La strategia terapeutica

(1)

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

(2)

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, …

(3)

Examples of treatment strategies in MCRC

Treatment 1 PD Treatment 2 PD Treatment 3

TREAT UNTILL PD AND SWITHC («old fashioned»)

Treatment 1

Maintenance 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

(4)

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, …

(5)

Upfront treatment is still a crucial “step” to …

Achieve disease control Allow further

interventions (surgery and other systemic

treatments)

(6)

The ‘funnel effect’

1st line 2nd line

3rd line 4th line

5th line

PATIENTS

(7)

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

1st line 2nd line

3rd line 4th line

5th line

PATIENTS

(8)

The ‘funnel effect’ in the case of initial PD

1st line 2nd line

3rd line

PATIENTS

PD, progressive disease

(9)

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

(10)

(11)

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

R

280 mCRC pts

1st line mCRC

AGE >70 yrs

Capecitabine Capecitabine + BV

(12)

Cunningham D. et al, Lancet Oncol‘13

AVEX - Progression Free Survival

(13)

.

The TASCO 1 trial

(14)

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

CAPECITABINE

Twice 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

(15)

(16)

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

PD

INDUCTION MAINTENANCE

Primary Endpoint: PFS

Loupakis et al., NEJM 2014

(17)

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

(18)

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.

(19)

FOLFIRI + bev, median OS: 25.8 mos FOLFOXIRI + 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

(20)

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

(21)

“Decision drivers for FOLFOXIRI”

FOLFOXIRI plus bev “appropriateness”

(22)

• Doublets (FOLFOX or FOLFIRI) + anti-EGFR

(23)

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

(24)

(25)

 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)

(26)

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

(27)

PFS chemotherapy + bevacizumab superiority:

XELOX and FOLFOX subgroups

XELOX subgroup

HR = 0.77 [97.5% CI 0.63–0.94] (ITT) p = 0.0026

9.3 7.4

1.0 0.8 0.6 0.4 0.2 0

0 5 10 15 20 25

Months

PFS estimate

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

9.4 8.6

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

(28)

Maughan et al, ESMO 2009

(29)

Maughan et al, ESMO 2009

(30)

 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!!!

(31)

(32)

(33)

WHICH BIOLOGIC IN FIRST-LINE?



Direct comparisons anti-EGFRs vs bev

•

^FIRE-3

•

CALGB C80405

•

^PEAK

(34)

• 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 + Cetuximab

Cetuximab: 400 mg/m² i.v. 120min initial dose 250 mg/m² i.v. 60min q 1w

FOLFIRI + Bevacizumab

Bevacizumab: 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)

(35)

Progression-free survival

0.75 1.0

0.50

0.25

12 24 36 48 60 72

months since start of treatment 297

295 numbers at risk

100 99

19 15

10 6

5 4

3 0.0

Probability of survival

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

(36)

Overall survival

Events n/N (%)

95% CI

28.7 24.0 – 36.6

25.0 22.7 – 27.6

HR 0.77 (95% CI: 0.62 – 0.96) Log-rank p= 0.017

0.0

12 24 36 48 60 72

months since start of treatment 297

295 numbers at risk

218 214

111 111

60 47

29 18

9 2 0.75

1.0

0.50

0.25

0.0

(37)

Events n/N (%)

95% CI

33.1 24.5 – 39.4

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

0.0

12 24 36 48 60 72

months since start of treatment

171 171 No. at

risk

128 127

71 68

39 26

20 9

6 1

0.75 1.0

0.50

0.25

0.0

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

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

(38)

CALGB/SWOG 80405:

FINAL DESIGN

N = 1140

1° Endpoint: Overall Survival

Chemo + Cetuximab

Chemo + Bevacizumab

mCRC 1st-line

KRAS wild type (codons 12,13)

FOLFIRI

or

FOLFOX

MD choice

(39)

CALGB/SWOG 80405: Overall Survival

Presented by: Venook A

Arm N (Events) ^{OS (m)}

Median 95% 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)

(40)

CALGB 80405: Overall Survival By Arm

(All RAS Wild Type Patients)

Arm N

(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

(41)

(42)

(43)

OS

(44)

PFS

(45)

RR

(46)

 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

(47)

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

(48)

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 shrinkage^1,2 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)

(49)

(50)

(51)

Courtesy :Andrea Sartore Bianchi AIOM 2015

(52)

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

= First-line FOLFIRI+BEV

(53)

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

(54)

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= 0.05

Fisher 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

(55)

RIGHT

LEFT

X Colon??

(56)

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/BEV OS (MOS)

24.8 18.0 14.6

42.0 23.0 24.0

Metastatic Colorectal Cancer:

Does Side Matter?

(57)

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

(58)

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

(59)

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

FOLFIRI+cetuximab FOLFIRI+bevacizumab

Heinemann et al., ASCO ‘14

(60)

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

(61)

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

(62)

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)

Left Right

(63)

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

(64)

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)

(65)

Bettington, et al. Histopathology. 2013.

