MEDIZINISCHE KLINIK UND POLIKLINIK III DIREKTOR: PROF. … · Yamauchi et al. Gut. 2012...

KLINIKUM DER UNIVERSITÄT MÜNCHEN®

21.03.20181 MEDIZINISCHE KLINIK UND POLIKLINIK III

Sidedness is very important to colorectal cancer treatment !

PD Dr. med. Dominik Paul Modest

Department tof Medicine III

University Hospital Munich, LMU Munich

MEDIZINISCHE KLINIK UND POLIKLINIK III

DIREKTOR: PROF. DR. DR. M. VON BERGWELT



Stintzing S et al Eur J Cancer. 2017 Oct;84:69-80



Mid and Hindgut – a continous change from right to leftData on gentics

Yamauchi et al. Gut. 2012 Jun;61(6):847-54



What is the differenceOverview

Salem et al Oncotarget, 2017, Vol. 8, (No. 49), pp: 86356-86368



Summary 1

PTL differs in molecular signature,

Without single black/white information

PTL is prognostic

WHAT ELSE?



Primary tumor locationand OS

Arnold D. et al Ann Oncol. 2017 Aug 1;28(8):1713-1729



Primary tumor locationOS data from FIRE-3 and CLAGB80405 for LEFT Sided Tumors

Holch et al Eur J Cancer. 2017 Jan;70:87-98.

40

30

20

0

Me

dia

n O

S (

mo

nth

s)

Phase III CALGB/SWOG 804051,2(retrospective analysis of patients with left-sided RAS wt mCRC)

10

39.3

32.6

+6.7 monthsHR=0.77

(p=0.05)

Bevacizumab + CT

(n=152)

Cetuximab + CT

(n=173)

38.3

Bevacizumab + CT

(n=149)

Cetuximab + CT

(n=157)

40

30

20

0

Me

dia

n O

S (

mo

nth

s)

Phase III FIRE-31–3

(retrospective analysis of patients with left-sided RAS wt mCRC)

28.0

10

+10.3 monthsHR=0.63

(p=0.002)



Primary tumor locationand ORR




Meta-Analysis ORR data (only H2H-trials)

Holch JW et al. Eur J Cancer 2016



PHASE II TRIAL DESIGN

mCRC

Unresectable

1st-line

WT RAS**

Age ≥ 18yrs

ECOG PS 0-1

(n=96)

Randomization:

6/2011 - 1/2017

R

Treatment until PD, resectability,

or to maximum 12 cycles

mFOLFOXIRI +panitumumab 6 mg/kg

Q2WN=63

Irinotecan 150 mg/m2***, oxaliplatin 85 mg/m2,

LV 200 mg/m2, 5-FU 3000 mg/m2 CIV;

Planned safety analysis after 10 patients treated in panitumumab arm

FOLFOXIRI Q2WN=33

2:1

If resectable:

Surgery, then

protocol treatment to

maximum 12 cycles

If CR/PR/SD after 12 cycles:

re-induction

(same combination)

recommended on PD

Strata:

Cohort 1: histologically confirmed and definitively inoperable or unresectable

Cohort 2: chance of secondary resection with curative intent (*pretreatment liver/tumor biopsy)

*

*

• 21 active centers in Germany***Trial started with irinotecan 165 mg/m2 (n=2), first amendment to 130 mg/m2

(n=9) and final amendment to 150 mg/m2 (n=52)

1 cycle FOLFXIRI prior R was allowed



FOLFOXIRI plus PanitumumabData from the VOLFI trial

Geissler M. ESMO 2017

FOLFOXIRI + Panitumumab

FOLFOXIRIR

EVALUATION OF RESPONSESIDEDNESS + GENOTYPE

mFOLFOXIRI +

panitumumab

mFOLFOXIRI +

panitumumab

FOLFOXIRIFOLFOXIRI

left right

ORR (%)

10

20

30

40

50

60

70

80

90

100

90,6

68,0

60,0

37,5

mFOLFOXIRI +

panitumumab

mFOLFOXIRI +

panitumumab

FOLFOXIRIFOLFOXIRI

super wild-type

ORR (%)

BRAF mutation

10

20

30

40

50

60

70

80

90

100

86,0

64,7

71,4

22,2

MacBeth FOLFOXIRI plus cetuximab

-100

-80

-60

-40

-20

0

20

40

60

80

100

Arm A (N pts= 56): median DoR 49%

Arm B (N pts= 53): median DoR 56%

Distribution of DoR

Falcone A, ESMO2016

No declaration of

RPT/LPT, but not really

important…



First-line treatment of mCRC

RAS mutant

50-55%

RAS wild-type

45-50%

RAS wild-type

Tumor location

Right sidedCoecum, C. ascendens

hepatic flexure

C. transversum

FOLFOX or FOLFIRI

+

anti-VEGF

Left-sidedSplenic flexure

C. descendens, sigma

rectum

FOLFOX or FOLFIRI

+

anti-EGFR

RAS

Mutational analysis

Goal ORR?



Association of response and resection

Folprecht Ann Oncol 2005



How to treat right-sided RAS WT mCRC?

Intensifiy

first-line

treatment!

Use FOLFOX

instead of

FOLFIRI

Modify

treatment

with „toolbox“



MAVERICC trial

FOLFOX + Bevacizumab

FOLFIRI + BevacizumabR



MAVERICC trialFOLFOX better on right sided tumors?

FOLFOX + Bevacizumab




FOLFOXIRI plus BevacizumabData from the TRIBE trial

FOLFOXIRI + Bevacizumab




Treatment of right sided tumorsSIRFLOX data

Van Hazel et al WCGIC 2017



Treatment of right sided tumorsSIRFLOX OS data

Van Hazel et al WCGIC 2017



Summary

Left sided, RAS wild-type tumors should be treated with chemotherapy plus anti-EGFR

RAS mutant tumors and right sided tumors may be treated with chemotherapy plus anti-VEGF. If

ORR is the primary goal, the application of chemotherapy plus anti-EGFR should be discussed.

For right sided, RAS wild-type tumors, anti-EGFR stays to be a valid option in further-line treatment



Sequence in RAS WT: how it could be done:

RAS/BRAF WT

CTX + EGFR CTX + Bev CTX + EGFR

CTX + VEGFCTX + VEGFCTX + VEGF CTX + VEGF

(CTX) + EGFRTAS 102

RegoEGFR

TAS 102

RegoEGFR

TAS 102

RegoEGFR TAS 102/ Rego

HER2 (if pos.) HER2 (if pos.)

TAS 102

RegoEGFR

HER2 (if pos.)

LPT RPT RPT- Conversion


21.03.201825 MEDIZINISCHE KLINIK UND POLIKLINIK IIIKLINIKUM DER UNIVERSITÄT MÜNCHEN®

MEDIZINISCHE KLINIK UND POLIKLINIK III

MEDIZINISCHE KLINIK UND POLIKLINIK III DIREKTOR: PROF. … · Yamauchi et al. Gut. 2012...

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