CORREGIDA: Tratamiento de cáncer de colon metastásico: de las guías de práctica, genómica a la...

Tratamiento del cáncer colorectal metastásico: de las guías de práctica clínica, pasando por la genómica y la realidad

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

Cartagena, Colombia09.07.2014

FULVFULV

CapecCapec

IriIri

BevBev

CetCet

PanPan

Regor.Regor.

SurgerySurgery

Ablative Rx

Ablative Rx

OxOx Aflib.Aflib. Ramuc.Ramuc.

FULVFULV BevBevCapecCapec BevBev

FULVFULVCapecCapec

FULVFULV OxOx IriIri

FULVFULV OxOx BevBev CapecCapec OxOx BevBev

FULVFULV OxOx IriIri BevBev FULVFULV OxOx

FULVFULV IriIri BevBev CapecCapec IriIri BevBev

FULVFULV OxOx CetCet CapecCapec OxOx CetCet

FULVFULV IriIri IriIri CetCet

FULVFULV IriIri CetCet CapecCapec IriIri CetCet

CetCet

FULVFULV OxOx PaniPani CapecCapec OxOx PaniPani

FULVFULV IriIri IriIri PaniPani

FULVFULV IriIri PaniPani CapecCapec IriIri PaniPani

PaniPani

FULVFULV OxOx AflibAflib CapecCapec OxOx AflibAflib

FULVFULV IriIri IriIri AflibAflib

FULVFULV IriIri AflibAflib CapecCapec IriIri AflibAflib

“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 0Group 0

Group 1Group 1

Group 2Group 2

Group 3Group 3

Resectable R0

Convertible

Unlikely resectable/High tumor burden

Never resectable

Surgery/ +/- Adj CTSurgery/ +/- Adj CT

Conversion CT/SurgeryConversion CT/Surgery


Less-toxic CTLess-toxic CT

Cure

Cure

Long OS

QoL

Criticism: solely based on DISEASE characteristics


mCRC: ESMO Clinical Practice Guidelines


Group 0Group 0

Group 1Group 1

Group 2Group 2

Group 3Group 3

Resectable R0

Convertible

Unlikely resectable/High tumor burden

Never resectable

Surgery/ +/- Adj CTSurgery/ +/- Adj CT


Active CT + BiologicActive CT + Biologic

Less-toxic CTLess-toxic CT

FOLFOX

FOLFOXIRI-Bev

FOLFIRI-Cet

FOLFOX-BevXELOX-BevFOLFOX-CetFOLFIRI-Cet

FP-Bev

Criticism: solely based on DISEASE characteristics


Do THESE guidelines, guide?

Let’s start with curative intent

Continuum of care

SurgerySurgery FULVFULV OxOx

FULVFULV OxOx IriIri SurgerySurgery

FULVFULV IriIri CetCetSurgerySurgery

OS after resection in liver metastasis

Adam R, Oncologist, 2012

OS after resection in liver metastasis, after preoperative chemotherapy

Adam R, Oncologist, 2012

FOLFIRINOX combined to targeted therapy according RAS status for colorectal cancer patients with liver

metastases initially non-resectable: A phase II randomized Study—Prodige 14 – accord 21 (METHEP-2), a unicancer

GI trial. Mark Ychou. Proc ASCO, 2016, Abstract 3512

Proc ASCO, 2016, Discussion.

FOLFIRINOX as induction treatment in rectal cancer patients with synchronous metastases (RCSM): Results of

the FFCD 1102 phase II trial. JB Bachet. Proc ASCO, 2016, Abstract 3513

Is More Better?, Steven J Cohen

Proc ASCO, 2016, Discussion.

THAT was easy, what about the rest?

