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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 1st-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?»



STAR-01

trial




predictive marker?


immunotherapy


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?



To Oxa or not to Oxa in CRT for LARC?

NSABP R04 FOWARC

STAR-1

ACCORD-12 AIO04 PETACC-6

Primary endpoints

NSABP R04 FOWARC ACCORD-12 AIO04 PETACC-6

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 FOWARC ACCORD 12 AIO04 PETACC-6

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



Consolidation CT CRT (or 5x5) Surgery

Total Mesorectal Excision

Induction CT CRT (or 5x5) Surgery

Total Mesorectal Excision






predictive marker?


immunotherapy


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

A

Arm

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


Prodige-14 (Methep-2): secondary endpoint OS


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






predictive marker?


immunotherapy


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


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


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.






predictive marker?


immunotherapy


HERACLES

and

MyPathway

trials

27 HER-2 +, KRAS wt mCRC pts

progressed after fluoropyr,

oxaliplatin, irinotecan and

an anti-EGFR moAb

Trastuzumab +

Lapatinib PD

Phase 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



with anti-EGFR

N=114

HER-2 ampl

N=14

HER-2 non ampl

N=110


HER-2 ampl

N=37

HER-2 non ampl

N=62

Cohort 1 Cohort 2

PFS during anti-EGFR PFS during anti-EGFR



with anti-EGFR

N=114

HER-2 ampl

N=14

HER-2 non ampl

N=110


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






predictive marker?


immunotherapy


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.

[email protected]

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