Novità sul trattamento delle neoplasie del colon-retto

(1)

Supernovae in Oncologia

Pisa, 13 Novembre 2015

Novità sul trattamento

delle neoplasie del colon-retto

Carlotta Antoniotti Polo Oncologico

Azienda Ospedaliero-Universitaria Pisana

Università di Pisa

(2)

 Supernovae in first-line therapy

«Chemo-intensity»

Maintenance with bevacizumab

 Supernovae in second- and further lines therapies

Ramucirumab TAS-102

 Supernovae in molecular subgroups

HER2 BRAF MSI

My agenda

(3)

 Supernovae in first-line therapy

«Chemo-intensity»

Maintenance with bevacizumab

 Supernovae in second- and further lines therapies

Ramucirumab TAS-102

 Supernovae in molecular subgroups

HER2 BRAF MSI

My agenda

(4)

(5)

The concept of «chemo-intensity»

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The concept of «chemo-intensity»

Courtesy of Fotios Loupakis

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TRIBE trial

R

508 mCRC pts 1st line

unresectable stratified by

 center

 PS 0/1-2

 adjuvant CT

FOLFIRI+bev

(up to 12 cycles)

FOLFOXIRI+bev

(up to 12 cycles)

5-FU/LV +Bev

PD

INDUCTION MAINTENANCE

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Primary Endpoint: PFS

Loupakis et al, N Eng J Med 2014

FOLFIRI + bev, median PFS : 9.7 mos FOLFOXIRI + bev, median PFS : 12.1 mos

HR: 0.75 [0.62-0.90]

p=0.003

(9)

TRIBE: Updated OS Results

Cremolini et al, Lancet Oncol 2015 MEDIAN F-UP 48.1 mos (74% events)

FOLFIRI + bev: N = 256 / Died = 200 FOLFOXIRI + bev: N = 252 / Died = 174

FOLFIRI + bev, median OS : 25.8 mos FOLFOXIRI + bev, median OS : 29.8 mos

HR: 0.80 [0.65-0.98]

p=0.030

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TRIBE: OS in molecular subgroups

Cremolini et al, Lancet Oncol 2015

Median OS (months)

N FOLFIRI + Beva

FOLFOXIRI +

Beva

HR (95% CI) P Value

for Interaction

RAS and BRAF WT 93 33.5 41.7 0.77 (0.46–1.27)

.522

RAS MT 236 23.9 27.3 0.88 (0.65–1.18)

BRAF MT 28 10.7 19.0 0.54 (0.24–1.20)

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RAS and BRAF wt

RAS or BRAF mut

Cremolini et al. Nat Rev Clin Oncol 2015

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Maintenance therapy

SAKK trial

Koeberle et al, Ann Oncol 2015

AIO-KRK 0207 trial

Hegewisch-Becker et al, Lancet Oncol 2015

CAIRO-3 trial

Simkens et al, Lancet 2015

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Maintenance therapy: Pooled analysis

Progression-free survival

Favours active tx. Favours no tx.

Arnold et al, ASCO Ann Meeting 2014

Overall survival

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 Supernovae in first-line therapy

«Chemo-intensity»

Maintenance with bevacizumab

 Supernovae in second- and further lines therapies

Ramucirumab TAS-102

 Supernovae in molecular subgroups

HER2 BRAF MSI

My agenda

(15)

modified from Ferrara et al, Nature 2005 Ramucirumab

Ramucirumab: mechanism of action

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RAISE trial – Study design

Primary endpoint = OS

mCRC pts PD during or after bev, oxaliplatin, and

a fluoropyrimidine

Ramucirumab and FOLFIRI

every 2 weeks n = 536

Placebo and FOLFIRI every 2 weeks

n = 536 R

1:1

Tabernero et al, Lancet Oncol 2015

(17)

RAISE trial – Overall Survival

24 April 2015

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FOLFIRI + Placebo N = 528

FOLFIRI + Ramucirumab N = 529

All grades,

%

Grade 3/4,

%

All grades,

%

Grade 3/4,

%

Diarrhea _51.3

9.7

^59.7

10.8

Stomatitis 20.8

2.3

^30.8

3.8

Fatigue _52.1

7.8

^57.7

11.5

Neutropenia _45.6

23.3

58.8

38.4

Thrombocytopenia 13.6

0.8

^28.4

3.0

Hypertension _8.5

2.8

^25.7

10.8

Febrile neutropenia _2.7

-

3.6

-

RAISE trial - Safety profile

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Angiogenesis inhibition in 2 ^nd line

Bevacizumab Ziv-aflibercept Ramucirumab

Study TML BEBYP VELOUR RAISE

CT+

BEV CT CT +

BEV CT FOLFIRI

+ AFL FOLFIRI FOLFIRI

+ RAM FOLFIRI

N pts 409 410 92 92 612 614 536 536

mOS 11.2 9.8 14.1 15.5 13.5 12.1 13.3 11.7

HR 0.81* 0.77 0.82* 0.84*

mPFS 5.7 4.1 6.8 5.0 6.9 4.7 5.7 4.5

HR 0.68* 0.70* 0.76* 0.79*

RR (%) 5.4 3.9 21 17 19.8* 11.1 13.4 12.5

100% prior Beva 100% prior Beva 30% prior Beva 100% prior Beva

* p<0.05

Bennouna et al, Lancet Oncol 2012; Masi et al, Ann Oncol 2015 Van Cutsem et al, J Clin Oncol 2012; Tabernero et al, Lancet Oncol 2015

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TAS-102: mechanism of action

