Scelta delle linee successive nel paziente RAS e BRAF wild-type con particolare accento su nuovi bersagli terapeutici

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Scelta delle linee successive nel paziente RAS e BRAF wild-type con particolare accento su nuovi bersagli terapeutici

Francesca Battaglin

AIOM GIOVANI 2017

Perugia, 07-08 Luglio 2017

Regione del Veneto

U.O.C. Oncologia Medica 1

Dipartimento di Oncologia Clinica e Sperimentale Istituto Oncologico Veneto – IRCCS, Padova

Tutor: Dr. Antonio Galvano

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FOLFIRI + Cetuximab

N= 297

FOLFIRI + Bevacizumab

N= 295

p

Any 2nd-line therapy, % 65.7 61.7 0.347

2nd-line beva, % 48.2 17.6

2nd-line anti-EGFR, % 14.4 42.9

Heinemann H et Al, Lancet Oncology 2013

Not all patients receive a second-line therapy

An example: FIRE-3: subsequent lines of treatment

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Impact of second-line CT on OS

Modest et Al JCO 2015

ESMO

guidelines 2016

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✓ First-line treatment:

a. What did he get?

b. How did he tolerate it?

c. Did he benefit?

✓ Patients conditions and motivation

Facing a progressing mCRC patient

✓ Treatment goal

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WHICH CHEMO? WHICH BIOLOGIC?

BOTTOM-LINE:

- Few data available in a “real world” setting - Most indications derived from:

a) subgroup analyses;

b) indirect comparisons

Which second-line treatment?

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to SWITCH chemo!

Tournigand et al, J Clin Oncol 2004

Which chemo? Standard is…

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Progression-free survival probability

F-up time (months)

FOLFIRI + bev FOLFOXIRI + bev

0–6 mos

I N D U C T I O N

6–12 mos

MA I N T E N

…

FOLFOXIRI + bev

5-FU “only” + bev

6 mos median OXALIPLATIN and

IRINOTECAN-free interval

Which second-line treatment after FOLFOXIRI (+bev)?

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R 1:1

FOLFOX + bev*

FOLFOXIRI + bev*

PD1

PD2

5FU/bev

FOLFIRI + bev*

FOLFOXIRI + bev*

5FU/bev

*all repeated for 8 cycles (4 months) followed by maintenance with 5FU/bev until PD

Primary endpoint: Progression-free survival 2

Next effort: TRIBE-2 trial

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WHICH BIOLOGIC?

After BEV After anti-EGFR

Which second-line treatment?

 Bevacizumab

 Aflibercept (+ FOLFIRI)

 [Ramucirumab (+ FOLFIRI)]

 Anti-EGFR

 Bevacizumab

 Aflibercept (+ FOLFIRI)

 [Ramucirumab (+ FOLFIRI)]

 Anti-EGFR?

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Angiogenesis inhibition in second-line

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Second-line anti-VEGF in RAS WT

Wirapati et al, ASCO Annual Meeting 2017

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OS PFS RR AEs Early PD Bev

Iri I Line Bevacizumab

beyond PD

     

Aflibercept

     

Ramucirumab

 

^NA

 

How to choose the right antiangiogenic drugs?

 CT back-bone

 Treatment goal

 Toxicity profile

 Economic costs

 Need of predictive biomarkers!!!

How can we choose?

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Study (drug) OS (HR)

EPIC (Cet)

No molec selection

HR=0.98

p=0.71

PICCOLO (Pani)

KRAS wt (cod 12, 13, 61)

HR=1.01

p=0.91

PICCOLO (Pani)

All wt

HR=0.92

Second line anti-EGFR

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Peeters et al, Ann Oncol 2014

 1186 mCRC pts

 PD after 1st- line fluoro-

based CT

R

FOLFIRI

FOLFIRI+Pan

OS: KRAS wt subgroup receiving 1^st-line bev 20050181 Study

Panitumumab after PD on Bev

↑ ORR and PFS, not in OS

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 182 KRAS wt mCRC pts

 PD after at least 4 cycles of FOLFOX/XELOX

Bev

R

FOLFIRI+Bev

FOLFIRI+Pan

Phase II study

Hecht et al, ASCO GI 2013

A direct comparison: the SPIRITT study

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Adam et al, J Clin Oncol 2007

6% of patients receiving 2^nd-line chemo+Cet conversion to resectability

Still a chance

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Heinemann et al, ASCO Annual Meeting 2013

FIRE-3 trial

Bevacizumab after PD on Cetuximab

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 340 mCRC pts

 KRAS exon 2 wt

FOLFOX

FOLFOX+

Cet FOLFIRI +

Cet

R PD 1:1

Primary endpoint: PFS

GOIM CAPRI trial

Cetuximab beyond PD?

