La strategia terapeutica del carcinoma del colon...

Dalla Capecitabina al TAS-102

Milano, 29 settembre 2016

La strategia terapeutica del

carcinoma del colon metastatico

Gianluca Masi

U.O. di Oncologia Medica Universitaria

Azienda Ospedaliero-Universitaria Pisana

Istituto Toscano Tumori

MCRC: KEY POINTS FOR A WINNING STRATEGY

1. MULTI-DISCIPLINARY ASSESSMENT

• Opportunity & timing for resect primary T

• Opportunity & timing for resect sites of M

2. CHOICE OF “FIRST-LINE” TREATMENT

• Set chemo-intensity (mono, doublet, triplet)

• Pick the best biological partner (anti-VEGF vs anti-EGFR)

3. ASSURE THE BEST “CONTINUUM OF CARE”

• Maintenance, Re-inducion, Re-challenge

• Second-line, Third-line, …

Examples of treatment strategies in MCRC

Treatment 1 PD Treatment 2 PD Treatment 3

TREAT UNTILL PD AND SWITHC («old fashioned»)

Treatment 1 PD Treatment 2 PD Treatment 3

Treatment 1 PD Treatment 1 PD Treatment 2

Treatment 1Maintenance PD Treatment 1 PD

CHEMO HOLIDAYS AND SWITHC AT PD

CHEMO HOLIDAYS AND REINTRODUCTION AT PD

MAINTENANCE AND REINTRODUCTION AT PD

Treatment 1 PD Treatment 2 PD

SWITHC AT PD AND RECHALLENGE

Treatment 1

Tr 2

MCRC: CHOOSE THE FIRST-LINE THERAPY

RESECATBILITY of MTS

• Easy, Border-line, Potentially

CLINICAL PRESENTATION

• Sites of Mts & Burden

• Symptoms

• Side of Primary T (!?)

MOLECULAR PROFILE

• RAS, RAF

• MSI (?), HER2 (?), …

THE PATIENT

• Comorbidities

• Expectations, …

Upfront treatment is still a crucial “step” to …

Achieve disease control Allow furtherinterventions (surgery

and other systemictreatments)

The ‘funnel effect’

1st line

2nd line

3rd line

4th line

5th line

PATIENTS

The ‘funnel effect’ in the case of disease control/response

1st line

2nd line

3rd line

4th line

5th line

PATIENTS

The ‘funnel effect’ in the case of initial PD

1st line

2nd line

3rd line

PATIENTS

PD, progressive disease

What are our best “evidenced-based” options in first-line?

• Fluoropyrimidine + BV

• Doublets (FOLFOX, XELOX or FOLFIRI) + BV

• Doublets (FOLFOX or FOLFIRI) + anti-EGFR

• Triplet (FOLFOXIRI) + BV

Less intense

More intense

What are our best “evidenced-based” options in first-line?

• Fluoropyrimidine + BV

• Doublets (FOLFOX, XELOX or FOLFIRI) + BV

• Triplet (FOLFOXIRI) + BV

Less intense

More intense

Stratification factors:ECOG PS (0–1 vs 2)Geographic region

Key inclusion criteria

– ECOG PS 0–2

– Prior adjuvant chemotherapy allowed if completed >6 month before inclusion

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

Cunningham D. et al, Lancet Oncol ‘13

The AVEX study

R280 mCRC pts

1st line mCRC

AGE >70 yrs

Capecitabine

Capecitabine + BV

Cunningham D. et al, Lancet Oncol ‘13

AVEX - Progression Free Survival

.

The TASCO 1 trial

TAS-102 Twice a day 35 mg/m² orally

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

BEVACIZUMAB 5 mg/kg IV

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

28-day cycle

CAPECITABINETwice a day

1250mg/m² orally

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

BEVACIZUMAB 7.5 mg/kg IV

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

OR

21-day cycle

The TASCO 1 trial

What are our best “evidenced-based” options in first-line?

