NOVITA’ IN TEMA DI TERAPIA
DEL CARCINOMA DEL COLON-RETTO
Congresso AIOM Giovani Perugia, 9 luglio 2016
Carlotta Antoniotti Polo Oncologico
Azienda Ospedaliero-Universitaria Pisana
Università di Pisa
What news for mCRC in 2015-16?
#1) To Oxa or not to Oxa in neoadjuvant chemo- radiotherapy for locally advanced rectal cancer?
Breaking news from 2015-2016
#2) New evidences about the 1
st-line intensified triplet
#4) HER-2: the new target in mCRC! Also a new predictive marker?
#5) A confirmed happy marriage: MSI and immunotherapy
#3) mCRC: «Does the sideness matter?»
#1) To Oxa or not to Oxa in neoadjuvant chemo- radiotherapy for locally advanced rectal cancer?
STAR-01 trial
Breaking news from 2015-2016
#2) New evidences about the 1
st-line intensified triplet
#4) HER-2: the new target in mCRC! Also a new predictive marker?
#5) A confirmed happy marriage: MSI and immunotherapy
#3) mCRC: «Does the sideness matter?»
Locally advanced rectal cancer: the standard paradigm
CRT (or 5x5) Surgery
Total Mesorectal Excision Adjuvant CT
RT 50.4 Gy +
5-FU or Capecitabine
Locally advanced rectal cancer: the standard paradigm
RT 50.4 Gy +
5-FU or Capecitabine
+ OXALIPLATIN?
CRT (or 5x5) Surgery
Total Mesorectal Excision Adjuvant CT
To Oxa or not to Oxa in CRT for LARC?
NSABP R04 FOWARC
STAR-1
ACCORD-12 AIO04 PETACC-6
Primary endpoints
NSABP R04 ACCORD-12 AIO04 PETACC-6 FOWARC
Time to locoreg failure
Pathologic complete
response 3ys-DFS 3ys-DFS 3ys-OS
STAR-1
OS ?
STAR-01: study design
Aschele et al., ASCO Ann Meet ‘16
STAR-01: primary endpoint OS
Statistical hypothesis:
H0: 3ys-OS: 75%
H1: 3ys-OS: 82%
Aschele et al., ASCO Ann Meet ‘16
Primary endpoints
NSABP R04 ACCORD 12 AIO04 PETACC-6 FOWARC
Time to locoreg failure
Pathologic complete
response 3ys-DFS 3ys-DFS 3ys-OS
STAR-1
OS
To Oxa or not to Oxa?
NOT TO OXA!
A relatively small benefit from the addition of oxaliplatin to neoadjuvant CRT is
however observed
A metanalysis of available studies will be probably performed
New approaches to integrate active agents in the treatment strategy for LARC are
under investigation
New approaches: induction and consolidation
CRT (or 5x5) Surgery
Total Mesorectal Excision Adjuvant CT
Consolidation CT
CRT (or 5x5) Surgery
Total Mesorectal Excision
Induction CT CRT (or 5x5) Surgery
Total Mesorectal Excision
#1) To Oxa or not to Oxa in neoadjuvant chemo- radiotherapy for locally advanced rectal cancer?
Breaking news from 2015-2016
#2) New evidences about the 1
st-line intensified triplet
#4) HER-2: the new target in mCRC! Also a new predictive marker?
#5) A confirmed happy marriage: MSI and immunotherapy
#3) mCRC: «Does the sideness matter?»
MACBET and METHEP-2
trials
Modulation of «chemo-intensity» in mCRC
Modulation of chemo-intensity in mCRC…with bev
Modulation of chemo-intensity in mCRC…with anti-EGFRs
Macbeth trial: study design
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
*centrally assessed: KRAS 12,13,61 wt until Oct 2013, then RAS and BRAF wt
§administered biweekly. Stratification factor: center
Phase II randomized non-comparative trial
INDUCTION MAINTENANCE
Primary endpoint: 10months-PFR
Antoniotti et al., ASCO Ann Meet 2016
Modified FOLFOXIRI schedule
5FU continuous infusion 2400 mg/sqm 48h
L-LV 200 mg/sqm
oxaliplatin 85 mg/sqm irinotecan
130 mg/sqm Cetuximab
500 mg/sqm
1 hour 2 hours 48 hours
1 hour
mFOLFOXIRI + cet
5FU continuous infusion 3200 mg/sqm 48h
L-LV 200 mg/sqm
oxaliplatin 85 mg/sqm irinotecan
165 mg/sqm
1 hour 2 hours 48 hours
“Classic” FOLFOXIRI
Toxicity Profile – Safety population
G3/4 adverse events,
% patients
Arm A N = 59
Arm B N = 57
Overall N = 116
Nausea 1.7% 0% 0.9%
Vomiting 3.4% 1.0% 2.6%
Diarrhea 20.3% 15.8% 18.1%
Stomatitis 6.8% 5.3% 6.0%
Neutropenia 28.8% 33.3% 31.0%
Febrile neutropenia 3.4% 1.8% 2.6%
Neurotoxicity 6.7% 0% 3.5%
Asthenia 10.1% 8.8% 9.5%
Skin rash 18.6% 12.3% 15.5%
Venous Thrombosis 1.7% 3.5% 2.6%
Arterial Thrombosis 1.7% 0% 0.9%
Primary endpoint: 10m-PFR – mITT population
Arm A N = 59
Arm B N = 57
N pts observed at 10 months 50 52
N pts progression-free at 10 months 26 23
Median follow-up: 25.5 months
“…if at least 33 pts out of 53 per arm will be alive and
progression-free at 10 months.”
