25.7-31.2)

HR 0.925 (0.78-1.09)P = 0.34

Venook AP, et al. ASCO 2014. Abstract LBA3.

012 24 36 48 60 72

Mos

80

100

60

40

0

OS

(%)

20

84

Retrospective US study of real-world costs of cancer regimens

Cetux = cetuximab; CR = cost ratio; panit = panitumumab; PPPM = per patient per monthJohnston, et al. ASCO GI 2016. Abstract 636

Objective: to compare healthcare costs between mCRC patients treated with either 1L Avastin- or cetuximab-containing regimens, who continued to a 2L biologic-containing regimen (Avastin, cetuximab, panitumumab, aflibercept or regorafenib)

$0

$1,000

$2,000

$3,000

$4,000

$5,000

$845

$1,402

$2,179

$4,279

PPPM

cos

ts d

iffer

ence

vs

1L A

vasti

n/2L

Ava

stin

1L Avastin/2L other‡

(n=221)

1L cetux/2L other§

(n=71)

1L Avastin/2L cetux(n=391)

1L cetux/ 2L Avastin

(n=63)

CR=1.04p=0.2265

CR=1.07p=0.0101

CR=1.11p=0.0707

CR=1.21p=0.0012

Adjusted total healthcare cost differences,

with 1L/2L Avastin as reference

Mean total cancer regimen costs for the 1L and 2L sequence were lower for patients who received 1L Avastin-containing regimens, compared with 1L cetuximab-containing regimens,

due to the higher cost of cetuximab

The majority of 1L Avastin patients also received Avastin in 2L (i.e. TML)

*regorafenib or aflibercept ‡panitumumab, regorafenib or aflibercept§cetuximab, panitumumab, regorafenib or aflibercept

PPPM

cost

s

$0

$2,000

$4,000

$6,000

$8,000

$10,000

$12,000

$14,000

$16,000

$18,000

$4,070 $3,465 $3,276 $2,831 $3,570$2,297 $1,898

$1,097$1,066 $775 $923

$1,214

$705 $1,074

$6,738 $8,077$7,886

$7,140

$10,067

$10,380$12,568

$957$1,038

$836$795

$1,285

$1,082

$1,090

1L Avastin/2L Avastinn=1,606

Chemotherapy drugBiologic drugChemotherapy administrationBiologic administration

1L Avastin/2L cetuxn=391

1L Avastin/2L panitn=108

1L Avastin/2L other*

n=113

1L cetux/2L Avastin

n=63

1L cetux/2L cetux

n=54

1L cetux/2L other‡

n=17

$12,862$13,646

$12,773$11,690

$16,136

$14,464

$16,629

Unadjusted mean PPPM cancer regimen costs

“Thou shall not use anti-EGFR agents in mutated RAS CRC patients”

mCRC: ESMO Clinical Practice Guidelines

http://www.esmo.org/Guidelines/Gastrointestinal-Cancers/Metastatic-Colorectal-Cancer

Group 0

Group 1

Group 2

Group 3

Resectable R0

Convertible

Unlikely resectable/High tumor burden

Never resectable

Surgery/ +/- Adj CT

Conversion CT/Surgery

Active CT + Biologic

Less-toxic CT

Cure

Cure

Long OS

QoL

Criticism: solely based on DISEASE characteristics


mCRC: ESMO Clinical Practice Guidelines


Group 0

Group 1

Group 2

Group 3

Resectable R0

Convertible

Unlikely resectable/High tumor burden

Never resectable

Surgery/ +/- Adj CT

Conversion CT/Surgery

Active CT + Biologic

Less-toxic CT

FOLFOX

FOLFOXIRI-BevFOLFIRI-Cet

FOLFOX-BevXELOX-BevFOLFOX-CetFOLFIRI-Cet

FP-Bev

Criticism: solely based on DISEASE characteristics


Grupos 0 y 1

Quirúrgicos

OS after resection in liver metastasis

Adam R, Oncologist, 2012

Avastin(n=205)

NED, % (95% CI) Patients without detectable metastatic disease (n=194) 47 (40–55)

