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NOVITÀ E SEQUENZE TERAPEUTICHE NELLE NEOPLASIE DEL COLON-RETTO :

ALGORITMO TERAPEUTICO

FEDERICA MORANO

ISTITUTO NAZIONALE DEI TUMORI

MILANO

(2)

Yoshino et al, Ann Oncol 2018

ESMO GUIDELINES (PAN-ASIAN ADAPTED)

(3)

Yoshino et al, Ann Oncol 2018

ESMO GUIDELINES (PAN-ASIAN ADAPTED)

(4)

WHAT DOES INFLUENCE TREATMENT CHOICES IN MCRC?

WHAT DOES INFLUENCE TREATMENT CHOICES IN mCRC?

Patient characteristics

Tumor characteristics comorbidities

Age

Prior Adjuvant treatment

ECOG PS

Tumor burden Resectability

Tumor location

Molecular characteristics

Patient preference RAS

QoL Toxicity profile

MSI-High HER2

BRAF

(5)

Selection Improvement

Dienstmann. ASCO Ed Book, 2018

(6)

Arnold D et al, Annal Oncol 2016

(7)

Negative selection (mutually exclusive)

• KRAS/ NRAS/ HRAS exon 2, 3, 4 wild-type -55%

• No BRAF V600E mutation -8%

• (No HER-2 amplification -2.5%)

Further exclusion criteria (not mutually exclusive)

• Right-sided cancers 30 %

THE “PERFECT” CANDIDATE FOR FIRST-LINE EGFR mABS

Grothey, WGCI 2019

(8)

48%

17%

9%

6%

11%

9%

Cremolini et al, Ann Oncol 2017

42%

8%

50%

RAS and BRAF wild-type RAS mutations

BRAF V600E mutations

HER2 amplification MET amplification ALK/ROS1/RET/NTRKs fusions

PI3KCA/AKT/PTEN mutations

Low frequency RAS mutations

Unknown PRESSING Panel : genomic mechanisms of intrinsic resistance to anti-EGFR

NEGATIVE HYPERSELECTION FOR ANTI-EGFRs

(9)

Morano et al, J Clin Oncol 2019

NEGATIVE HYPERSELECTION FOR ANTI-EGFRs IN THE VALENTINO STUDY

In red: point mutations; in green: amplification; in purple: gene fusions; in blue: high microsatellite instability; in black: right-sided primary tumor

A subgroup of 199 RAS/BRAF wt evaluable pts had available tumor tissue for this pre-specified exploratory analyses.

Among these, 49 pts had a PRESSING-positive tumor.

(10)

PROGNOSTIC ANALYSES ACCORDING TO SIDEDNESS AND PRESSING PANEL

Morano et al, J Clin Oncol 2019

(11)

PREDICTIVE ANALYSES ACCORDING TO SIDEDNESS AND PRESSING PANEL

Morano et al, J Clin Oncol 2019

(12)

WHAT DOES INFLUENCE TREATMENT CHOICES IN MCRC?

WHAT DOES INFLUENCE TREATMENT CHOICES IN mCRC?

Patient characteristics

Tumor characteristics comorbidities

Age

Prior Adjuvant treatment

ECOG PS

Tumor burden Resectability

Tumor location

Molecular characteristics

Patient preference RAS

QoL Toxicity profile

MSI-High HER2

BRAF

(13)

One size doesn’t fit

all!

UNFIT for combo and/or elderly patients

FIT for combo

MONOCHEMO TRIPLET

DOUBLET

(14)

Previously untreated mCRC, age 70 years

N = 280

Capecitabine 1000 mg/m2BID days 1–14, q21d Capecitabine 1000 mg/m2BID

days 1–14, q21d +

Bevacizumab 7.5 mg/kg day 1, q21d Randomize

1:1

Cunningham et al, Lancet Oncol 2013

THE AVEX TRIAL

(15)

PANDA PHASE 2 STUDY

RANDOM

1st line unresectable

mCRC

≥70 yrs

FOLFOX + PANI

up to 12 cycles

PANI maintenance

5FU + PANI

up to 12 cycles

PANI

maintenance PR OG RE SS IO N

Primary endpoint: median PFS

p0: mPFS < 6.0 months (literature-based), mPFS > 9.5 months Design: Fleming single-stage

Alpha error: 0.05, Beta error: 0.10

90 patients per arm had to be enrolled

(16)

R 1:1

FOLFOX + bev*

FOLFOXIRI + bev*

5FU/bev

PD1

5FU/bev

PRIMARY ENDPOINT: Progression Free Survival 2

FOLFIRI + bev*

5FU/bev

PD2

PD1 FOLFOXIRI +

bev*

5FU/bev

PD2

Arm A

Arm B

* Up to 8 cycles

Cremolini C et al, ASCO 2018

TRIBE2 STUDY

(17)

TRIPLETE trial

Primary endpoint: Objective Response Rate

Borelli et al, ESMO Open 2018

This trial is evaluating chemo intensification

when choosing an anti-EGFR-based regimen

(18)

Phase II randomized AtezoTRIBE trial

Stratification factors:

• Center

• PS 0 vs 1-2;

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

• Previous adjuvant CT

Primary endpoint: PFS

Target accrual: 201 patients

30 Italian Centers

(19)

What about Maintenance?