CAPOX + Bevacizumab

6 meses

“Continuum of care” in mCRC – “blurring line descriptions”

Cape + Bevacizumab

Hasta progresión1o línea

FOLFIRI + Bevacizumab

Oxaliplatino hasta neuropatía

QT + Bevacizumab

Hasta progresión2o línea

Cetuximab +/- Irinotecán

Regorafenib

Hasta progresión≥3o línea (KRAS nativo)

Hasta progresión

CAIRO-3

TML

Cunningham D, et al. N Engl J Med 2004;351:337-45. CORRECT Trial (Van Cutsem 2012)

In the RAS wt, which first-line agent?

clinicaloptions.com/oncologyOptimizing Treatment of Metastatic Colorectal Cancer

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

BRAF mutation All patientsAny mutationKRAS mutation

KRAS WTAll WT

Mutation Status

0

6

12

Me

dia

n P

FS

(M

os

)

Arm A Arm B

0

6

12

18

Me

dia

n O

S

(Mo

s)

57

34

02

68

81

53

67

28

9

45

36

62

97

81

53

62

29

20

10

20

30

40

2-Y

r O

S (

%)

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

Impact of primary (1º) tumor location on overall survival (OS) and progression-free survival (PFS) in patients (pts)

with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance). Alan P. Venook.

Proc ASCO, 2016, 3504.

The relationship between primary tumor sidedness and prognosis in colorectal cancer. Deborah Schrag

Proc ASCO, 2016, 3505.

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 ( EGFR) therapy. Michael Sangmin αLee

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


Proc ASCO, 2016, 3505.

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


Side Matters. Kimmie Ng

Proc ASCO, 2016, Dicussion..

What should we do with BRAF mutated mCRC?

FULVFULV OxOx IriIri BevBev

What about mBRAF mCRC?

• Not very clear• TRIBE study suggests FOLFOXIRI-Bev(1)

• Further studies of anti-BRAF coupled with other agents are expected (ie, Cetuximab).

1. Loupakis F, NEJM, 2014

Continuum of care in mCRC

Continuum of care

FULVFULV OxOx BevBev

What to do in second line?

clinicaloptions.com/oncologyColorectal Cancer: Individualizing Therapy Beyond Second-line Treatment

Phase III ML18147 (TML): Continuing Bevacizumab Beyond Progression

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

(n = 411)

Bevacizumab 2.5 mg/kg/wk + standard second-line CT (oxaliplatin or

irinotecan-based) until PD(n = 409)

Progressive mCRC after BEV + standard first-line CT (either oxaliplatin or

irinotecan based)(n = 820)

Bennouna J, et al. Lancet Oncol. 2013;14:29-37.

Stratified by first-line CT (oxaliplatin or irinotecan based), first-line PFS (≤ 9 vs > 9 mos), time

from last BEV dose (≤ 42 vs > 42 days),ECOG PS at baseline (0/1 vs 2)


Secondary endpoints: PFS, ORR, safety


Continuing Bevacizumab Beyond Progression (TML): OS, PFS

OS

(%

)

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

100

80

60

40

20

00 6 12 18 24 30 36 42 48

9.8 mos9.8 mos 11.2 mos11.2 mos

Unstratified* HR: 0.81 (95% CI: 0.69-0.94; log-rank P = .0062)

Stratified† HR: 0.83 (95% CI: 0.71-0.97; log-rank P = .0211)

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

Bennouna J, et al. Lancet Oncol. 2013;14:29-37.

100

80

60

40

20

0

PF

S (

%)

0 6 12 18 24 30 36 42

Mos

Unstratified* HR: 0.68 (95% CI: 0.59-0.78; log-rank P < .0001)

Stratified† HR: 0.67 (95% CI: 0.58-0.78; log-rank P < .0001)

4.1

mo

4.1

mo

5.7 mo5.7 mo

Overall Survival Progression-Free Survival


Phase III VELOUR Study: FOLFIRI ± ziv-Aflibercept as Second-line Therapy in mCRC


Secondary endpoints: PFS, ORR, safety, immunogenicity

No correlatives

Patients with mCRC progressing on first-line

oxaliplatin-based chemotherapy*

(planned N = 1226)

FOLFIRI + ziv-Aflibercept 4 mg/kg q2w(n = 612)

FOLFIRI + Placebo q2w(n = 614)

*30% had previous bevacizumab.

Stratified by previous bevacizumab (yes vs no),ECOG PS (0 vs 1 vs 2)

Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506. ClinicalTrials.gov. NCT00561470.