No detectable metastases after surgery 85 (76–91)

No detectable metastases after complete response 4 (1–11)

mPFS, months (95% CI) 11.5 (10.4–12.4)

36-month OS rate, % (95% CI) 52 (44–59)

PICASSO: prospective, non-interventional cohort study

Malka, et al. ASCO 2016. Abstract 3554

Untreated mCRC with potentially resectable

liver and/or lung metastases(N=218)

• Primary endpoint: Patients without detectable metastatic disease • Secondary endpoints: PFS, relapse-free survival after surgery, OS, safety, criteria to define patients

unresectability

Avastin + chemotherapy

Primary endpoint

OS for the total efficacy population was not reached

35CONFIDENTIAL – for internal use only

PICASSO: final efficacy results

Use of 1L Avastin + chemotherapy was effective in mCRC patients with potentially resectable

lung/liver metastases

Secondary resection rate of 47% resulted in a high 3-year OS rate (52%)

Without detectable metastatic disease (n=92)

With detectable metastatic disease (102)

mPFS, months (95% CI) 15.7 (12.9–18.9) 8.7 (7.8–10.4)

36-month PFS, % (95% CI) 21 (1330) 3 (19)

1.0

OS

estim

ate

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 42

Time (months)

OS(total population)

24 3027 36 3933

Time (months)

1.0

PFS

estim

ate

0.8

0.6

0.4

0.2

0

PFS (with or without detectable metastases)

No detectable metastatic disease

Detectable metastatic disease

0 3 6 9 12 15 18 21 4224 3027 36 3933

mOS not reached

Malka, et al. ASCO 2016. Abstract 3554

OS after resection in liver metastasis, after preoperative chemotherapy

Adam R, Oncologist, 2012

FOLFIRI+bev (up to 12 cycles)

5FU/LV +Bev

508 mCRC pts 1st line unresectablestratified by center PS 0/1-2 adjuvant CT

R PD

FOLFOXIRI+bev 5FU/LV +Bev (up to 12

cycles)

TRIBE Study Design

INDUCTIONMAINTENANCE

Primary Endpoint: PFSSecondary Endpoints:

Response rate, secondary R0-resection rate, safety profile, biomarkers evaluation

Falcone A, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3505

Courtesy of: Fotios Loupakis

FOLFIRI + bevFOLFOXIRI + bev

-Fre

e Su

rviv

al P

roba

bilit

y

Median follow-up: 32.3 mos

FOLFIRI + bev: N = 256 / Progressed = 226 FOLFOXIRI + bev: N = 252 / Progressed = 213

FOLFIRI + bev, median PFS : 9.7 mos FOLFOXIRI + bev, median PFS : 12.1 mos

Unstratified HR: 0.77 [0.64-0.93] P = .006

Prog

ress

ion Stratified HR: 0.75 [0.62-

0.90] P = .003

Follow-Up Time, Months

Primary Endpoint: PFS

Falcone A, et al. J Clin Oncol. 2013;31(Suppl):Abstract 3505


Secondary Endpoint: Response Rate

Falcone A, et al. J Clin Oncol. 2013;31(Suppl):Abstract 3505

FOLFIRI + bev

N = 256Best Response, %

FOLFOXIRI + bev

N = 252 P

Complete Response 3% 5%

Partial Response 50% 60%

Response Rate 53% 65% .006

Stable Disease 32% 25%

Progressive Disease 11% 6%

Not Assessed 4% 4%


• STEAM is a phase II, randomised, open-label, US-based study

• Primary endpoints: – Investigator-assessed ORR during 1L therapy for Avastin + concurrent FOLFOXIRI vs Avastin + FOLFOX– PFS during 1L therapy (PFS1) for Avastin + FOLFOXIRI regimens (concurrent and sequential) vs

Avastin + FOLFOX

STEAM: preliminary efficacy results

1L = first line; 2L = second line; 5-FU = 5-fluorouracil; CI = confidence interval; FP = fluoropyrimidine; LV = leucovorin; ORR = overall response rate; PD1 = progression on 1L therapy; PD2 = progression on 2L therapy

