OBJECTIVES OF TREATMENT CHANGE ACCORDING

TO LINE OF THERAPY

Adjuvant

First Line

Second Line

Third Line

Subsequent

Lines …

• “Cure”.

• Reduce risk of recurrence

• Durable Tumoral Response

• Long duration low/null tumor burden

• Tumoral Response if necessary

• Durable disease control

↑ OS

• Durable Disease Control

• Maintain quality of life and PS.

• Disease Control – Maintain quality of life

• Palliative Care

Courtesy of Dirk Arnold; supported also by Stintzing S. F1000 Prime Rep. 2014;6:108.

Lín

ea

de

Tra

tam

ien

to

Treatment Objective “Realistics”

Median Survival Increases with Increased Lines of Therapy

SEER Medicare Database Analysis for mCRC (2003-2007; N = 5,129)

Med

ian

OS,

mo

nth

s

Total Lines of Therapy

HR = 0.604*

HR = 0.398*

HR = 0.364*

*P<.001Hanna N, et al. J Clin Oncol. 2014;32(suppl 3):abstract 559.

What options after second line?

MSI-H---------------------Immunotherapy

BRAF mut---------------- “Combinations”

Other targets.- HER2, ……

LOCAL THERAPIES(LIVER DIRECTED)

Reintroduction

Oxaliplatin/antiEGFR

Rechallenge

“New Molecules”

Regorafenib, Trifluridine-Tipiracil, Fruquintinib

RAS/BRAF WT---------antiEGFR±CT

CLINICAL TRIALS

“New Molecules”

Regorafenib, Trifluridine-tipiracil, Fruquintinib

Regorafenib 160 mg/day

3 weeks on /1 week off

(cycle 4 weeks)

Placebo

• All patients received best supportivecare

• Treatment until disease progression, death, unnaceptable toxicity orwithdrawal consent

• Radiologic assessment every 8 weeks

mCCR patients withdisease progression

after standard therapy

A2:1

Primary EndpointOverall Survival

CORRECT1 CONCUR2

Number of included patients 760 204

Recruitment. 16 countries of Europe, Northamerica, Asia-

Pacific area, rest of the worldChina, Hong Kong, Taiwán,

South Korea, Vietnam

Targeted biologic treatment previous: bevacizumab; cetuximab/panitumumab (KRAS WT)

Required Allowed, but not required

Primary analysis of survival (an increased 33,3 %; CRI 0,75 in favor of regorafenib)

Alfa unilateral 0,025Potency 90 %

Alfa unilateral 0,20 Potency 80 %

Stratification factors for randomizationPrevious treatment with antiVEGF therapy;

time from diagnosis mCRC (>18 vs <18 months); geografic area

Number of metastatic sites (one vs multiple)

(>18 vs <18 months)

Diseño del estudio1,2

A, aleatorización; CCRm, cáncer colorrectal metastásico; CRI cociente de riesgos instantáneos; SG, supervivencia global.1. Grothey A, Van Cutsem E, et al. Lancet. 2013; 381:303–312; 2. Li J, et al. Lancet Oncol. 2015; 16:619–629.

1. Grothey A, et al. Lancet 2012; 381:303-12; 2. Li J, et al. Lancet Oncol 2015; 16:619-29.

-10%

0%

10%

20%

30%

40%

50%

60%

CR+PR SD

Regorafenib Placebo

CORRECT1 CONCUR2

Regorafenib – Disease Control in 2 Fase III trials in mCCR

DCR 41% DCR 51%

CORRECTRegorafenib

n = 505

Placebo

n = 255

Median OS, months 6,4 5,0

HR (95% CI) 0,77 (0,64–0,94)

P value 0,0052

BSC, best supportive care

1. Grothey A, et al. Lancet 2013; 381:303-12; 2. Li J, et al. Lancet Oncol 2015; 16:619-29.

Time from randomization (months)

00 6 10 14842 12

Regorafenib 160 mg + BSCPlacebo + BSC

100

75

50

25

Ove

rall

Surv

ival

%

CORRECT1: 23% reduction risk of

death

(primary endpoint)

CONCUR2: 45% reduction risk of

death

(primary endpoint)

CONCUR Regorafenib

n = 136

Placebo

n = 68

Median OS, months 8,8 6,3

HR (95% CI) 0,550 (0,395–0,765)

P value 0,0002 (1-sided)

Regorafenib 160 mg + BSC Placebo + BSC

0

1

0,75

0,50

0,25

0 100 200 300 400 500

Time from randomization (days)

EFFICACY: OVERALL SURVIVAL

CLINICAL FACTORS

TOXICITY DEPENDENT

MOLECULAR FACTORS

PREDICTIVE FACTORS?

