Scelta della I linea di trattamento nel paziente RAS e BRAF wt

Scelta della I linea di trattamento nel paziente RAS e BRAF wt

Tutor: A. Inno

Congresso Nazionale AIOM Giovani 2017 Perugia, 7-8 Luglio 2017

Federica Marmorino Polo Oncologico

Azienda Ospedaliero-Universitaria Pisana Università di Pisa

RAS/BRAF wt

RAS mut

BRAF mut

Molecular characterization

Upfront treatment has a crucial “mission”

Achieve disease control Allow further interventions (surgery and other systemic

treatments)

Patient clinical characteristics

(age, PS, patients’ expectations and motivation, comorbidities, prior adjuvant treatment)

Main ingredients according to ESMO guidelines

Treatment characteristics

(QoL, toxicity profile, flexibility of tx administration, socioeconomic factors)

Tumour clinical characteristics

(Tumour burden and localisation, resectability, Related symptoms, tumour biology)

Van Cutsem et al, Ann Oncol ‘16 a) According to medical condition not due to malignant disease

Patient

The ‘major’ driver for treatment choice

Goal / condition Molecular Preferred 1st line regimen

„frail“, or chosen sequential

treatment

no BRAF ! Cape or FU + beva

The modulation of chemo intensity

TRIBE¹ n=252

OPAL² n=97

STEAM³ n=93

MOMA⁴ n=232*

CHARTA⁵ n=125

Regimen FOLFIRI/Bev +/- Oxa

FOLFOXIRI/

Bev  FU/Bev maintenance

FOLFOXIRI/

Bev vs FOLFIRI/Bev

FOLFOXIRI/

Bev

 Bev ± metroCT

FOLFOX/Be v

± IRI

Response rate 65% 64% 60% 63% 70%

Disease control rate 90% 87% 91% 91% N/A

Median PFS, months 12.3 11.1 11.7 9.5 12.0

Median OS, months 29.8 32.2 Too early Too early Too early

1. Cremolini et al. Lancet Oncol 2015 2. Stein et al. Br J Cancer 2015; 3. Bendell et al. ASCO GI 2016 4. Falcone et al. ESMO 2016; 5. Schmoll et al. ESMO 2016

FOLFOXIRI + bev: consistent results

Grade 3/4 Adverse Events, %

TRIBE¹ n=252

OPAL² n=97

STEAM³ n=93

MOMA⁴ n=232

CHARTA⁵ n=125

Diarrhoea 18.8% 11% 10% 13% 16%

Stomatitis 8.8% 4% 3% 4% 3%

Neutropenia 50.0% 26% 57% 52% 21%

Hypertension 5.2% 3% 22% 4% 7%

VTE events 7.2% 5.0% 7% 3% 2%

1. Loupakis et al. N Engl J Med 2013 2. Stein et al. Br J Cancer 2015; 3. Bendell et al. ASCO GI 2017 4. Falcone et al. ESMO 2016; 5. Schmoll et al. ASCO GI 2017

FOLFOXIRI + bev: safety results

FOLFOXIRI plus bev: WHO?

Patient selection

• NEVER

• NEVER

• NEVER in the case of contraindications to single drugs

Patients previously exposed to oxa-based adjuvant are NOT the optimal candidates

Loupakis et al. N Engl J Med 2014

N

FOLFIRI + bev Median OS

FOLFOXIRI + bev

Median OS

HR [95% CI] p

ITT population 508 25.8 29.8 0.80 [0.65-0.98] 0.030

RAS and BRAF

evaluable 357 24.9 28.6 0.84 [0.66-1.07] 0.159

RAS and BRAF wt 93 33.5 41.7 0.77 [0.46-1.27]

0.522*

RAS mutated 236 23.9 27.3 0.88 [0.65-1.18]

BRAF mutated 28 10.7 19.0 0.54 [0.24-1.20]

* p for interaction

Treatment effect in molecular subgroups - OS

Cremolini et al, Lancet Oncol ’15

Events Median 28 41.7 months 32 33.5 months 88 27.3 months 93 23.9 months 14 19.0 months 11 10.7 months RAS and BRAF wild-type – arm B RAS and BRAF wild-type – arm A RAS mutant – arm B RAS mutant– arm A

BRAF mutant – arm B BRAF mutant– arm A

Treatment effect in molecular subgroups - OS

Cremolini et al, Lancet Oncol ’15

Van Cutsem et al, Ann Oncol ‘16

GOAL

Tumour clinical characteristics

Doublet+ antiEGFR Or

Doublet+ BV

Doublet+ antiEGFR Or

Triplet+ BV

FIRE-3 and PEAK: Depth of response

Stintzing et al, Lancet Oncol ‘16

p<0.0001

CI, confidence interval; DoR, duration of response;

DpR, depth of response; ETS, early tumor shrinkage;

HR, hazard ratio; TTR, time to response

Tumor Response-Related Efficacy – RAS WT Population

Panitumumab + mFOLFOX6 (n = 88) Bevacizumab + mFOLFOX6 (n = 82)

Median DoR, months (95% CI) 11.4 (10.0, 16.3) 9.0 (7.6, 9.5)

HR (95% CI); P value 0.59 (0.39, 0.88); 0.011

Median TTR, months (95% CI) 2.3 (1.9, 3.7) 3.8 (2.1, 5.7)

HR (95% CI); P value 1.19 (0.81, 1.74); 0.37

Median DpR, months (Q1, Q3) 65.0 (45.7, 89.5) 46.3 (29.5, 63.3)

P value 0.0018

Mean (95% CI) Percentage Change From Baseline In Tumor Load Over Time

0

Mean Change From Baseline, %

-20 -40 -60 -80 -100

0 8 16 24 32 40 48 56 64 72 80 Pmab + mFOLFOX6 88 80 70 63 53 42 42 27 25 17 17 Bmab + mFOLFOX6 81 74 66 57 45 36 26 22 13 11 8

Weeks Bmab + mFOLFOX6

Pmab + mFOLFOX6

Rivera F, et al. Eur J Cancer. 2015;51(Suppl 3): Abstract 2014.Rivera et al, ECC ‘15

Intensification of the chemotherapy backbone: WHEN?