Bendell, et al. ASCO GI 2016. Abstract 492

Treatment-naïve patients

with mCRC(N=280)

R

Avastin + concurrent FOLFOXIRI

(n=93)Avastin + sequential FOLFOXIRI

(n=92) Avastin + FOLFOX

(n=95)

Avastin + 5-FU/LV

or

Avastin + capecitabine

PD1

PD2

Avastin + FP-based

chemotherapy (investigator’

s choice)

Induction Maintenance

2L

Avastin + cFOLFOXIRI

(n=93)Avastin +

sFOLFOXIRI (n=92)

Pooled Avastin + FOLFOXIRI(n=185)

Avastin + FOLFOX(n=95)

ORR, % 60.2 62.0 61.1 47.4Odds ratio vs Avastin + FOLFOX (90% CI); p value

1.7 (1.05–2.77); p=0.075

1.8(1.12–2.97); p=0.040

1.8(1.16–2.68); 0.025

STEAM: interim PFS and liver resection rates

*Stratified HR vs Avastin + FOLFOXAvastin + cFOLFOXIRI: HR=0.672 (90% CI: 0.489–0.922)Avastin + sFOLFOXIRI: HR=0.738 (90% CI: 0.537–1.012)HR = hazard ratio; ITT = intent-to-treat

Bendell, et al. ASCO GI 2016. Abstract 492

Interim PFS (ITT population)

Interim PFS (pooled Avastin + FOLFOXIRI vs Avastin +

FOLFOX)

PFS

est

imat

e

1.0

0.4

0

Time (months)0

0.6

0.2

0.8

11.49.3

Pooled Avastin + FOLFOXIRI (n=185)Avastin + FOLFOX (n=95)HR=0.704 (90% CI: 0.537–0.923)

3 9 12 18 276 15 21 24Time (months)

PFS

est

imat

e

1.0

0.4

0

0.6

0.2

0.8

0 9 12 18 276 15 21 24

Avastin + cFOLFOXIRI (n=93)*Avastin + sFOLFOXIRI (n=92)*Avastin + FOLFOX (n=95)

10.79.3

3

11.7

Avastin + cFOLFOXIRI

(n=93)

Avastin + sFOLFOXIRI

(n=92)

Pooled Avastin + FOLFOXIRI(n=185)

Avastin + FOLFOX(n=95)

Liver resection rates, % 15.1 9.8 12.4 7.4R0 resection rates, % 15.1 8.7 11.9 6.3

• No increase in serious chemotherapy-associated TEAEs

• Safety profile was consistent with known side effects of Avastin

STEAM: safety

AE = adverse event; CNS = central nervous system; TEAE = treatment-emergent adverse eventsBendell, et al. ASCO GI 2016. Abstract 492

STEAM is the first study to compare head-to-head Avastin + cFOLFOXIRI, Avastin + sFOLFOXIRI and Avastin + FOLFOX

The results of STEAM confirm findings from TRIBE, with high ORR, PFS and resection rates

TEAE of special interest for Avastin, %Avastin + cFOLFOXIRI

(n=91)Avastin + sFOLFOXIRI

(n=90)Avastin + FOLFOX

(n=90)Any TEAE of special interest 32 29 24

Grade ≥3 hypertension 20 16 12

Grade ≥3 venous thromboembolic events 5 6 6

Arterial thromboembolic events 2 4 0

Bleeding/haemorrhage (grade ≥3; any grade CNS bleeding; grade ≥2 haemoptysis) 2 1 4

GI perforation, abscess or fistula 3 1 2

Grade ≥2 non-GI fistula or abscess 1 0 2

Grade ≥3 proteinuria 0 2 0

PRODIGE 14-ACCORD 21: resection rates with 1Lbi- or tri-chemotherapy plus Avastin or cetuximab

mCRC with non-

resectable hepatic

metastasis

Resection yes/no

• PRODIGE 14-ACCORD 21 is a phase II, randomised• Key eligibility criteria: hepatic metastases, not resectable with curative intent for technical (<30% remaining

liver health) or oncological (0.5 and bilateral) reasons, 1-3 lung metastase (<2cm) • Primary endpoint: resection rate for liver metastases• Hypothesis: increase rate of resection of hepatic metastasis from 50% with bi-chemotherapy to 70% with tri-

chemotherapy• 94% patents had 4 cycles of chemotherapy before first evaluation • SAEs of grade ≥3 were 27% with Avastin and 48% with cetuximab (p<0.001)