WE WANT YOU!

(20)

THE VALENTINO STUDY

Pietrantonio et al, JAMA Oncol 2019

Primary objective: the real data

RAS wt untreated unresectable

mCRC pts N=224

R 1:1

Diseaseprogression/unacceptabletoxicity/consentwithdrawal

FOLFOX-4

5-FU/LV

Panitumumab

FOLFOX-4 up to 8 cycles

FOLFOX-4 up to 8 cycles

Maintenance therapy Induction therapy

Stratification factors:

Center Prior adjuvant

(Y/N) N. metastatic sites

(1/>1)

oxaliplatin 85 mg/m2 d1 q14 LV 200 mg/m2 d1,2 q14 5FU bolus 400 mg/m2 d1,2 q14 5FU pvi 600 mg/m2 d1,2 q14

LV 200 mg/m2 d1,2 q14 5FU bolus 400 mg/m2 d1,2 q14 5FU pvi 600 mg/m2 d1,2 q14

panitumumab 6 mg/kg d1 q14

Arm B

Arm A

(21)

THE VALENTINO STUDY: PFS

Pietrantonio et al, JAMA Oncol 2019

(22)

ONGOING: THE PANAMA STUDY

• Primary endpoint: PFS

• Target: 218 events

• Sponsor: AIO – Germany

• Clinical Trial ID: NCT01991873

PD

PD 5FU +

pani

5-FU

FOLFOX+pani

12 weeks

PR/SD

R

(23)

Overall study design

Cohort 1 BRAFmut

Cohort 2 BRAFwt

R

R

5-FU/LV + cetuximab + vemurafenib

FP + bevacizumab + atezolizumab FP + bevacizumab

FP + bevacizumab Induction treatmenta,b Biomarker-driven maintenance treatment

Cohort 3 HER2+

FP + bevacizumab

Capecitabine + trastuzumab + pertuzumab

R

Cobimetinib + atezolizumab FP + bevacizumab Cohort 4

HER2– BRAFwt R

T R E A T M E N T U N T I L P D Follow-up

aKey eligibility criteria: histologically confirmed mCRC; measurable, unresectable disease (RECIST 1.1); no prior chemotherapy for mCRC; age 18 years; ECOG PS 2

bPatients with disease progression following Induction treatment can receive further treatment at the discretion of their physician

Primary objective: Progression-free survival (PFS; RECIST v1.1) measured from randomization in each maintenance treatment cohort

Secondary objectives: Overall survival (OS); overall response rate (ORR); disease control rate (DCR); time to treatment response (TTR); duration of response (DoR); change in ECOG performance status; safety

FOLFOX + bevacizumab 8 cycles (16w)

or FOLFOX + bevacizumab 6 cycles (12w)

then 5-FU/LV + bevacizumab 2 cycles (4w)

CR PR SD

MODUL: MAINTENANCE MULTI-COHORT TRIAL

Grothey et al, ESMO Congress 2018

(24)

Grothey et al, ESMO Congress 2018

MODUL: PRIMARY ENDPOINT - PFS

(25)

WHAT DOES INFLUENCE TREATMENT CHOICES IN MCRC?

WHAT DOES INFLUENCE TREATMENT CHOICES IN mCRC?

Patient characteristics

Tumor characteristics comorbidities

Age

Prior Adjuvant treatment

ECOG PS

Tumor burden Resectability

Tumor location

Molecular characteristics

Patient preference RAS

QoL Toxicity profile

MSI-High ?

BRAF

(26)

WHAT DOES INFLUENCE TREATMENT CHOICES IN mCRC?

(27)

REGO or TAS? THAT’S THE QUESTION!

Considerations:

✓ No predictive markers for benefit, nor clearly differential patient characteristics

✓ Different safety pattern: Trifluridine/tipiracil: more favourable safety patterns, but what if compared to lower starting dose of regorafenib

REGO TAS

(28)

Siravegna et al, Nat Med 2015 Misale et al, Nature 2012

Emergence of RAS mutations as a dynamic mechanism of acquired resistance

(29)

CRICKET TRIAL

Cremolini et al, JAMA Oncol 2018

Phase II, non comparative study.

Target accrual: 27 pts with RAS/BRAF wt mCRC

FOLFIRI/FOLFOXIRI + Cetuximab

FOLFOX/XELOX/

FOLFOXIRI + Bevacizumab

Irinotecan + Cetuximab

PD PD

1

st

line ≥ 6 mos 2

nd

line ≥ 4 mos CRICKET study

• At least a RECIST 1.1 partial response

• 1st-line PFS ≥6 months

• PD to 1st-line cetuximab within 4 weeks after the last cetuximab administration

• Time between the end of 1st- line therapy and the start of 3rd-line ≥4 months

Study treatment:

- Irinotecan 180 mg/sqm iv - Cetuximab 500 mg/sqm iv

Statistics: Primary endpoint: Response Rate

H0: RR=5%; H1: RR=20%; α error: 0.05; β error: 0.20 Sample size: 27 patients

At least 4 responses to deem the rechallenge strategy promising

(30)

All reported in patients with RAS wt cfDNA at baseline of rechallenge

CRICKET TRIAL: PRIMARY END-POINT MET!