• Fluoropyrimidine + BV

• Doublets (FOLFOX, XELOX or FOLFIRI) + BV

• Triplet (FOLFOXIRI) + BV

Less intense

More intense

TRIBE Study Design

R

508 mCRC pts

1st line

unresectable

stratified by

center

PS 0/1-2

adjuvant CT

FOLFIRI + bev(up to 12 cycles)

FOLFOXIRI + bev(up to 12 cycles)

5-FU/LV

+ bev

5-FU/LV

+ bev

PD

INDUCTION MAINTENANCE

Primary Endpoint: PFS

Loupakis et al., NEJM 2014

FOLFIRI + bev, median PFS : 9.7 mos

FOLFOXIRI + bev, median PFS : 12.1 mos

HR: 0.75 [0.62-0.90]

p=0.003

Primary endpoint: PFS

Loupakis et al., NEJM 2014

TRIBE: FOLFOXIRI + bev improves RECIST response, ETS and DoR

-100

-80

-60

-40

-20

0

20

40

60

80

-100

-80

-60

-40

-20

0

20

40

60

80 FOLFIRI + bevacizumab (37.8%)FOLFOXIRI + bevacizumab (43.4%)

P = .003

62.7%

51.9%

FOLFOXIRI + bevacizumab

FOLFIRI + bevacizumab

Tumour shrinkage ≥20% at 8 wks

P = .025

Cremolini C, et al. Ann Oncol. 2015;26(6):1188-1194.

Depth of response

RECIST Response: 53% vs 65 % p=0.006

Loupakis F, et al. N Engl J Med. 2014;23;371(17):1609-1618.

FOLFIRI + bev, median OS: 25.8 mosFOLFOXIRI + bev, median OS: 29.8 mos

HR: 0.80 [0.65–0.98]P = .030

5-year OS rate

24.9% vs 12.4%

TRIBE: Updated OS results

Median follow-up: 48.1 mos

Cremolini C, et al. Lancet Oncol 2015

Median OS

41.7 months

33.5 months

27.3 months

23.9 months

19.0 months

10.7 months

RAS and BRAF wild-type – arm B

RAS mutant – arm B

BRAF mutant – arm B

RAS and BRAF wild-type – arm A

RAS mutant– arm A

BRAF mutant– arm A

TRIBE in molecular subgroups - OS

Cremolini et al, Lancet Oncol ’15

“Decision drivers for FOLFOXIRI”

FOLFOXIRI plus bev “appropriateness”

What are our best “evidenced-based” options in first-line?

• Fluoropyrimidine + BV

• Doublets (FOLFOX, XELOX or FOLFIRI) + BV

• Doublets (FOLFOX or FOLFIRI) + anti-EGFR

• Triplet (FOLFOXIRI) + BV

Less intense

More intense

N RR PFS OS

German AIO

CapOx 241 48% 7.1 16.8

FUFOX 233 54% 8.0 18.8

Spanish TTD

Xelox 171 37% 8.9 18.1

FUOX 171 46% 9.5 20.8

NO16966

Xelox 350 n.a. 8.0 19.6

FOLFOX 351 n.a. 8.5 19.8

Capecitabine + Oxaliplatin vs 5FU + Oxaliplatin

6 randomized trials (N=3494)

• Decreased RR (OR= 0.85, p=0.02)

• Equivalent PFS (HR= 1.04, p=0.17)

• Equivalent OS (HR= 1.04, p=0.41)

XELOX + placebo

N=350

FOLFOX4 + placebo

N=351

XELOX +

bevacizumab

N=350

FOLFOX4 +

bevacizumab

N=350

XELOX

N=317

FOLFOX4

N=317

Initial 2-arm

open-label study

(N=634)

Protocol amended to 2x2 placebo-

controlled design after bevacizumab

phase III data1 became available

(N=1401)

Recruitment

June 2003 – May 2004

Recruitment

Feb 2004 – Feb 2005

NO16966 study design

Saltz et al, JCO 2009

PFS chemotherapy + bevacizumab superiority:

XELOX and FOLFOX subgroups

XELOX subgroup

HR = 0.77 [97.5% CI 0.63–0.94] (ITT)

p = 0.0026

9.37.4

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15 20 25

Months

PF

S e

sti

ma

te

XELOX+placebo N=350; 270 events

XELOX+bevacizumab N=350; 258 events

FOLFOX subgroup

HR = 0.89 [97.5% CI 0.73–1.08] (ITT)

p = 0.1871

9.48.6

FOLFOX+placebo N=351; 277 events

FOLFOX+bevacizumab N=349; 255 events

1.0

0.8

0.6

0.4

0.2

0

0 5 10 15 20 25

Months

Saltz et al, JCO 2009

Maughan et al, ESMO 2009

Maughan et al, ESMO 2009

EORTC 40015

• CAPIRI vs FOLFIRI: suspended due to

occurrence of 6 treatment related deaths

in the CAPIRI arm

BICC-C

• CAPIRI vs FOLFIRI: efficacy safety

CAIRO-1

• CAPIRI: is safe

Capecitabine + Irinotecan vs 5FU + Irinotecan

Oral chemotherapy

needs ACTIVE

management!!!