R

Bi-chemotherapy

(N=126)Tri-

chemotherapy(N=130)

FOFIRINOX + Avastin/cetuxi

mab

R

FOLFIRI + Avastin/cetuxi

mabFOLFOX4 +

Avastin/cetuximab

Bi-chemotherapy Tri-chemotherapy p value

AEs grade ≥3, % 37.6 41.7 0.503

2-year OS, % (95% CI) 60 (48–70) 73 (62–81)

mOS, months (95% CI) 36 (23.5–40.6) Not reached 0.048

Ychou, et al. ASCO 2016. Abstract 3512

100

80

60

40

20

0

100

80

60

40

20

0

Per chemotherapy

PRODIGE 14-ACCORD 21: resection rates with bi- or tri-chemotherapy plus Avastin or cetuximab

FOLFIRI/FOLFOX + Avastin/cetuximab

FOLFIRINOX + Avastin/cetuximab

Avastin + chemotherapy

Patie

nts w

ith L

M R

0/R1

re

secti

on (%

)

Per targeted therapy

Cetuximab + chemotherapy

45.2%

56.9%

44.7%55.6%

p=0.062 p=0.087

Patie

nts w

ith L

M R

0/R1

re

secti

on (%

)PRODIGE 14-ACCORD 21 demonstrates that combination of targeted therapy (Avastin or cetuximab) with triplet chemotherapy increases resection rate for

liver metastasis and OS compared with targeted therapy + doublet chemotherapy

Incidence of grade ≥3 SAEs was lower with Avastin than with cetuximab

Ychou, et al. ASCO 2016. Abstract 3512

Para pacientes metastásicos marginalmente resecables puedo aumentar la tasa de respuesta (y, potencialmente el % de resección R0/1) con tripletas + biológico (ie, FOLFOXIRI + Bevacizumab o Cetuximab)

La toxicidad se incrementa sustancialmente con la tripleta, especialmente si se combina con biológicos de alta toxicidad

Grupo 3

No resecables

Capecitabine 1000 mg/m2BID days 1–14, q21d +

Bevacizumab 7.5 mg/kg day 1, q21d

Previously untreated mCRC, age 70 years N = 280

Randomize 1:1

Capecitabine 1000 mg/m2BID days 1–14, q21d Stratification factors:

– ECOG PS (0–1 vs 2)

– Not optimal candidates for a combination chemotherapy with irinotecan or oxaliplatin

AVEX - Study Design

– Geographic region • Key inclusion criteria– ECOG PS 0–2 – Prior adjuvant chemotherapy allowed if completed >6 month before inclusion

• Key exclusion criteria– Prior chemotherapy for mCRC or prior adjuvant anti-VEGF treatment– Clinically significant cardiovascular disease– Current or recent use of aspirin (>325 mg/day) or other NSAID – Use of full-dose anticoagulants or thrombolytic agents

Cunningham D. J Clin Oncol. 2012;30(34): Abstract 337 [Gastrointestinal Cancers Symposium 2013]. Courtesy of: Fotios Loupakis

1.0 Cape + BEV (n = 140) Cape (n = 140) 0.8

HR=0.53 (95% CI: 0.41–0.69) 0.6 P<.00

1 0.4

0.2

5.1 mo 9.1 mo 0.0

Progression-Free Survival PF

S Es

timat

e

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Time, Months

Cunningham D. J Clin Oncol. 2012;30(34): Abstract 337 [Gastrointestinal Cancers Symposium 2013]. Courtesy of: Fotios Loupakis

CASSIOPEE: Non interventional study of 1L Avastin+ chemotherapy in patients ≥75 years with mCRC

• CASSIOPEE is a non-interventional, real world study of patients aged ≥75 years with mCRC, treated with 1L Avastin + CT in daily practice in France

• Primary endpoints: 12-month PFS rate• Secondary endpoints: description of patient characteristics, OS, Avastin

regimen, safety and autonomy criteria such as Lawton Instrumental Activities of Daily Living Scale (IADL 4 items) and Balducci score.