MIDGUT HINDGUT

Bettington, et al Histopathology, 2013

(66)

(67)

(68)

(69)

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 ???

(70)

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 response Which chemo

Tolerance

First-line related factors

Which biologic

Residual toxicities Drug free-interval

(71)

(72)

(73)

COMBINATION STUDY RR PFS OS

Bevacizumab + IRI or LOHP-based CT

(E3200) TML

BEPYP NO YES YES

Aflibercept +

FOLFIRI VELOUR YES YES YES

Ramucirumab + FOLFIRI RAISE NO YES YES

Cetuximab + IRI EPIC

YES YES NO

Panitumumab + IRI PICCOLO Panitumumab + FOLFIRI 181

Targeted agents in second line MCRC

(74)

Bevacizumab Aflibercept Ramucirumab

FDA and EMA approved

VEGF-A

VEGF-A VEGF-B PlGF

VEGFR-2

Anti-angiogenic agents in 2nd line

(75)

R

820 mCRC pts progressed to a

1st line chemo plus Beva*

2^nd line chemo^§

2^nd line

chemo^§ + BEV

Primary 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

(76)

Bennouna, Lancet Oncol 2013

Bevacizumab Beyond Progression: TML trial - OS

11.2 9.8

(77)

FDA and EMA approved

VEGF-A

VEGFR-2

(78)

R

1st line

oxaliplatin-based therapy*

Primary Endpoint:

Overall survival

Aflibercept: VELOUR trial

Van Cutsem et al, J Clin Oncol 2012

2^nd line FOLFIRI

2^nd line FOLFIRI+afl

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

(79)

VELOUR trial: Primary endpoint met (OS)

Van Cutsem et al, J Clin Oncol ‘12

(80)

VELOUR trial: PFS & Response Rate

(81)

VEGF-A

VEGFR-2

(82)

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

2^nd line FOLFIRI+ram

(83)

RAISE trial: OS results

Tabernero et al, Lancet Oncol 2015

(84)

Angiogenesis inhibition in second line

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 30% prior Beva 100% prior Beva

* p<0.05

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

(85)

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 Prior Bev 100% prior Bev

subgroup ITT

population

(86)

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 …

(87)

Panitumumab in 2nd line: 181 trial

R

1st line

fluoropyrimidine-based therapy

Primary Endpoints:

Overall survival and Progression-free Survival, by KRAS status

2^nd line FOLFIRI+Pan

Peeters et al, JCO 2010

(88)

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

(89)

In the Event that Tumor Shrinkage Is Needed

20050181 Study: ORR and Depth of response

Peeters et al, Clin Cancer Res 2015

(90)

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 -

(91)

Which Biologic After CT+Bev?

✓ Bevacizumab  both after Oxa-based and CPT-based 1^st line and with FOLFIRI or FOLFOX or XELOX

✓ Aflibercept  only after oxa-based 1^st-line and only with FOLFIRI

✓ Ramucirumab  only after oxa-based+Beva 1^st-line and only with FOLFIRI

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

mainly if shrinkage is needed

(92)

Third and further-line

treatments

(93)

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

(94)

Regorafenib: indication and approval

30 August 2013 27 September 2012

 mCRC pts, pretreated or not considered candidates for available tx

20 August 2015

(95)

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

(96)

CORRECT trial: Patients’ characteristics

Grothey et al, Lancet 2013

(97)

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

(98)

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

(99)

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

(100)

CORRECT CONCUR

Rego (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

(101)

27 April 2016 22 September 2015

Pending

TAS-102: indication and approval

 mCRC pts, pretreated or not considered candidates for available tx

(102)

F₃TMP

(inactive form)

TPI

FTY

TPase

F₃TDP

FTD

FTD incorporation into DNA

F₃TTP

FTD

TPI

TAS-102

DNA dysfunction Inhibition of tumor growth

FTD：Trifluorothymidine TPI：Tipiracil-HCl

Molar ratio = 1:0.5 +

15mg tablet 20mg tablet

TAS-102: mechanism of action

(103)

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

(104)

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

(105)

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 2 4 6 8 10 12 14 16 18 20 22 24 26 28

Survival distribution function

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

266 232 163 114 71 56 43 27 16 14 8 6 4 1 0

534 499 406 308 231 180 137 95 59 38 20 14 10 4 0

Recourse trial – updated OS

(106)

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/tipiracilvs. placebo (95% CI)

Recourse trial – subgroup analysis OS

(107)

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 rate Disease control rate

44%

16%

Placebo Trifluridine/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

(108)

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

(109)

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

(110)

REGO vs TAS: how can we choose?

 Toxicity profile

 Previous treatments toxicities

 Previous treatments efficacy

 Biomarkers ???

 … COST !!!

(111)

Mayer et al, NEJM 2015

Recourse trial: Subgroup analysis for OS

(112)

CORRECT

Clinical selection in advanced lines is essential

TAS-102 mPFS = 2.0 mos Placebo 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