Pooled analysis of patients with liver-limited disease (LLD) from FOIB, TRIBE and MOMA

Characteristics,

% patients n=205

Synchronous metastases 90%

≥4 metastases 61%

Bilobar distribution 79%

Larger metastasis >5cm 42%

Patients with clearly initially unresectable LLD, not selected with conversion

intent n=205

RECIST response n=137 (69%)

R0/R1 resection n=75 (37%)

Cremolini et al. Eur J Canc ’17

R0/R1 resected

(n=75)

R0 resected

(n=63) Median PFS,

months 18.1 18.3

5-year PFS rate 10% 12%

Median OS,

months 44.3 56.6

5-year OS rate 42% 43%

MACBETH trial

R 1:1

mFOLFOXIRI + cetuximab^§

up to 8 cycles

cetuximab^§ until PD

bevacizumab^§ until PD mFOLFOXIRI +

cetuximab^§

up to 8 cycles

mCRC pts:

 Unresectable disease

 Previously untreated for mts disease

 RAS and BRAF wt*

Arm AArm B

Phase II randomized non-comparative trial

INDUCTION MAINTENANCE

Primary endpoint: 10m-PFS

Antoniotti, WGI 2016

Best Response, %

Arm A N = 59

Arm B N = 57

Overall N = 116

Complete Response 5% 4% 4%

Partial Response 63% 72% 67%

Response Rate 67.8% 75.4% 71.6%

Stable Disease 24% 14% 19%

Disease Control Rate 92% 89% 91%

Progressive Disease 3% 4% 3%

Not Assessed 5% 7% 6%

Secondary endpoint: Response rate (mITT)

Out of 109 pts evaluable for RECIST response, RR and DCR were 76% and 96%, respectively.

Antoniotti, WGI 2016

TRIPLETE study

R

RAS and BRAF wt mCRC pts

1st line unresectable

mFOLFOX6+pani

(up to max 12 cycles)

mFOLFOXIRI+pani

(up to max 12 cycles)

5-FU/LV +Pani

5-FU/LV +Pani

PD

INDUCTION MAINTENANCE

Phase III random

Stratification factors:

• PS 0-1 vs 2;

• primary tumor location (right vs left or rectum);

• liver-only metastases.

Primary endpoint: Response Rate

Patient

“Decision drivers” for First Line in RAS/BRAF wt

Goal

Right versus Left…colon

Prognostic impact

1.437.846 patients in 66 studies (stage IIV)

HR: 0.82 [95%CI: 0.79-0.84], p<0.001

No different effect according to stage

Is a better selection for anti-EGFR vs Beva possible?

Predictive impact

FIRE 3 CALGB PEAK

RAS wt

FOLFIRI+

CET FOLFIRI+

BEV RAS

wt

CHEMO+

CET CHEMO+

BEV RAS

wt

FOLFOX+

PAN FOLFOX+

BEV

Chemo+anti-EGFR vs Chemo+Bev

Right versus Left: metanalysis of head-to-head trials - OS

Left-sided

Right-sided

Holch et al, EJC 2016

Right versus Left: summary

1) Prognostic impact

Right-sided tumours have worse prognosis

2) Predictive impact

More benefit from anti-EGFRs in left- than right-sided tumours

1st line treatment of mCRC: an evidence-based algorithm

modified from Cremolini et al, Nat Rev Clin Oncol ‘17 Side

The dark «SIDE»

BRAF-like signature PIK3CA mutations

dMMR CIMP-high Low AREG-EREG

expression

CMS1(Immune)

HER-2 overexpression

High AREG-EREG expression

EGFR amplification

Lee et al., Br J Can ’16 Missiaglia et al., Ann Oncol ’14 Guinney et al., Nat Med ’15 Laurent-Puig et al., ESMO ’16 Puzzoni et al, ASCO GI ’17 Pietrantonio et al, JNCI ‘17 miR-31-3p high

miR-31-3p low

Right versus Left in RAS and BRAF wt: Molecular make-up

EGFR promoter methylation

ALK/ROS1/NTRK rearrangements

Her2

MSI

CMS

New ingredients: molecular markers

RAS wt pts screened for advanced lines protocols, previously treated

with anti-EGFR N=114

HER-2 ampl N=14

HER-2 non ampl N=110

MD Anderson experience

HER-2 ampl N=37

HER-2 non ampl N=62

Cohort 1 Cohort 2

PFS during anti-EGFR PFS during anti-EGFR

Raghac et al, ASCO ‘16

Innocenti et al, ASCO 2017

MSI in mCRC

Consensus molecular subtyping (CMS)

Guinney et al, Nat Med 2015

Stintzing et al., ASCO’17

CMS in FIRE3 e CALGB

Lenz et al., ASCO’17

HER 2

MSI

CMS

Molecular markers Clinical considerations

A very special thanks to

A very special thanks to

federica.marmorino@gmail.com