Francois, et al. ASCO 2016. Abstract 3555

Patients aged ≥75 years with

previously untreated mCRC(n=401)

Avastin + CT Follow-up to 24 months

CASSIOPEE: Non interventional study of 1L Avastin+ chemotherapy in patients ≥ 75 years with mCRC

Efficacy population (n=351) mPFS, months 9.2

12 month PFS rate, % 35.5

mOS, months 18.5

12 month OS rate 69.6

• Interim results: mOS and PFS comparable to randomised studies, and autonomy and frailty scores unaffected by 1L Avastin + chemotherapy in elderly patients.

• Avastin-related grade ≥3 AEs =7%• Safety was comparable to the general population

Data showed treatment benefit and acceptable safety of 1L Avastin combined with chemotherapy in elderly patients

Francois, et al. ASCO 2016. Abstract 3555

Primary tumour location: retrospective single-institution study

Please note the median OS values and K-M curves appear as presented

He, et al. ASCO GI 2016. Abstract 683

Objective: retrospective analysis of the prognostic impact of primary tumour location on survival in Chinese patients with mCRC

Time (months)

OS e

stim

ate

1.0

0.4

0

0.6

0.2

0.8

0 48 60 84 12036 72 96 108

Avastin + chemotherapy (n=78)Chemotherapy (n=222)p=0.556

20.219.7

2412

OS e

stim

ate

1.0

0.4

0

Time (months)

0.6

0.2

0.8 Avastin + chemotherapy (n=86)Chemotherapy (n=259)p=0.021

0 48 60 84 12036 72 96 108241226.322.3

OS in patients with right-sided tumours

OS in patients with left-sided tumours

OS increase with Avastin was significant in patients with left-sided tumours, but only borderline non-significant

in patients with right-sided tumoursThere was a limited number of patients in this single institution retrospective cohort studyNo difference between left- vs right-sided tumours was observed in the chemotherapy-only

cohortThe effect of tumour location seem to most pronounced in the WT population treated with

biologics

No hay razón para NO ofrecer terapia sistémica efectiva a pacientes con cáncer colorrectal metastásico porque son ancianos.

Grupo 2

Alta carga tumoral, no resecables

55

Mutaciones clínicamente relevantes de la vía MAPKAprox. 65% mCRC

Codon 61/146 mKRAS5%

V600E BRAF

8%

Codon 12/13 mKRAS48%

mNRAS6%

Schirripa M, et al. J Clin Oncol. 2013;31(Suppl): Abstract 3613.

57CONFIDENTIAL – for internal use only

Retrospective analysis of two RAS/BRAF WT, mCRC cohorts: Cohort 1: HER2 tested by IHC / ISH, 14/97 HER2 amplified Cohort 2: all patients HER2 tested by next generation sequencing (n=37)

HER2 amplification as a negative predictor of efficacy of anti-EGFR inhibitors

In this retrospective analysis, HER2 amplification was indicated to be a negative predictive biomarker of efficacy of anti-EGFR inhibitors

Raghav, et al. ASCO 2016. Abstract 3517

Cohort 1: PFS on anti-EGFR txMedian 2.9 vs 8.1 months(p<0.001)

Cohort 2: PFS on anti-EGFR txMedian 2.9 vs 9.3 months(p<0.001)

Months Months

Perc

ent s

urvi

val

Perc

ent s

urvi

val

HER2 amplifiedHER2 non-amplified

HER2 amplifiedHER2 non-amplified

Primary tumour location

• Incidence: ~40% (increasing)• Older patients• Microsatellite instability• BRAF mutations• Worse prognosis

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

Left-sided tumours

R L

Iacopetta, et al. Int J Cancer 2002; Brule, et al. ASCO 2013. Abstract 3528;Missiaglia, et al. ASCO 2013. Abstract 3526