Cremolini et al, JAMA Oncol 2018

(31)

✓ Detection of RAS mutations (12/25, 48%) on ctDNA at baseline of rechallenge strategy predicits no response and worse clinical outcome.

✓ No BRAF or PI3KCA mutations were found.

Dynamics of response according to RAS status on ctDNA

Progression-free Survival Overall Survival

Cremolini et al, JAMA Oncol 2018

CRICKET TRIAL: PREDICTIVE ROLE OF ctDNA

(32)

Study

Phase, Prospective/

retrospective

Treatment strategy Pts.

(N) RAS/BRAF Liquid Biopsy

Selection Status

A-REPEAT

II Anti-EGFR -> CT +

Pmab 33 RAS wt NO Recruiting

CAVE

II

CT + anti-EGFR -> II line -> Avemab +

Cmab

75 RAS wt

MSS/MSI-H No Recruiting

CHRONOS

II CT + anti-EGFR

-> CT -> Pmab 27 RAS/BRAF wt Yes Recruiting

FIRE-4

III

FOLFIRI+Cmab (+/- Bmab)

->CT+Bmab->

CT+Cmab vs Rego

230 RAS wt NO Recruiting

NCT03524820

II

CT + anti-EGFR -> CT ->CT +/-

Cetuximab

60 RAS wt NO Recruiting

RECHALLENGE: ONGOING TRIALS

(33)

Overman et al, Lancet Oncol 2017 Andrè et al, J Clin Oncol 2018

IO in MSI-HIGH PRETREATED PTS: CheckMate-142 study

Nivolumab 74 48 41 32 17 12 12 11 6 3 0

Nivolumab

Months No. at Risk

Nivolumab + ipilimumab119 95 86 78 39 12 11 10 3 0 0 100

90 80 70 60 50 40 30 20 10 0

0 3 6 9 12 15 18 21 24

Progression-free survival(%)c

27 30

Nivolumab + ipilimumab

100 90 80 70 60 50 40 30 20 10 0

0 3 6 9 12 15 18 21 24

Overall Survival (%)

27 30 33

Months

119 113 107 104 78 33 19 17 11 0 0 0

Nivolumab + ipilimumab

74 64 59 55 37 21 19 17 11 6 1 0

Nivolumab

Nivolumab +

ipilimumaba,d Nivolumab1,e,f 9-mo rate (95% CI), % 87 (80.0, 92.2) 78 [66.2, 85.7]

12-mo rate (95% CI),

% 85 (77.0, 90.2) 73 [61.5, 82.1]

Nivolumab +

ipilimumaba,b Nivolumab1,e,f 9-mo rate (95% CI), % 76 (67.0, 82.7) 54 [41.5, 64.5]

12-mo rate (95% CI],

% 71 (61.4, 78.7) 50 [38.1, 61.4]

12m-OS rate Rego: 24%

TAS-102: 27%

(34)

Bringing IO to MSS pts

✓ MSS mCRC pts

✓ high MGMT promoter metilation

✓ low MGMT IHC-expression

✓ TMZ-based treatment

MSI-like status!

MSI-like status!

RP SD

SD

RP RP

Bes t R es p on se

A new rationale for sequential strategy: TMZ → anti-PD1/PD-L1

Germano et al, Nature 2017

(35)

Studio ARETHUSA - IFOM-CPT002/2018/PO001 Protocol v1.0 06-08-2018

Confidential

19 4.2 Trial Diagram

Phase II proof-of-concept studies

COURTESY OF SALVATORE SIENA AND SILVIA MARSONI

(36)

Phase II proof-of-concept studies

P D

C1 C2

CT Scan:

mCRC patients

•ECOG PS 0-1

•≥ 2 prior lines of treatment for advanced disease Centrally

confirmed:

•MSS

•Negative IHC for MGMT

•MGMT methylation

I P I

- TMZ: temozolomide 150 mg/sqm daily on days 1-5, every 4 weeks.

- NIVO: nivolumab 480 mg i.v. every 4 weeks.

- IPI: ipilimumab 1 mg/Kg i.v. every 8 weeks.

27 patients with benefit from TMZ enrolled

C1 C2 C3

CR PR SD

PD

OUT OF STUDY

Rebiopsy (optional)

T M Z T

M Z

T M Z T

M Z

T M Z N

I V O

N I V O

N I V O I

P

MAYA STUDY

I

PI: Filippo Pietrantonio

(37)

federica.morano@istitutotumori.mi.it

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