NOVITÀ E SEQUENZE TERAPEUTICHE NELLE NEOPLASIE DEL COLON-RETTO :
ALGORITMO TERAPEUTICO
FEDERICA MORANO
ISTITUTO NAZIONALE DEI TUMORI
MILANO
Yoshino et al, Ann Oncol 2018
ESMO GUIDELINES (PAN-ASIAN ADAPTED)
Yoshino et al, Ann Oncol 2018
ESMO GUIDELINES (PAN-ASIAN ADAPTED)
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
Selection Improvement
Dienstmann. ASCO Ed Book, 2018
Arnold D et al, Annal Oncol 2016
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
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
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.
PROGNOSTIC ANALYSES ACCORDING TO SIDEDNESS AND PRESSING PANEL
Morano et al, J Clin Oncol 2019
PREDICTIVE ANALYSES ACCORDING TO SIDEDNESS AND PRESSING PANEL
Morano et al, J Clin Oncol 2019
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
One size doesn’t fit
all!
UNFIT for combo and/or elderly patients
FIT for combo
MONOCHEMO TRIPLET
DOUBLET
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
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
R 1:1
FOLFOX + bev*
FOLFOXIRI + bev*
5FU/bev
PD1
5FU/bev
PRIMARY ENDPOINT: Progression Free Survival 2
FOLFIRI + bev*
5FU/bevPD2
PD1 FOLFOXIRI +
bev*
5FU/bevPD2
Arm A
Arm B
* Up to 8 cycles
Cremolini C et al, ASCO 2018
TRIBE2 STUDY
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
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
What about Maintenance?
WE WANT YOU!
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
THE VALENTINO STUDY: PFS
Pietrantonio et al, JAMA Oncol 2019
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/SDR
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
Grothey et al, ESMO Congress 2018
MODUL: PRIMARY ENDPOINT - PFS
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
WHAT DOES INFLUENCE TREATMENT CHOICES IN mCRC?
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
Siravegna et al, Nat Med 2015 Misale et al, Nature 2012
Emergence of RAS mutations as a dynamic mechanism of acquired resistance
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
stline ≥ 6 mos 2
ndline ≥ 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
All reported in patients with RAS wt cfDNA at baseline of rechallenge
CRICKET TRIAL: PRIMARY END-POINT MET!
Cremolini et al, JAMA Oncol 2018
✓ 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
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
IICT + 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
IIIFOLFIRI+Cmab (+/- Bmab)
->CT+Bmab->
CT+Cmab vs Rego
230 RAS wt NO Recruiting
NCT03524820
IICT + anti-EGFR -> CT ->CT +/-
Cetuximab
60 RAS wt NO Recruiting
RECHALLENGE: ONGOING TRIALS
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%
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
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
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