FOLFIRI ± ziv-Aflibercept as Second-line Therapy in mCRC (VELOUR): OS, PFS

Van Cutsem E, et al. J Clin Oncol. 2012;30:3499-3506.

Stratified HR: 0.817 (95.34% CI: 0.713-0.937; log-rank P = .0032)

Placebo/FOLFIRIMedian: 12.06 mos

Aflibercept/FOLFIRIMedian: 13.50 mos

PF

S (

%)

100

80

60

40

20

0

Mos

0 3 6 9 12 15 18 21 24 27 30

Stratified HR: 0.758 (95% CI: 0.661-0.869; log-rank P < .0001)




OS

(%

)

100

80

60

40

20

0

Mos

0 3 6 9 12 15 18 21 24 27 30 33 36 39


Tabernero J, et al. Eur J Cancer. 2014;50:320-331.

OS

(%

)

100

80

60

40

20

0

Mos

0 3 6 9 12 15 18 21 24 27 30 33 36 39

HR: 0.862 (95.34% CI: 0.673-1.104)



Pts at Risk, n PlaceboAFL

187186

170178

138150

115121

8189

5459

3736

2222

1313

Previous Bevacizumab

OS

(%

)

100

80

60

40

20

0

Mos

0 3 6 9 12 15 18 21 24 27 30 33 36 39

HR: 0.788 (95.34% CI: 0.699-0.927)



Pts at Risk, n PlaceboAFL

427426

403388

347348

286295

205222

139157

94112

6582

3862

No Previous Bevacizumab

2nd-Line FOLFIRI ± ziv-Aflibercept in mCRC (VELOUR): OS by Prior Bevacizumab


Phase III RAISE Study: Second-Line Ramucirumab/FOLFIRI vs FOLFIRI

Patients with CRC and progression during or within 6

months of first-line bevacizumab,

oxaliplatin, and a fluoropyrimidine

(N = 1072)

Treat until PD or unacceptable

toxicity

Ramucirumab 8 mg/kg +FOLFIRI q2w per cycle

(n = 536)

Placebo +FOLFIRI q2w per cycle

(n = 536)

Stratified by geographic region, KRAS mutation status, TTP after start of first-line therapy

Ramucirumab: anti-VEGFR2 antibody


Tabernero J, et al. Lancet Oncol. 2015;16:499-508.


Ramucirumab + FOLFIRI

Placebo + FOLFIRI

Median OS, mo(95% CI)

13.3(12.4-14.5)

11.7(10.8-12.7)

HR (95% CI) 0.844 (0.73-0.976) (stratified)P Value (log-rank) .0219 (stratified)

Second-Line Ramucirumab/FOLFIRI vs FOLFIRI (RAISE): Overall Survival

Tabernero J, et al. Lancet Oncol. 2015;16:499-508.

497 345 195 78 34 12 0536 421 269 114 53 422 0

486 329 166 66 22 2 1536 400 228 108 44 210 0

Pts at Risk, n

Placebo +

FOLFIRI

Ram + FOLFIRI

Ramucirumab + FOLFIRI Placebo + FOLFIRI

Overall S

urvival

0.2

0.4

0.6

0.8

1.0

00 6 12 18 24 30 3633 399 15 21 273 42

Mos

Continuum of care



FULVFULV BevBev

FULVFULV IriIri BevBev

LL

TML

OxOx Aflib.Aflib. Ramuc.Ramuc.

IriIri PanPan Ablative Rx

Ablative Rx

What to do when all else has failed?

CapecCapec CetCet SurgerySurgery

FULVFULV BevBev


Inhibition of neoangiogenesis

Inhibition of tumor microenvironment

signaling

Inhibition of proliferation

Regorafenib: Oral Multikinase Inhibitor Targeting Multiple Tumor Pathways

Wilhelm SM, et al. Int J Cancer. 2011;129:245-255. Mross K, et al. Clin Cancer Res. 2012;18:2658-2667. Strumberg D, et al. Expert Opin Invest Drugs. 2012;21:879-889.