Ciardiello et al, Ann Oncol 2016

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FIRST-LINE

SECOND-LINE

Angiogenesis inhibitors

- Bevacizumab - Aflibercept

- Ramucirumab Anti-EGFR

- Panitumumab - Cetuximab

THIRD/FOURTH LINE

- Cetuximab/Panitumumab - Regorafenib

- TAS 102

- Rechallenge

CONTINUUM OF CARE early integration of SIMULTANEOUS CARE

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Grothey et al, Lancet 2013

Regorafenib mOS = 6.4 mos Placebo mOS = 5.0 mos

HR=0.77 (95%CI 0.64-0.94) p=0.0052

CORRECT trial: primary endpoint

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✓ Predictive markers

✓ New response parameters (other than RECIST)

✓ Adverse event management / Dose reduction?

Regorafenib: open issues

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About 20% rego-pretreated

TAS-102: the RECOURSE trial

mOS 7.1 vs 5.3 months

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Lab abnormalities, % TAS-102 (n=533) Placebo (n=265) All Gr Gr 3 Gr 4 All Gr Gr 3 Gr 4

Leukopenia ^77.1 ^18.6 ^2.8 ^4.6 ⁰ ⁰

Anemia ^76.5 18.2 0 ^33.1 ^3.0 ⁰

Neutropenia ^66.9 26.5 11.4 ^0.8 ⁰ ⁰

Lymphocytopenia ^64.6 ^18.2 ^3.3 ^39.7 ^9.2 ^0.8

Thrombocytopenia ^42.2 ^4.5 ^0.6 ^8.9 ⁰ ^0.4

Adverse events, % TAS-102 (n=533) Placebo (n=265) All Gr Gr 3 Gr 4 All Gr Gr 3 Gr 4

Febrile neutropenia ^3.8 2.8 0.9 ⁰ ⁰ ⁰

Yoshino et al, WCGIC 2014

RECOURSE trial: safety profile

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✓ Predictive markers

✓ Drug availability

TAS 102: open issues

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Regorafenib vs TAS-102: the REGOTAS Study

Fukuoka et al, ASCO Annual Meeting 2017

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Rechallenge with EGFR Inhibitors: pooled data from the PRIME and PEAK Studies

Siena et al, WCGIC 2017

Median OS after rechallenge of 14.2 mo

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The CRICKET Study

Primary endpoint: ORR Secondary endpoints: PFS, OS, Toxicity rate

Rossini et al, WCGIC 2017 First line

irinotecan based CT + Cetux

Second line oxa-based CT

+ Bev Iri-Cetux

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50%

RAS mutations

BRAF mutation

RAS/BRAF wild-type

40%

10%

How “targeted” are we?

50%

RAS mutations

BRAF mutation

RAS/BRA F wild-type

40%

^10%

MSI 5%

HER-2 3%

Going deeper….

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Sartore Bianchi et al, Lancet Oncology 2016

anti-HER2: real results!

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HERACLES study:

PFS

Sartore-Bianchi A et al. Lancet Oncol 2016

HERACLES results: PFS by HER2 gene copy number

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Immunotherapy: the rising star

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 PFS results: MSI-H vs non-MSI-H

Presented By Dung Le at ASCO Annual Meeting 2016

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Andre et al, ASCO Annual Meeting 2017

CTLA-4 Blockade (Ipilimumab) PD-1 Blockade

(Nivolumab) APC – T-cell

Interaction

Activation

(cytokine secretion, lysis, proliferation, migration to tumor)

Tumor Microenvironment

Dendritic

cell T cell Tumor cell

MHC TCR TCR

PD-L1 PD-L2 MHC PD-1

PD-1 B7

B7 CD28

CTLA-4 anti-CTLA-4

+++

---

+++ ^{T cell}

+++

--- ---

anti-PD-1 anti-PD-1

Phase 2 CheckMate 142 Study Design

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Phase 2 CheckMate 142: Investigator-Assessed Overall Response Rate

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Phase 2 CheckMate 142: Nivo +Ipi PFS and OS

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Future prospectives: where are we going?

 Liquid biopsy

Primary and acquired resistance, dynamic clonal evolution

 Anti-EGFR Rechallenge

The CHRONOS Study

 New strategies to overcome secondary resistance

• Panitumumab+MEK inhibitor (NCT01927341)

• Cetuximab+MET inhibitor (NCT02205398)

• SYM004 (NCT02083653)

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francesca.battaglin@iov.veneto.it