Adenis et al. BMC Cancer (2016) 16:412

NO DIFFERENCES IN TOXICITY

Trifluridina/tipiracilo (TAS-102)

a new antitumoral nucleoside

NH

HN O

O

N

Cl

HCl.HN

HN

N

O

O

CF3

OHO

OH

+

2’-desoxi-5-(trifluorometilo)uridina

(trifluridina, FTD) [1]

monohidrocloruro de 5-cloro-6-

[(2-iminopirrolidin-1-il)metil]pirimidina-2,

4(1H,3H)-diona

(hidrocloruro de tipiracilo, TPI) [0,5]

[Fracción molar][1:0,5]

• Tipiracil hidroclorure (TPI) is a Thymidine

phosphorylase inhibitor that avoids FTD

degradation

• Increase effective concentration in vivo of

FTD

TAS-102

FTD is the active

component

• Trifluridina (FTD) is a thymidine-based

nucleoside, that is incorporated into DNA of

tumor cells after its phosphorylation (active

component)

Different mechanism of action than fluorpyrimidines

RECOURSE: OVERALL SURVIVAL

RECOURSE: OS Subgroup analysis

Subgroups

Favourable

TAS-102

Favourable

placebo Events /N HR (IC 95 %)

All Patients 574/800 0,68 (0,58-0,81)

KRAS Mutation status

No 280/393 0,58 (0,45-0,74)

Yes 294/407 0,80 (0,63-1,02)

Time from diagnosis first metastases

< 18 months 131/ 166 0,84 (0,58-1,21)

≥ 18 months 443/634 0,64 (0,53-0,78)

Geographic Region

Japan 227/266 0,75 (0,57-1,00)

USA, Europe and Australia 347/534 0,64 (0,52-0,80)

Age

< 65 years 316/448 0,74 (0,59-0,94)

≥ 65 years 258/352 0,62 (0,48-0,80)

Gender

Male 348/491 0,69 (0,56-0,87)

Female 226/309 0,68 (0,51-0,90)

ECOG Performance Status

0 298/448 0,73 (0,58-0,93)

1 276/352 0,61 (0,48-0,79)

Primary Tumor Site

Colon 361/499 0,68 (0,55-0,85)

Rectum 213/301 0,64 (0,48-0,85)

Number of previous regimens

2 106/140 1,05 (0,68-1,63)

3 137/173 0,74 (0,51-1,08)

≥ 4 331/487 0,59 (0,47-0,73)

Use previous regorafenib

Yes 94/144 0,69 (0,45-1,05)

No 480/656 0,69 (0,57-0,83)

Refractory to fluoropyrimidine

Part of the last régimen 329/455 0,75 (0,59-0,94)

0,3 0,5 1 2,0

Hazard ratio (HR): TAS-102 vs placebo (IC 95 %)

CLINICAL FACTORS

TOXICITY DEPENDENT

MOLECULAR FACTORS

PREDICTIVE FACTORS?

RECOURSE: Onset of neutropenia predicts outcomes with LONSURF

in patients with mCRC

Ohtsu A, et al. ASCO 2016. Abstract 3556 (poster presentation).

Grade ≥3 neutropenia was associated with longer OS for LONSURF vs placebo, irrespective of timing of onset

Outcome

Earliest onset of grade ≥3 neutropenia

Cycle 1 Cycle 2 (L) or ≥2 (P) Cycle ≥3 No grade ≥3 neutropenia

LONSURF

(n=75)

Placebo

(n=265)†

LONSURF

(n=86)

Placebo

(n=215)

LONSURF

(n=39)

Placebo

(n=48)

LONSURF

(n=333)