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.
Secondary endpoint: Resection of Metastases (mITT)
Arm A N = 59
Arm B N = 57
All N = 117
R0/R1/R2 surgery 45.8% 29.8% 37.9%
R0 secondary surgery 32.2% 22.8% 27.6%
Liver-only subgroup N = 28 N = 24
R0/R1/R2 surgery 71.4% 58.3% 65.4%
R0 secondary surgery 53.6% 45.8% 50.0%
Prodige-14 (Methep-2): study design
Pts with potentially
resectable LLD*
Primary endpoint: R0/R1 resection rate
H0: R0/R1 resection rate with BiCT = 50%
H1: R0/R1 resection rate with TriCT = 70%
2sided-alpha error: 0.05; beta-error: 0.10
*Unresectable liver mets for technical (<30% residual liver) or oncological reasons (>5 bilobar lesions)
Ychou et al., ASCO Ann Meet ‘16
Prodige-14 (Methep-2): primary endpoint
R0/R1 resection rate
p=0.06
Ychou et al., ASCO Ann Meet ‘16
Prodige-14 (Methep-2): secondary endpoint OS
Ychou et al., ASCO Ann Meet ‘16
Intensified first-line regimens in mCRC?
Reassuring safety results with triplet plus anti-EGFR (with a modified schedule of FOLFOXIRI)
Impressive activity results translate into consistent rates of conversion to
resectability
The intensification of the chemotherapy backbone may be of special interest when secondary resection is a pursuable
objective
#1) To Oxa or not to Oxa in neoadjuvant chemo- radiotherapy for locally advanced rectal cancer?
Breaking news from 2015-2016
#2) New evidences about the 1
st-line intensified triplet
#4) HER-2: the new target in mCRC! Also a new predictive marker?
#5) A confirmed happy marriage: MSI and immunotherapy
#3) mCRC: «Does the sideness matter?»
Right vs left colon
Right vs left: prognostic!
Venook et al., ASCO 2016
p for interaction=0.002
Brulé et al., Eur J Can 2015
Right-sided tumors Left-sided tumors
Higher incidence of other RAS and BRAF mutations
Right versus Left: subgroup analysis of CO.17 in KRAS wt
Right vs left: subgroup analysis of CALGB80405 in KRAS wt
Venook et al., ASCO ‘16 Right-sided tumors Left-sided tumors
p for interaction=0.005
OS
FOLFIRI+cetuximab FOLFIRI+bevacizumab
Heinemann et al., ASCO ‘14
Right versus Left: subgroup analysis of FIRE-3 in RAS wt
Our recent experience
Patients with RAS and BRAF wt mCRC clearly evaluable for anti-EGFR
efficacy*
N=75
Right-sided tumors
N=14
*anti-EGFR monotherapy or cetuximab + irinotecan in irinotecan-refractory pts
Left-sided tumors
N=61
Moretto et al., Oncologist 2016
RECIST Response
Best Response
Evaluable for response
Right-sided primary N = 13
n (%)
Left-sided primary N = 59
n (%)
p
Complete Response 0 (0) 0 (0)
Partial Response 0 (0) 24 (40.7)
Response Rate 0% 41% 0.0032
Stable Disease 2 (15.4) 23 (39.0)
Progressive Disease 11 (84.6) 12 (20.3)
Disease Control Rate 15% 80% <0.0001
Moretto et al., Oncologist 2016
Progression-free survival
Right-sided primary (N=14), median PFS : 2.3 months Left-sided primary (N=61), median PFS : 6.6 months
HR: 3.97 [95%CI: 2.09 – 7.53]
P<0.0001
Moretto et al., Oncologist 2016
Right vs left: predictive?
Primary tumor location may become a driver in our therapeutic decision-making, but results from randomized studies in well selected pts are awaited.
Available data from retrospective series suggest a larger benefit from anti-EGFR for left-sided than right-sided tumors.
#1) To Oxa or not to Oxa in neoadjuvant chemo- radiotherapy for locally advanced rectal cancer?