CALGB 80405: retrospective analysis of effect of primary tumour location on OS and PFS

Venook, et al. ASCO 2016. Abstract 3504

• CALGB 80405 (NCT00265850) is a phase III, randomised, open-label study• Primary endpoint: OS• Secondary endpoints: PFS, time to treatment failure, DoR

Avastin + FOLFOX/FOLFIRIPreviously untreated patients with mCRC(N=1137 KRAS WT)

252 KRAS MT patients enrolled prior to KRAS WT

protocol amendment

Cetuximab + FOLFOX/FOLFIRI

R

All KRAS WT Avastin

Cetuximab

All KRAS MT

All KRAS WT Avastin

Cetuximab

Right Left

Right Left

Right Left

Right Left

Right Left

Right Left

Right Left

OS (months)

19.4

33.3

24.2

31.4

16.7

36.0

23.1

30.3

PFS (months)

8.9 11.7

9.6 11.2

7.8 12.4

HR (95% CI)

1.55 (1.32–1.82)

1.32 (1.05–1.65)

1.87 (1.48–2.32)

1.28 (0.95–1.73)

HR (95% CI)

1.03 (1.11–1.50)

1.06(0.86–1.31)

1.56(1.26–1.94)

p value <0.0001 0.01 <0.0001 p value 0.0006 0.55 <0.0001

CALGB 80405: OS by primary tumour location

1.0

OS e

stim

ate

0.8

0.6

0.4

0.2

00 12 24 36 48 60 108

Time (months) Time (months)

1.0

OS e

stim

ate

0.8

0.6

0.4

0.2

0

LeftRightHR=1.55 (1.32–1.82)p<0.0001

Left/AvastinRight/Avastin

72 84 96

Total population By treatment

0 12 24 36 48 60 10872 84 96

19.4

33.3

16.7

24.2 36.0

31.4

This CALGB 80405 retrospective subset analysis was hypothesis generatingand should be interpreted with caution

Primary tumour location is a prognostic factor for poorer outcome in patients with right-sided tumours irrespective of therapy

More biomarker data are needed to fully understand the predictive value of these dataIn previous studies, Avastin has consistently shown efficacy in both right- and left-sided

tumours

Cetuximab vs Avastin

HR (95% CI)p

valueLeft 0.817

(95% CI: 0.69–0.96)

0.018

Right

1.269 (95% CI: 0.98–

1.63)

0.065

Venook, et al. ASCO 2016. Abstract 3504

Left/CetuximabRight/Cetuximab

Relationship between primary tumour sidedness and prognosis in CRC

• Observational analysis from the SEER database• Primary endpoints: median OS and 3-year OS

Provides further evidence from a large population that right-sided stage III and IV tumours are associated with poor survival

Stage III and IV primary CRC PDSEER

analysis

Stage IV (N=64,770) Stage III (N=91,009)Right Left Rectal Right Left Rectal

mOS (months) 9.5 15.5 15.5 62.5 93.5 85.5Survival probability Unadjusted HR (95% CI)

1.32 (1.30–1.35)

1.0 1.01 (0.99–1.03)

1.35 (1.32–1.38)

1.0 1.03 (1.01–1.06)

Survival probabilityAdjusted HR (95% CI)

1.25 (1.22–1.27)

1.0 0.83 (0.81–0.85)

1.12 (1.09–1.15)

1.0 1.11 (1.08–1.14)

Schrag, et al. ASCO 2016. Abstract 3505

Association of tumour location and molecular features with PFS and OS after anti-EGFR therapy

• Retrospective study• Primary endpoint: PFS• Secondary endpoint: OS

Right CIMP-High BRAF MT NRAS MTPFS, HR (95% CI); p value 1.56 (1.01–

2.41); 0.0402.38 (1.47–

3.85); 0.00062.14 (1.26–3.65);

0.0042.12 (1.23–

3.65);0.006

OS, HR (95% CI); p value 1.45 (1.04–2.01); 0.028

1.53 (1.08–2.16); 0.001

2.46 (1.61–3.74); <0.0001

NA

KRAS WT mCRC treated with anti-

EGFR therapy(N=198)