WHICH BIOLOGIC IN FIRST-LINE?

Direct comparisons anti-EGFRs vs bev

• FIRE-3

• CALGB C80405

• PEAK

• Key inclusion criteria

– Patients ≥18 years with histologically confirmed diagnosis of mCRC

– ECOG PS 0-2

– prior adjuvant chemotherapy allowed if completed >6 month before

inclusion

• Amendment in October 2008 to include only KRAS wildtype patients

• 150 active centers in Germany and Austria

Phase III study design

FOLFIRI + CetuximabCetuximab: 400 mg/m2 i.v. 120min initial dose

250 mg/m2 i.v. 60min q 1w

FOLFIRI + BevacizumabBevacizumab: 5 mg/kg i.v. 30-90min q 2w

mCRC

1st-line therapy

KRAS wild-type

N= 592

Randomize 1:1

FOLFIRI: 5-FU: 400 mg/m2 (i.v. bolus); folinic acid: 400mg/m2

irinotecan: 180 mg/m2

5-FU: 2,400 mg/m2 (i.v. 46h)

Progression-free survival

0.75

1.0

0.50

0.25

12 24 36 48 60 72

months since start of treatment

297

295numbers

at risk100

99

19

15

10

65

4

3

0.0

Pro

ba

bilit

y o

f s

urv

iva

l

Events

n/N (%)

Median

(months)

95% CI

― FOLFIRI + Cetuximab 250/297

(84.2%)

10.0 8.8 – 10.8

― FOLFIRI + Bevacizumab 242/295

(82.0%)

10.3 9.8 – 11.3

HR 1.06 (95% CI 0.88 – 1.26)

Log-rank p= 0.547

Overall survival

Events

n/N (%)

Median

(months)

95% CI

― FOLFIRI + Cetuximab 158/297

(53.2%)

28.7 24.0 – 36.6

― FOLFIRI + Bevacizumab 185/295

(62.7%)

25.0 22.7 – 27.6

HR 0.77 (95% CI: 0.62 – 0.96)

Log-rank p= 0.017

0.012 24 36 48 60 72

months since start of treatment

297

295numbers

at risk218

214

111

111

60

4729

18

9

2

0.75

1.0

0.50

0.25

0.0

Pro

ba

bilit

y o

f s

urv

iva

l

Events

n/N (%)

Median

(months)

95% CI

― FOLFIRI + Cetuximab 91/171

(53.2%)

33.1 24.5 – 39.4

― FOLFIRI + Bevacizumab 110/171

(64.3%)

25.6 22.7 – 28.6

HR 0.70 (95% CI: 0.53 – 0.92)

p (log-rank)= 0.011

Overall survival

RAS* wild-type

0.012 24 36 48 60 72

months since start of treatment

171

171No. at

risk128

127

71

68

39

2620

9

6

1

0.75

1.0

0.50

0.25

0.0

Pro

ba

bilit

y o

f s

urv

iva

l

* KRAS and NRAS exon 2, 3 and 4 wild-type

Adapted from Heinemann V, et al. ECCO-ESMO 2013

CALGB/SWOG 80405:

FINAL DESIGN

N = 1140

1° Endpoint: Overall Survival

Chemo + Cetuximab

Chemo + Bevacizumab

mCRC

1st-line

KRAS wild type

(codons 12,13)

FOLFIRIor

FOLFOX

MD choice

CALGB/SWOG 80405: Overall Survival

Presented by: Venook A

Arm N (Events)OS (m)

Median95% CI

Chemo + Cetux 578 (375) 29.9 27.0-32.9

Chemo + Bev 559 (371) 29.0 25.7-31.2

P=0.34

HR 0.925 (0.78-1.09)

CALGB 80405: Overall Survival By Arm(All RAS Wild Type Patients)

ArmN

(Events)

Median

(95% CI)

HR

(95% CI)p

Chemo

+ Bev

256

(178)

31.2

(26.9-34.3)0.9

(0.7-1.1)0.40

Chemo

+ Cetux

270

(177)

32.0

(27.6-38.5)