KITPDGFR

RET

PDGFR-βFGFR

VEGFR1-3TIE2

RegorafenibF

Cl

F

F F

OO

O

NH

NH

NH

N

BiochemicalActivity

Regorafenib IC50 Mean ±SD nmol/L (n)

VEGFR1 13 ± 0.4 (2)

Murine VEGFR2 4.2 ± 1.6 (10)

Murine VEGFR3 46 ± 10 (4)

TIE2 311 ± 46 (4)

PDGFR-β 22 ± 3 (2)

FGFR1 202 ± 18 (6)

KIT 7 ± 2 (4)

RET 1.5 ± 0.7 (2)

RAF-1 2.5 ± 0.6 (4)

B-RAF 28 ± 10 (6)

B-RAFV600E 19 ± 6 (6)


Phase III CORRECT: Regorafenib After Failure of Standard Therapy in mCRC

Primary endpoint: overall survival

Prior systemic, anticancer therapies (palliative)

– 1-2 prior lines: 26%

– 3 prior lines: 26%

– ≥ 4 prior lines: 48%

Patients with progression

after all available standard therapy

(N = 760)

Arm A: Regorafenib 160 mg po qd + BSC3 wks on, 1 wk off

(n = 505)

Arm B: Placebo + BSC3 wks on, 1 wk off

(n = 255)

Grothey A, et al. Lancet. 2013;381:303-312.

2:1


Regorafenib After Failure of Standard Therapy in mCRC (CORRECT): OS, PFS

Primary endpoint met prespecified stopping criteria at second interim analysis (1-sided P ≤ .009279 at approximately 74% of events required for final analysis)

100

50

25

0

75

Mos From Randomization

OS

(%

)

HR: 0.77 (95% CI: 0.64-0.94;P = .0052)

Regorafenib Placebo

Median OS, mo 6.4 5.0

IQR 3.6-11.8 2.8-10.4

Placebo (n = 255)Regorafenib (n = 505)

Grothey A, et al. Lancet. 2013;381:303-312.

0 2 4 6 8 10 12 14

Regorafenib Placebo

Median PFS, mo 1.9 1.7

IQR 1.6-3.9 1.4-1.9

0 2 4 6 8 10 12

Mos From Randomization

100

50

25

0

75

PF

S (

%)

Placebo (n = 255)Regorafenib (n = 505)

HR: 0.49 (95% CI: 0.42-0.58; P < .0001 )


Continuum of care



FULVFULV BevBev

FULVFULV IriIri BevBev Regor.Regor.

LL

TML

Continuum of care



FULVFULV BevBev

FULVFULV IriIri BevBev Cetuxi.Cetuxi.

wtRAS(1)

2. Cunningham, D, NEJM, 2004

Continuum de tratamiento en mCRC no resecableKRAS no mutado

Bev+CAPOX x6Bev+Cap

Bev+CAPOXFOLFIRI+Bev

Cet+/-IriRegorafenib

CAIRO-3 (2013) TML (2012) C0.17 (2008) CORRECT (2012)

Continuum of care



FULVFULV BevBev


Capecitabina

Capecitabina

Capecitabina

Afliberce

tp

Continuum of care



FULVFULV BevBev


Capecitabina

Capecitabina

Capecitabina

CetuxiCetuxi

Cetuxim

Continuum of careKRAS mutated

Bev+CAPOX x6Bev+Cap

Bev+CAPOXFOLFIRI+Bev

Regorafenib

What about patient related issues?

What to do with a patient only able to tolerate some chemo.

Continuum of careKRAS wt, un-fit

Bev+CapBev+FOLFOX

FOLFIRI+BevCet+/-Iri

Regorafenib

AVEX (2013)

Continuum of careKRAS mutated, un-fit

Bev+CapBev+FOLFOX

FOLFIRI+Bev

Regorafenib

Do THESE guidelines, guide?

Maybe, but a more comprehensive strategy NEEDS to be thought –out

BEFORE therapy initiation.

Conclusions

Clinical presentation

Treatment toolkit

Rules of engagement

What WE desire

Patient preference

Tumor biology

Cost

Patient access

As of today, clinical practice guidelines for mCRC are but a

repository of treatment options filled with soft statements aimed more to convince insurers rather

than to truly guide clinicians.

CORREGIDA: Tratamiento de cáncer de colon metastásico: de las guías de práctica, genómica a la...

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