CIMP testing

BRAF, NRAS and PIK3CA sequencingMSI status

• On multivariate analysis, BRAF MT (p=0.001), and NRAS MT (p=0.060) remained significant for OS, but primary tumour location did not (p=0.121)

• Right-sided CRC and CIMP-high were associated with hypermethylation of EREG and AREG, and distinct expression patterns of consensus molecular subtypes (CMS) 1 and 3

Lee, et al. ASCO 2016. Abstract 3506

Right-sided tumours were associated with inferior OS and PFS after anti-EGFR therapy Factors influencing outcome in right-sided tumours were BRAF MT, NRAS MT, molecular

subtypes, and tumour methylation

Primary tumour location: combined analysis of JACCRO CC-05 and -06 studies

Sunakawa, et al. ASCO GI 2016. Abstract 613

Cetuximab + mFOLFOX6(n=57)

Cetuximab + S-1 + oxaliplatin

(n=67)

Patients with KRAS exon 2 WT mCRC with EGFR-expressing

tumours

JACCRO CC-05

JACCRO CC-06

Objective: to assess the prognostic impact of primary tumour location on clinical outcomes of Japanese patients with KRAS exon 2 WT mCRC enrolled in the JACCRO CC-05 or -06 trials

PFS in ITT population OS in ITT population

Time (months)0 6 12 18 24 30 36 42

5.6 11.1

Left-sided tumours (n=90)Right-sided tumours (n=20)HR=0.47 (95% CI: 0.28–0.80); p=0.0041

1.0

PFS

estim

ate

0.8

0.6

0.4

0.2

0

Time (months)

12.6

36.2

Left-sided tumours (n=90)Right-sided tumours (n=20)HR=0.28 (95% CI: 0.15–0.52); p<0.0001

0 6 12 18 24 30 36 42 48

1.0

OS e

stim

ate

0.8

0.6

0.4

0.2

0

Primary tumour location: combined analysis of JACCRO CC-05 and -06 studies

Sunakawa, et al. ASCO GI 2016. Abstract 613

PFS in FOLFOX group

Left-sided tumours (n=43)Right-sided tumours (n=9)HR=0.15 (95% CI: 0.06–0.37); p<0.0001

Time (months)

5.7 42.8

0 6 12 18 24 30 36 4248

1.0

OS e

stim

ate

0.8

0.6

0.4

0.2

0

OS in FOLFOX group

Primary tumour location may be a negative predictive factor in patients with mCRC and KRAS WT tumours who receive

cetuximab + oxaliplatin-based therapy

Left-sided tumours (n=43)Right-sided tumours (n=9)HR=0.26 (95% CI: 0.12–0.56); p=0.0002

Time (months)

3.0

11.3

0 6 12 18 24 30 3642

1.0

PFS

estim

ate

0.8

0.6

0.4

0.2

0

Proc ASCO, 2016, 3505.Association of primary (1°) site and molecular features with progression-free survival (PFS) and

overall survival (OS) of metastatic colorectal cancer (mCRC) after anti-epidermal growth factor receptor (αEGFR) therapy. Michael Sangmin Lee

Association of primary (1°) site and molecular features with progression-free survival (PFS) and


Proc ASCO, 2016, 3505.

Proc ASCO, 2016, 3505.Association of primary (1°) site and molecular features with progression-free survival (PFS) and


Los pacientes con cáncer de colon metastásico derechos tienen una biología compleja que posiblemente causan alteraciones a las vías de señalización intracelular (mBRAF, MSI, disminución del AREG, EREG, etc). La terapia anti-VEGF es igualmente eficaz, pues es de entorno y no contra la célula maligna directamente

BEV + standard first-line CT (either oxaliplatin or

irinotecan-based)(n=820)

Randomise 1:1

Standard second-line CT (oxaliplatin or irinotecan-based) until PD

(n=411)

BEV (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin

or irinotecan-based) until PD (n=409)

PD

TML18147 study design (phase III)