Lenz HJ et al, ESMO 2014

OS

PFS

RR

PEAK

• Phase II random

• Primary EP (PFS): negative

FIRE-3

• Primary EP (RR): negative

• Data interpretation

CALGB/SWOG 80405

• N. pts analyzed

• Data quality

Main troubles with H-H comparison trials

Choice and duration of

2nd line therapy

Depth of response

Change in tumor biology during 1st line therapy

OS

FIRE-3: possible explanations for OS

Early Tumor Shrinkage & Deepness of Response

Lethal

tumor

load

Baseline

tumor

load

Time under treatment

OS

ETSETS• ETS predicts sensitivity

• ETS predicts the

potential DpR

• DpR predicts OS

ETS: early tumor shrinkage1,2 At least 20% decrease (shrinkage) in the sum of the

longest diameter compared with baseline at week 8

DpR: depth of response3 Percentage of tumor shrinkage observed at the smallest

tumor size compared with baseline

adapted from Mansmann et al, ASCO GI 2013 abstract #427

DpR (smallest tumor size)

Courtesy :Andrea Sartore Bianchi AIOM 2015

PFS 2nd OS 2nd= First-line FOLFIRI+CET

= First-line FOLFIRI+BEV

BEV + FOLFIRI

(n=110)Randomise 1:1

Irinotecan/

CETUXIMAB

FOLFOX

PD

COMETS: Study design

Study conducted in 11 centres in Italy

Primary endpoint Progression-free survival (PFS)

Secondary endpoints Overall survival (OS) from randomisation;

PFS 2° and 3°line;

Overall response rate

Safety

FOLFOX

Irinotecan/

CETUXIMAB

Clinicaltrials.gov: NCT01030042

Research Funding Source: AIFA (Agenzia Italiana del Farmaco) Code FARM 6XB38F

101 events were required to achieve a power of 80% of detecting a HR of 0.57 in

favour of one of the two sequences, translating in an increase of median overall

PFS from 4 to 7 months, with a type I error of 5%, two-sided, using the Mantel-Cox

version of the log-rank test. 110 assessable patients were needed to reach the

target number of events.

PFS

Cascinu S., Labianca R. et al. ECC 2015

Efficacy data according to arm

Arma A

CETUX/CPT(55 patients)

Arm B

FOLFOX(55 patients)

Hazard ratio(95% CI)

Response rate (%) 19/52 (37%) 30/53 (57%) p= 0.05Fisher exact test

Overall median PFS (months)

9.9 11.3 HR 0.83(0.56-1.24); p= 0.37

Overall median survival(months)

12.3 18.6 HR 0.79(0.52-1.19); p= 0.26

Arm A: Cetuximab/irinotecan followed by FOLFOX

Arm B: FOLFOX followed by Cetuximab/irinotecan

Adapted: Cascinu S., Labianca R. et al. ECC 2015

RIGHT

LEFT

X Colon??

PUBLICATION

(Study)Patients

N

Molecular

Selection Treatment OUTCOME RIGHT LEFT

O’Dwyer

JCO, 2001

(E2290)

N = 1120 NONE 5FU

VARIATIONS OS (MOS) 10.9 15.8

Brule, Eur J

Can, 2015

(CO.17)

N =399 KRAS wt BSC v.

BSC + CET

PFS (MOS) 1.9

1.8

1.9

5.4

Loupakis,

JNCI, 2015

N = 2053 NONE FOLFIRI/BEV

FUOX/BEV

IFL/BEVOS (MOS)

24.8

18.0

14.6

42.0

23.0

24.0

Metastatic Colorectal Cancer:

Does Side Matter?

80405: Overall Survival by Sidedness

Presented by:

Side N (Events)Median

(95% CI)

HR

(95% CI)p

Left 732 (550)33.3

(31.4-35.7) 1.55

(1.32-1.82)< 0.0001

Right 293 (242)19.4

(16.7-23.6)

Right

Left

AVF2017g : p for interaction OS=0.38; PFS=0.59

NO16966 : p for interaction OS=0.29; PFS=0.62

Right versus Left and Bevacizumab

Right versus Left and anti-EGFR: OS in FIRE-3

FOLFIRI+cetuximab FOLFIRI+bevacizumab

Heinemann et al., ASCO ‘14

Impact of primary tumor location on

Overall Survival and Progression Free Survival

in patients with metastatic colorectal cancer:

Analysis of CALGB/SWOG 80405 (Alliance)