Breaking news from 2015-2016
#2) New evidences about the 1
st-line intensified triplet
#4) HER-2: the new target in mCRC! Also a new predictive marker?
#5) A confirmed happy marriage: MSI and immunotherapy
#3) mCRC: «Does the sideness matter?»
HERACLES and MyPathway
trials
27 HER-2 +, KRAS wt mCRC pts progressed after fluoropyr,
oxaliplatin, irinotecan and an anti-EGFR moAb
Trastuzumab +
Lapatinib
PDPhase II, primary endpoint: ORR (Recist 1.1)
H0: ORR: 10%
H1: ORR> 30%
a: 0.05; b:0.15
At least 6 responders out of 27 pts
Sartore Bianchi et al, Lancet Oncology ‘16
HERACLES trial
Clinically relevant and durable responses
Sartore Bianchi et al, Lancet Oncology ‘16
HER-2 BRAF Hedgehog EGFR
Overexpression or mutation
V600E or other mutations
SMO-activ mut
PTCH-1 loss Activating mut
Trastuzumab +
pertuzumab Vemurafenib Vismodegib Erlotinib
Hurwitz et al, ASCO GI ‘16
My Pathway
ORR in HER-2+ mCRC
ORR: 5/13 DCR: 10/13
Hurwitz et al, ASCO GI ‘16
The beginning of the story: HER-2 as a mechanisms of resistance to anti-EGFR moAbs
Bertotti et al, Cancer Discov ‘11
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 Cohort 1
14/114 = 12% in RAS wt
14/97 = 14% in RAS and BRAF wt
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
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 first-line without anti-EGFR PFS during first-line without anti-EGFR
HER-2: precision medicine in mCRC
HER-2 testing should be implemented in the daily clinical practice (according to Valtorta et al., Mod Path ‘15).
HER-2 is
• a promising target
• a positive predictive marker (an example of precision medicine in mCRC),
• a potential negative predictive marker with regard to anti-EGFRs, supported by a solid biologic background
#1) To Oxa or not to Oxa in neoadjuvant chemo- radiotherapy for locally advanced rectal cancer?
Breaking news from 2015-2016
#2) New evidences about the 1
st-line intensified triplet
#4) HER-2: the new target in mCRC! Also a new predictive marker?
#5) A confirmed happy marriage: MSI and immunotherapy
#3) mCRC: «Does the sideness matter?»
PEMBRO and NIVO+/-IPI
New CRC molecular subgroups
Guinney et al, Nature Med 2015
Pembrolizumab in MSI mCRC: updated results
Le et al, ASCO 2016
Type of response MSI
(n=28)
MSS (n=25)
Complete Response 11% 0%
Partial Response 46% 0%
Objective Response Rate 57% 0%
Disease Control Rate 89% 16%
Nivolumab 3 mg/kg (n = 47)a
ORR, n (%) (95% exact CI)
12 (25.5) (15.4, 38.1)
Complete response 0
Partial response 12 (25.5)
Stable disease 14 (29.8)
Progressive disease 17 (36.2)
Unable to determine 4 (8.5)
Median time to response, mo (range) 2.12 (1.3–13.6)
Median duration of response, mo (range) NE (0.0b–15.2b)
aPatients with ≥ 12 weeks of follow-up
bIncludes censored observations
CR = complete response; NE = not estimable; PR = partial response
Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg
(n = 27)a 9 (33.3) (18.6, 50.9)
0 9 (33.3) 14 (51.9)
3 (11.1) 0 2.73 (1.2–6.9)
NE (NE–NE)
Overman et al, ASCO 2016
Checkmate-142: ORR in MSI-H
Overman et al, ASCO 2016
Toxicity profile in MSI-H
Event, n (%) Nivolumab
3 mg/kg (n = 70)
Nivolumab 3 mg/kg + Ipilimumab 1 mg/kg
(n = 30)
Any grade Grade 3–4 Any grade Grade 3–4
Any event 41 (58.6)a 10 (14.3) 25 (83.3) 8 (26.7)
Fatigue 13 (18.6) 1 (1.4) 6 (20.0) 0
Diarrhea 10 (14.3) 1 (1.4) 13 (43.3) 0
Pruritus 8 (11.4) 0 5 (16.7) 1 (3.3)
Nausea 5 (7.1) 0 6 (20.0) 0
Pyrexia 3 (4.3) 0 7 (23.3) 0
Any event leading to
discontinuation 4 (5.7) 2 (2.9) 4 (13.3) 4 (13.3)
aOne Grade 5 event of sudden death
MSI and anti-PD1: a happy marriage
The blockade of PD-1 has a strong
biological rationale in the subset of MSI- high mCRC patients.
The anti-PD1 therapy (pembrolizumab alone and nivolumab+/-ipilimumab), shows
promising preliminary activity and safety data.
Waiting for data from larger ongoing phase II and III trials.
…Immunotherapy in mCRC is a planet to be discovered.