Placebo

(n=265)†

Median OS, months 9.7 5.3 8.7 6.3 16.4 10.2 5.5 5.3

HR 0.48 (95% CI: 0.32, 0.64) HR 0.56 (95% CI: 0.41, 0.78) HR 0.36 (95% CI: 0.17, 0.75) HR 0.97 (95% CI: 0.81, 1.16)

Median PFS, months3.7 1.7 3.7 1.8 6.5 3.7 1.9 1.7

HR 0.35 (95% CI: 0.25, 0.48) HR 0.34 (95% CI: 0.25, 0.46) HR 0.32 (95% CI: 0.18, 0.56) HR 0.69 (95% CI: 0.58, 0.82)

Consistent treatment benefit was observed for OS and PFS regardless of cycle of onset of grade ≥3 neutropenia

HR, adjusted HR for LONSURF vs placebo. †All placebo patients

Objective: Post-hoc analysis of the RECOURSE study to explore the association between the onset of grade ≥3neutropenia and OS/PFS, in mCRC patients treated with LONSURF or placebo

OS for patients with onset of grade ≥3neutropenia at cycle 1

OS for patients with no neutropenia onset

0 2 4 6 8 10 12 14 16 18 20

LONSURF

Placebo

Time (months)

0

0.2

0.4

0.6

0.8

1.0

OS

estim

ate

2 4 6 8 10 12 14 16 18 20

LONSURF

Placebo

Time (months)0

0

0.2

0.6

OS

estim

ate

0.4

0.8

1.0

Median 3,7 m

Median 11,4 m

Kuboki Y et al. Lancet Oncol 2017

TAS-102 (35 mg/m² given orally twice daily on days 1–5 and 8–12 in a 28-day cycle) Bevacizumab (5 mg/kg, every 2 weeks)

100% refractory angiogenesis inhibitor

Moriwaki et al. The Oncologist 2017

Regorafenib (REG) versus trifluridine/tipiracil (TAS-102) as salvage-line in

patients with metastatic colorectal cancer refractory to standard

chemotherapies (REGOTAS): A propensity score analysis from a JSCCR

multicenter observational study.

¿REGORAFENIB vs TAS102?

RAS/BRAF WT---------- antiEGFR±CT

antiEGFR naive-patients

Jonker et al. N Engl J Med 2007

Cunningham et al. N Engl J Med 2004

REINTRODUCTION

Oxaliplatin/antiEGFR

RECHALLENGE

Maindrault-Goebel et al. Ann Oncol 2004

Median PFS 18 weeks

No treatment between periodsof FOLFOX therapy

29 patients1 st line FOLFOX therapy

83% PR, 14% SD

33 pts PD ≥6 months after last dose Oxaliplatin (previous response or stabilization)

Disease control rate 12 weeks 39.4%Response rate 6.1%

Suenaga M et al. Drug, Design, Development Ther 2015

RECHALLENGE

antiEGFR therapy?

39 patients Kras exon2 WTProspective phase IIIri + CTX based 1st line PDResponse Rate 53.8%Disease stabilization 35.9 %Median PFS 6.6 m

89 patients Kras exon2 WTRetrospective studyantiEGFR 1st line PDClinical Benefit 58%Median PFS 4.9 vs 2.5

RECHALLENGE

Santini et al. Ann Oncol 2012 Liu et al. BMC Cancer 2015

Rossini et al. Asco Meeting 2018

Rossini et al. Asco Meeting 2018

Rossini et al. Asco Meeting 2018

MSI------------------------”Immunotherapy”

BRAF mut---------------- “Combinations”

Other targets.- HER2, ……

KRAS WT 52% ----- KRAS MUT 0%

The median DOR was 11 months

Montagut et al. JAMA Oncol 2018

Jonker DJ et al. Lancet Gastroenterol Hepatol 2018

¿Qué hacer tras fallo a Oxaliplatino e Irinotecan +/- Biológicos?

BEYOND SECOND LINE

Is the patient

RAS WT?

Has the patient

received antiEGFR?

antiEGFR

first-use

Is the patient

HER2+

MSI

BRAF mut?

Specific

treatment

Clinical trial

Has the patient a

liver-limited

disease?

Intraarterial

therapies

Trifluridine-

Tipiracil or

Regorafenib

Oxali or

antiEGFR

rechallenge

yes no

no

yes

no

no

yes

yes

then

then

CLINICAL TRIAL