A Venook, D Niedzwiecki, F Innocenti, B Fruth, C Greene, BH O’Neil,

J Shaw, J Atkins, LE Horvath, B Polite, JA Meyerhardt, EM O’Reilly,

R Goldberg, HS Hochster, CD Blanke, R Schilsky, RJ Mayer, M Bertagnolli,

HJ Lenz for SWOG and the ALLIANCE

Patient Characteristics by Tumor Side, 80405 (KRAS wt)

RIGHT-SIDED

(N = 293)

LEFT-SIDED

(N = 732)

TOTAL*

(N = 1137)

P

Age (mean) 61.2 57.3 58.4 < 0.0001

Gender (M %) 54.9% 65.0 % 62.1% 0.002

Synchronous

Stage IV

86.9% 76.0% 79.3% 0.0009

Prior Adjuvant 10.6% 15.7% 14.2% 0.03

FOLFOX / FOLFIRI 74.4 / 25.6 72.4 / 27.6 73.4 / 26.6 0.51

Primary in place 19.2% 29.6% 26.6% 0.0007

Pattern mets:

liver only

liver mets

extra-hepatic

27.5%

40.5%

32.0 %

32.1%

43.2%

24.7%

30.9%

42.8%

28.5%

0.02**

*Transverse colon – 66 (excluded from analysis); unknown - 46

**Test of any liver metastases versus extrahepatic

80405: OS by Sidedness (Bevacizumab)

Presented by:

Side N (Events)Median

(95% CI)HR(95% CI) p

Left 356 (280)31.4

(28.3-33.6)1.32

(1.05-1.65)0.01

Right 150 (121)24.2

(17.9-30.3)

LeftRight

80405: OS by Sidedness (Cetuximab)

Presented by:

Side N (Events)Median

(95% CI)

HR

(95% CI)p

Left 376 (270)36.0

(32.6-40.3)1.87

(1.48-2.32)<0.0001

Right 143 (121)16.7

(13.1-19.4)

Left

Right

80405: Overall Survival by Sidedness and Biologic

Presented by:

31.4 (28.3-33.6)

36.0 (32.6-40.3)

24.2 (17.9-30.3)

16.7 (13.1-19.4)

Bettington, et al. Histopathology. 2013.

MIDGUT HINDGUT

Bettington, et al Histopathology, 2013

Which is the best strategy in mcrc ?

RAS WT (and BRAF WT) pts have a MAJOR benefit

from anti-EGFR moAbs

Maintenance & Treatment Beyond PD maximize the

benefit of BEVA

WHAT IS THE NEED OF A RAPID & DEEP

RESPONSE ???

WHAT IS THE CHANCE TO RECEIVE A

THIRD-LINE THERAPY ???

Expectations

Patient preferences

Toxicity profile

Tumour burden Resectability

Aggressiveness

Tumour clinical characteristics

Patient clinical characteristics

Age

Comorbidities

Prior adjuvant

treatment

Tumour Molecular characteristics

RAS BRAF

Performance

status

Related symptoms

Which variables to consider in the choice of second-line?

Which responseWhich chemo

Tolerance

First-line related factors

Which biologic

Residual toxicities Drug free-interval

COMBINATION STUDY RR PFS OS

Bevacizumab + IRI or LOHP-based CT

(E3200) TMLBEPYP

NO YES YES

Aflibercept + FOLFIRI

VELOUR YES YES YES

Ramucirumab + FOLFIRI RAISE NO YES YES

Cetuximab + IRI EPIC

YES YES NOPanitumumab + IRI PICCOLO

Panitumumab + FOLFIRI 181

Targeted agents in second line MCRC

Bevacizumab Aflibercept Ramucirumab

FDA and

EMA

approved

VEGF-A

VEGF-A

VEGF-BPlGF

VEGFR-2

Anti-angiogenic agents in 2nd line

R

820 mCRC pts

progressed to a

1st line chemo

plus Beva*

2nd line

chemo§

2nd line

chemo§ + BEVPrimary Endpoint:

Overall survival

Bevacizumab beyond progression: TML trial

Bennouna et al, Lancet Oncol 2013

* progressed up to 3 months after discontinuing 1st-line bevacizumab

§ switched chemo

Bennouna, Lancet Oncol 2013

Bevacizumab Beyond Progression: TML trial - OS

11.29.8

Bevacizumab Aflibercept Ramucirumab

FDA and

EMA

approved

VEGF-A

VEGF-A

VEGF-BPlGF

VEGFR-2

Anti-angiogenic agents in 2nd line

R

1226 mCRC pts

progressed to a

1st line

oxaliplatin-based

therapy*

Primary Endpoint:

Overall survival

Aflibercept: VELOUR trial

Van Cutsem et al, J Clin Oncol 2012

2nd line

FOLFIRI

2nd line

FOLFIRI+afl

* 1st-line bev allowed and administered in ≈30% of pts

VELOUR trial: Primary endpoint met (OS)

Van Cutsem et al, J Clin Oncol ‘12

VELOUR trial: PFS & Response Rate

Bevacizumab Aflibercept Ramucirumab

VEGF-A

VEGF-A

VEGF-BPlGF

VEGFR-2

Anti-angiogenic agents in 2nd line

Ramucirumab: RAISE trial

Tabernero et al, Lancet Oncol 2015

R

1072 mCRC pts

progressed to a

1st line therapy

with oxaliplatin,

fluoropyrimidine

and BEV

Primary Endpoint: Overall survival

2nd line

FOLFIRI

2nd line

FOLFIRI+ram

RAISE trial: OS results

Tabernero et al, Lancet Oncol 2015

Angiogenesis inhibition in second line

Bevacizumab Aflibercept Ramucirumab

Study TML E3200 VELOUR RAISE

mOS 11.2 9.8 12.9 10.8 13.5 12.1 13.3 11.7

HR 0.81* 0.75* 0.82* 0.84*

mPFS 5.7 4.1 7.3 4.7 6.9 4.7 5.7 4.5

HR 0.68* 0.61* 0.76* 0.79*

RR (%) 5.4 3.9 22.7* 8.6 19.8* 11.1 13.4 12.5

100% prior Beva NO prior Beva 100% prior Beva30% prior Beva

* p<0.05

Bennouna Lancet Oncol 2012 - Giantonio JCO 2007 - Van Cutsem JCO 2012 – Tabernero Lancet Oncol 2015

Can toxicity profile help us?

G3/4 adverse events, %

Chemo +

bevacizumab

TML

FOLFIRI +

aflibercept

VELOUR

FOLFIRI +

ramucirumab

RAISE

Diarrhea 10% 19% 19% 11%

Stomatitis 3% 14% 11% 4%

Neutropenia 16% 37% 20% 38%

Hypertension 2% 19% 16% 11%

Venous thromboembolism 5% 8% 7% 3%

Arterial thromboembolism 2% 2% 2% <1%

Adapted from:

Bennouna et al, Lancet Oncol 2012; Tabernero et al, Eur J Cancer 2014;

Van Cutsem et al, J Clin Oncol 2012; Tabernero et al, Lancet Oncol 2015

100% prior Bev 100% prior BevPrior Bev

subgroup

ITT

population

Bevacizumab Beyond PD: alternatives ???

Anti EGFR

• EPIC, J Clin Oncol 2008

• PICCOLO, Lancet Oncol 2013

• Pmab 181, Ann Oncol 2014

→ No Formal Evidence of Survival Benefit

→ Cross over (activity in third-line)

→ Re-think on the basis of extended molecular selection …

Panitumumab in 2nd line: 181 trial

R

1186 mCRC pts

progressed to a

1st line

fluoropyrimidine-based

therapy

Primary Endpoints:

Overall survival and Progression-free Survival, by KRAS status

2nd line

FOLFIRI

2nd line

FOLFIRI+Pan

Peeters et al, JCO 2010

181 trial: OS and PFS results in RAS wt population

Peeters et al, Clin Cancer Res 2015

OVERALL SURVIVAL

PROGRESSION-FREE SURVIVAL

34% of patients assigned to FOLFIRI

eventually received anti-EGFR

In the Event that Tumor Shrinkage Is Needed

20050181 Study: ORR and Depth of response

Peeters et al, Clin Cancer Res 2015

Anti-EGFR moAbs in second line

Cetuximab Panitumumab

Study EPIC 2005-181 PICCOLO

mOS 10.7 10.0 16.2 13.9 10.5 10.4

HR 0.98 0.81 (p=0.08) 0.92

mPFS 4.0 2.6 6.4 4.6 NA NA

HR 0.69* 0.70* 0.68*

RR (%) 16.4* 4.2 41.0* 10.0 43.8* 12.3

No molecular selection RAS wt all-wt (RAS, BRAF, PIK3CA)

* p<0.05

Sobrero JCO 2008 – Peeters Clin Cancer Res 2015 - Seymour Lancet Oncol 2013 -

Which Biologic After CT+Bev?