CT switch:Oxaliplatin → IrinotecanIrinotecan → Oxaliplatin

Study conducted in 220 centres in Europe and Saudi Arabia

Primary endpoint • OS from randomisation

Secondary endpoints included

•PFS•Best overall response rate•Safety

Exploratory endpoints • Tumour, plasma and DNA biomarkers

Stratification factors • First-line CT (oxaliplatin-based, irinotecan-based)• First-line PFS (≤9 months, >9 months)• Time from last BEV dose (≤42 days, >42 days)• ECOG PS at baseline (0/1, 2)

Statistical considerations • Designed to detect 30% (HR 0.77) improvement in median OS(90% power, 2-sided 5%); 613 events required for analysis

Overall survival (ITT population)O

S es

timat

e

Time (months)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42 48

No. at riskCT 410 293 162 51 24 7 3 2 0BEV + CT 409 328 188 64 29 13 4 1 0

CT (n=410)BEV + CT (n=409)

9.8 11.2

Unstratifieda HR: 0.81 (95% CI: 0.69–0.94)p=0.0062 (log-rank test)

Stratifiedb HR: 0.83 (95% CI: 0.71–0.97)p=0.0211 (log-rank test)

aPrimary analysis method. bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG PS at baseline (0, ≥1)

Progression-free survival (ITT population)PF

S es

timat

e

Time (months)

1.0

0.8

0.6

0.4

0.2

00 6 12 18 24 30 36 42

No. at riskCT 410 119 20 6 4 0 0 0BEV + CT 409 189 45 12 5 2 2 0

CT (n=410)BEV + CT (n=409)

4.1 5.7

Unstratifieda HR: 0.68 (95% CI: 0.59–0.78) p<0.0001 (log-rank test)

Stratifiedb HR: 0.67 (95% CI: 0.58–0.78)p<0.0001 (log-rank test)

aPrimary analysis method. bStratified by first-line CT (oxaliplatin-based, irinotecan-based), first-line PFS (≤9 months, >9 months), time from last dose of BEV (≤42 days, >42 days), ECOG PS at baseline (0, ≥1)

• 110 patients with KRAS WT mCRC refractory to 1L Avastin + FOLFIRI were randomised to receive either cetuximab + irinotecan followed by FOLFOX, or vice versa

• A trend of better PFS (HR=0.83; p=0.35) and OS (HR=0.77;p=0.22) was observed in patients who received 2L FOLFOX 3L cetuximab + irinotecan compared with patients who received 2L cetuximab + irinotecan 3L FOLFOX

Sequence of treatment

3L = third line 1. Cascinu, et al. ASCO GI 2016. Abstract 6322. Burge, et al. ASCO GI 2016. Abstract 685

COMETS study: analysis of cetuximab treatment sequence after 1L Avastin-based therapy (Cascinu, et al. Abstract 632)1

Real-world Australian study on impact of 1L Avastin on subsequent anti-EGFR monotherapy (Burge, et al. Abstract 685)2

This study confirms the Avastin TML approach, as the highest effect was seen with the use of 3L anti-EGFRs

Conclusion on 1L treatment cannot be drawn from this study which only assessed 2L or 3L treatments

Prior Avastin treatment did not make tumours more or less sensitive to subsequent anti-EGFR therapy

• 77 patients had received 1L Avastin prior to 2L/3L anti-EGFR monotherapy, according to ACCORD and TRACC registries

• 1L Avastin treatment did not impact on efficacy of subsequent anti-EGFR monotherapy– Median PFS 2.7 vs 3.1 months (HR=1.03; p=0.95) in patients who received 1L Avastin vs those who did not – Median OS 8.9 vs 8.6 months (HR=0.95, p=0.80)

• For Avastin-treated patients, the time since last dose of Avastin to start of anti-EGFR did not impact on PFS or OS

Nuevo en mCRC en 2016

El lado importaRe-examine las opciones biológicas en tumores del lado derecho

Tentativa: algunos tumores resecables pueden entrar en CR con quimioterapia + bevacizumab

La edad en sí misma no debe ser criterio de exclusión para terapia sistémica en mCRC

@Onconerd

actualización en el abordaje terapéutico ante un cáncer colorrectal metastásico

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