F

₃

TMP

(inactive form)

TPI

FTY

TPase

F

₃

TDP FTD + TPI

FTD incorporation into DNA

F

₃

TTP

FTD

TAS-102

DNA dysfunction Inhibition of

tumor growth

FTD: Trifluridine TPI: Tipiracil-HCl

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N= 800

Primary end-point: OS

RECOURSE trial – Study design

N= 534 N= 266

(about 20% rego-pretreated)

Mayer et al, N Eng J Med 2015

R 1:2

Placebo + BSC

TAS-102 + BSC

mCRC pts

 treated with

≥2 tx lines

 refractory to

all standard tx

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RECOURSE trial – Overall Survival

Mayer et al, N Eng J Med 2015

22 September 2015

TAS-102: mOS 7.1 mos Placebo: mOS 5.3 mos

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RECOURSE trial – Safety profile

Lab abnormalities, %

TAS-102 (n=533)

Placebo (n=265)

All Gr Gr ≥3

All Gr Gr ≥3

Leukopenia

⁷⁷ ²¹ ⁵ ⁰

Anemia

⁷⁷

18

³³ ³

Neutropenia

⁶⁷

38

^<1 ⁰

Thrombocytopenia

⁴² ⁵ ⁸ ^<1

Adverse events, %

TAS-102 (n=533)

Placebo (n=265)

All Gr Gr≥ 3

All Gr Gr ≥3

Febrile neutropenia

⁴

4

⁰ ⁰

Adapted from Mayer et al, N Eng J Med 2015

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Refractory mCRC patients

TAS-102 REGORAFENIB

CORRECT trial RECOURSE trial

Mayer et al, N Eng J Med 2015 Grothey et al, Lancet 2013

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 Supernovae in first-line therapy

«Chemo-intensity»

Maintenance with bevacizumab

 Supernovae in second- and further lines therapies

Ramucirumab TAS-102

 Supernovae in molecular subgroups

HER2 BRAF MSI

My agenda

(26)

HER2: HERACLES trial

mCRC pts

 HER2+

 KRAS exon 2 wt

 refractory to all standard **tx*, resistant to anti-**

EGFR

*prior bevacizumab, aflibercept or regorafenib allowed but not mandatory

Cohort A

Trastuzumab+Lapatinib

Cohort B

Trastuzumab+Pertuzumab

Siena et al, ASCO Ann Meeting 2015

Primary end-point: ORR

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849 patients with mCRC KRAS exon 2 WT

803 HER2-negative

22 not eligible because PS ≥2 or tumor-related comorbidities

24 enrolled

23 evaluable for response

1 too early for safety & efficacy assessment

46 HER2+ (5.4%)

HER2: HERACLES trial

Best Response

RECIST 1.1 by centralized revision

N %

Responses (PR+CR) 8

34.7

Complete Response 1 4.3 Partial Response 7 30.4 Stable Disease >4 mos 7

30.4

Stable Disease <4 mos 3

13.0

Progressive Disease 5 21.7

Total 23 100

78%

DCR

Siena et al, ASCO Ann Meeting 2015

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Raf

MEK

Erk Tumor cell

proliferation and survival

EGF Tumor cell

P P

Ras

P P

Study

Reference N RR DCR PFS

Dabrafenib + Trametinib + Panitumumab

Atreya, ASCO Ann Meet ‘15 35 26% 60% 4.1

Encorafenib + Alpelisib + Cetuximab

Elez, WCGIC ‘15 28 32% 94% 4.3

BRAF mut V600E: BRAFi + EGFRi + MEKi

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New CRC molecular subgroups

Guinney et al, Nature Med 2015

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Pembrolizumab in MSI mCRC

Modified from Le et al, N Eng J Med 2015

Type of response MSI

(n=10)

MSS (n=18)

Complete Response

0% 0%

Partial Response

40% 0%

Objective Response Rate

40% 0%

Disease Control Rate 90% 11%

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Pembrolizumab in MSI mCRC

Le et al, N Eng J Med 2015

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Response assessment: Every 9 weeks Primary endpoint: ORR per RECIST v1.1

Secondary endpoints: Duration of response, disease control rate, PFS, OS, safety

No Patients

•Locally advanced

unresectable or metastatic (Stage IV) MSI high CRC

•≥2 prior treatments with standard therapy^a

•Provision of tumor and blood sample for evaluation and

confirmation of MSI status

•≥1 measurable lesion per RECIST 1.1

•ECOG PS 0 or 1

Pembrolizumab 200 mg Q3W

Complete Response

Partial Response or Stable Disease

Confirmed Progressive

Disease^b

Discontinuation Permitted^c

Treat for 35 cycles or until progression

or intolerable toxicity

Discontinue Confirmation of

MSI-high status at a central

laboratory

Not enrolled

Yes

Future perspective: KEYNOTE-164

https://www.clinicaltrials.gov/

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Take home messages

 The chemo-intensity should be modulated according to patients characteristics.

 Maintenance with bevacizumab (+/- fluoropyrimidines) is an

effective part of 1st-line therapy and should be considered after an

induction with chemo plus bevacizumab.

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 Ramucirumab and TAS-102 have recently widened the therapeutical scenario in mCRC, for second-line and heavily pretreated patients, respectively.

 The molecular landscape of mCRC is increasingly complex.

Up today precision medicine has provided interesting results but molecular markers able to allow a positive selection of patients are not yet ready for prime time (maybe in the future HER-2, BRAF V600E mutation).

 The immunotherapy will be a new planet to be deeply discovered in mCRC too.

Take home messages

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