✓ Bevacizumab both after Oxa-based and CPT-based

1st line and with FOLFIRI or FOLFOX or XELOX

✓ Aflibercept only after oxa-based 1st-line and only

with FOLFIRI

✓ Ramucirumab only after oxa-based+Beva 1st-line

and only with FOLFIRI

✓ Anti-EGFRs only RAS WT; only with CPT-based CT;

mainly if shrinkage is needed

Third and further-line

treatments

Well established «salvage» options

• Anti-EGFR (pani, cet +/- irinotecan)

• In RAS wt pts not previously treated with anti-EGFR

• Chemo Rechallenge

• No prospective evidences

• Carefully consider previous benefit and toxicity

REGORAFENIB

TAS-102

Regorafenib: indication and approval

30 August 2013

27 September 2012

mCRC pts, pretreated or not considered candidates for available tx

20 August 2015

Placebo +

BSC

Regorafenib +

BSC

• mCRC pts

treated with all

standard tx

• PD during or ≤3

months after

last tx

R

1:2

N= 760

Primary end-point: OS

CORRECT trial – Study design

Stratification by

Prior BV

Time from diagnosis of mets

Geographical region

N= 505

N= 255

Grothey et al, Lancet 2013

CORRECT trial: Patients’ characteristics

Grothey et al, Lancet 2013

CORRECT trial – Primary end-point MET

Grothey et al, Lancet 2013

Regorafenib mOS = 6.4 mos

Placebo mOS = 5.0 mos

HR=0.77 (95%CI 0.64-0.94)

p=0.0052

CONCUR trial – Outcome Results

Li et al, Lancet Oncol 2015

HR=0.31

95% CI 0.22-0.44

p<0.00001

Regorafenib mOS = 8.8 mos

Placebo mOS = 6.3 mos

HR=0.55 (95%CI 0.40-0.77)

p=0.00016

Regorafenib mPFS = 3.2 mos

Placebo mPFS = 1.7 mos

HR=0.31 (95%CI 0.22-0.44)

p<0.00001

Regorafenib: safety profile

G≥3 Adverse event %

CORRECT CONCUR CONSIGN

Rego(n=505)

Placebo(n=255)

Rego(n=136)

Placebo(n=68)

Rego(2872)

HFS 17 <1 16 0 14

Fatigue 10 5 3 1 13

Hypertension 7 1 11 3 15

Diarrhea 7 1 1 1 5

Rash 6 0 4 0 <5

Bilirubin increase 13 8 11 4 13

Grothey et al, Lancet 2013

Li et al, Lancet Oncol 2015

Van Cutsem et al, WCGIC 2015

CORRECT CONCURRego

(n=505)Placebo(n=255)

Rego(n=136)

Placebo(n=68)

G≥3 AE 54 16 54 14

Treatment

modification*76 38 75 22

AEs and dose modifications: CORRECT and CONCUR

Grothey et al, Lancet 2013

Li et al, Lancet Oncol 2015

*interruption, delay, dose reduction

27 April 2016

22 September 2015

Pending

TAS-102: indication and approval

mCRC pts, pretreated or not considered candidates for available tx

F3TMP

(inactive form)

TPI

FTYTPase

F3TDPFTD

FTD incorporationinto DNA

F3TTP

FTD

TPI

TAS-102

DNA dysfunction

Inhibition oftumor growth

FTD：TrifluorothymidineTPI：Tipiracil-HCl

Molar ratio = 1:0.5

+

15mg tablet 20mg tablet

TAS-102: mechanism of action

mCRC pts

treated with ≥

2 tx lines

refractory to

all standard tx*

Placebo +

BSC

TAS 102+

BSC

R

1 : 2

N= 800

Primary end-point: OS

RECOURSE trial – Study design

N= 534

N= 266

About 20% rego-pretreated

Mayer et al, NEJM 2015*PD during or ≤3 months after all active drugs

Recourse trial – Primary end-point OS MET

Mayer et al, NEJM 2015

TAS-102 mOS = 7.1 mos

Placebo mOS = 5.3 mos

HR=0.68 (95%CI 0.58-0.81)

p<0.001

Carried out at 89% of events (138 additional events)

Cut off October 8th, 2014: 712 events

Mayer R, et al. ASCO GI 2016 Abstract 634

0 6 12 282 4 8 10 14 16 18 20 22 24 26

Su

rviv

al

dis

trib

uti

on

fu

nc

tio

n

Months from randomization

0

50

100

Trifluridine/tipiracil

No. at Risk:

Placebo

Trifluridine/tipiracil

(N=534)

Placebo

(N=266)

Median OS (months) 7.2 5.2

Stratified log-rank test: p<0.0001

HR: 0.69, 95% CI [0.59, 0.81]

Alive at 12 months, % 27 17

266 01232 163 114 71 56 43 27 16 14 8 6 4

534 04499 406 308 231 180 137 95 59 38 20 14 10

Recourse trial – updated OS

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

Subgroup Favours trifluridine/tipiracil Favours placebo Events / N HR (95% CI)

All patients 574 / 800 0.68 (0.58-0.81)

KRAS status

Wild type

Mutant

280 / 393

294 / 407

0.58

0.80

(0.45-0.74)

(0.63-1.02)

Time since diagnosis of first metastasis

<18 months

≥18 months

131 / 166

443 / 634

0.84

0.64

(0.58-1.21)

(0.53-0.78)

Geographic region

Japan

US, Europe & Australia

227 / 266

347 / 534

0.75

0.64

(0.57-1.00)

(0.52-0.80)

Age

<65 years

≥65 years

316 / 448

258 / 352

0.74

0.62

(0.59-0.94)

(0.48-0.80)

Gender

Male

Female

348 / 491

226 / 309

0.69

0.68

(0.56-0.87)

(0.51-0.90)

ECOG performance status

0

1

298 / 448

276 / 352

0.73

0.61

(0.58-0.93)

(0.48-0.79)

Primary tumor site

Colon

Rectum

361 / 499

213 / 301

0.68

0.64

(0.55-0.85)

(0.48-0.85)

Number of prior regimens

2

3

≥4

106 / 140

137 / 173

331 / 487

1.05

0.74

0.59

(0.68-1.63)

(0.51-1.08)

(0.47-0.73)

Prior use of regorafenib

Yes

No

94 / 144

480 / 656

0.69

0.69

(0.45-1.05)

(0.57-0.83)

Refractory to fluoropyrimidine

part of last prior regimen 329 / 455 0.75 (0.59-0.94)

0.3 0.5 1 2.0

Hazard ratio: Trifluridine/tipiracil vs. placebo (95% CI)

Recourse trial – subgroup analysis OS

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

0%

10%

20%

30%

40%

50%

60%

Trifluridine/tipiracil Placebo

p<0.001

Response rateDisease control rate

44%

16%

PlaceboTrifluridine/tipiracil

Trifluridine/tipiracil

(N=112) %

Placebo

(N=57) %

CR 0 0

PR 1.6 0

SD 42.4 15.9

ORR (%) 1.6 0.4

Recourse trial – RR & DCR

REGO vs TAS– Efficacy

CORRECT RECOURSE

Rego(n=500)

Placebo(n=253)

TAS-102(534)

Placebo (266)

mPFS 1.9 1.7 2.0 1.7

HR 0.49 0.48

mOS 6.4 5.0 7.1 5.3

HR 0.77 0.68

RECOURSE trial – Safety profile

Lab abnormalities, %TAS-102 (n=533) Placebo (n=265)

All Gr Gr ≥3 All Gr Gr ≥3

Leukopenia 77 21 5 0

Anemia 77 18 33 3

Neutropenia 67 38 <1 0

Thrombocytopenia 42 5 8 <1

Adverse events, %TAS-102 (n=533) Placebo (n=265)

All Gr Gr≥ 3 All Gr Gr ≥3

Febrile neutropenia 4 4 0 0

Adapted from Mayer et al, NEJM 2015

REGO vs TAS: how can we choose?

Toxicity profile

Previous treatments toxicities

Previous treatments efficacy

Biomarkers ???

… COST !!!

Mayer et al, NEJM 2015

Recourse trial: Subgroup analysis for OS

CORRECT

Clinical selection in advanced lines is essential

TAS-102 mPFS = 2.0 mosPlacebo mPFS = 1.7 mos

HR= 0.48 (95%CI 0.41-0.57)p<0.001

RECOURSE

Mayer et al, N Eng J Med 2015

Grothey et al, Lancet 2013

How can I optimize the tx of my MCRC pt?

Use a comprehensive & carefull approach (clinical & molecular)

Plan a strategy

Modulate therapy

Assess & re-think the strategy

DON’T BE DOGMATIC, BUT RATHER PRAGMATIC!

Grazie per l’attenzione!

alfredo.falcone@med.unipi.it