Gastrointestinal colorectal cancer poster discussion session 3523 3528
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Gastrointestinal Colorectal Cancer Poster Discussion Session #3523 - #3528. Josep Tabernero, MD Vall d’Hebron University Hospital Barcelona, Spain. Disclosure. Consutant or Advisory Role: Amgen Biogen Idec Bristol-Myers Squibb Merck- Serono KGaA Novartis Onyx Pfizer Roche

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Gastrointestinal Colorectal Cancer Poster Discussion Session #3523 - #3528

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Gastrointestinal colorectal cancer poster discussion session 3523 3528

Gastrointestinal Colorectal CancerPoster DiscussionSession#3523 - #3528

Josep Tabernero, MD

Vall d’Hebron University Hospital

Barcelona, Spain


Disclosure

Disclosure

  • Consutant or Advisory Role:

    • Amgen

    • Biogen Idec

    • Bristol-Myers Squibb

    • Merck-SeronoKGaA

    • Novartis

    • Onyx

    • Pfizer

    • Roche

    • Sanofi-Aventis


Outline

Outline

  • New therapeutic options in mCRC:

    • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al

    • A phase III study of SOX (S-1/oxaliplatin) versus COX (capecitabine/oxaliplatin) in mCRC. A 3524. Park, et al

    • Phase II trial of figitumumab in mCRC. A3525. Becerra, et al

  • Maintenance treatment in mCRC:

    • A phase III trial on maintenance treatment with erlotinib + bevacizumabvsbevacizumab in mCRC. A3526. Johnsson, et al

    • A randomized phase II study of maintenance enzastaurin with 5-FU/leucovorin plus bevacizumab in mCRC. A3527. Wolff, et al

  • Predictive/prognostic biomarkers in mCRC:

    • An international consortium study in chemorefractory mCRC patients to assess the impact of FCGR polymorphisms on cetuximab efficacy. A3528. Geva, et al

    • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al


Outline1

Outline

  • New therapeutic options in mCRC:

    • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al

    • A phase III study of SOX (S-1/oxaliplatin) versus COX (capecitabine/oxaliplatin) in mCRC. A 3524. Park, et al

    • Phase II trial of figitumumab in mCRC. A3525. Becerra, et al

  • Maintenance treatment in mCRC:

    • A phase III trial on maintenance treatment with erlotinib + bevacizumabvsbevacizumab in mCRC. A3526. Johnsson, et al

    • A randomized phase II study of maintenance enzastaurin with 5-FU/leucovorin plus bevacizumab in mCRC. A3527. Wolff, et al

  • Predictive/prognostic biomarkers in mCRC:

    • An international consortium study in chemorefractory mCRC patients to assess the impact of FCGR polymorphisms on cetuximab efficacy. A3528. Geva, et al

    • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al


Piccolo initial trial design dec 2006

PICCOLO: initial trial design (Dec 2006)

target n = 1125

(494 accrued by end of May 2008)

confirmed aCRC, measurable disease

progression during/after prior FP ± oxali

no prior irinotecan

WHO PS 0-2

IrCs

irinotecan + ciclosporin

Ir

irinotecan alone

IrPan

irinotecan + panitumumab

Irvs IrCs

non-inferior efficacy

primary endpoint PFS at 12 wks

Irvs IrPan

superior efficacy

primary endpoint OS


Piccolo amendment from june 2008

PICCOLO: amendment from June 2008

target total n = 1200

(including 494 accrued under previous design)

eligibility as before

KRAS mutated or unknown

KRAS-wt (c.12/13 & 61)

IrCs

irinotecan + c’sporin

IrPan

irinotecan + pan’mab

Ir

irinotecan alone

Ir

irinotecan alone

Irvs IrCs

non-inferior efficacy

primary endpoint PFS at 12 wks

Irvs IrPan

superior efficacy

primary endpoint OS


Piccolo ir vs irpan analysis populations

PICCOLO: Ir vs. IrPan – Analysis populations

Primary analysis population (red circle, n=460): KRAS12-13,61-wt, unpretreated

“Double wild-type” (n=384): confirmed to also be BRAF-wt

“All wild-type” (n=265): wt at KRAS12-13,61 KRAS146 NRAS12-13,61and BRAF


Piccolo ir vs irpan efficacy analysis

PICCOLO: Ir vs. IrPan – Efficacy analysis

Statistics: Ir versus IrPan:

  • Superiority on OS, primary analysis KRAS-wt, no prior anti-EGFR

  • 80% power, 2-sided 5% significance, HR = 0.7, mOS 9  12.7 m, 246 events

    Response rate:

  • Response rate:12% vs 34%;p < 0.0001

  • Disease Control rate: 51% vs 59%;p = 0.10

Progression-free Survival; KRAS-wt

Overall Survival; KRAS-wt

HR=0.78 [0.64, 0.95], p=0.01

460 patients, 399 events

mPFS: 4.7 mo (Ir), 5.5 mo (IrPan)

HR=0.91 [0.73, 1.14], p=0.44

460 patients, 312 events

mOS: 10.5 mo (Ir), 10.4 mo (IrPan)

Ir

IrPan

Ir

IrPan


Piccolo clinical implications 2 nd line mcrc

PICCOLO: Clinical implications – 2nd line mCRC

D Morton, et al. for the FOxTROT Collaborative Group. ASCO 2011, Abstract #3568

A Sobrero et al. EPIC study, J ClinOncol 2008; 26:2311-2319; M Peeters et al. J CinOncol 2010; 28:4706-4713


Outline2

Outline

  • New therapeutic options in mCRC:

    • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al

    • A phase III study of SOX (S-1/oxaliplatin) versus COX (capecitabine/oxaliplatin) in mCRC. A 3524. Park, et al

    • Phase II trial of figitumumab in mCRC. A3525. Becerra, et al

  • Maintenance treatment in mCRC:

    • A phase III trial on maintenance treatment with erlotinib + bevacizumabvsbevacizumab in mCRC. A3526. Johnsson, et al

    • A randomized phase II study of maintenance enzastaurin with 5-FU/leucovorin plus bevacizumab in mCRC. A3527. Wolff, et al

  • Predictive/prognostic biomarkers in mCRC:

    • An international consortium study in chemorefractory mCRC patients to assess the impact of FCGR polymorphisms on cetuximab efficacy. A3528. Geva, et al

    • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al


Sox vs cox in mcrc study design

SOX vs COX in mCRC: Study design

S-1

80 mg/m2 days 1-14

Oxaliplatin

130 mg/m2 day 1

q3w

Primary

Site

Prior

Adjuvant

Treatment

Measurable or Evaluable Disease

  • Primary objective:

    • PFS

  • Secondary objectives:

    • OS

    • ORR

    • QoL

    • Safety

A

Stratification

Randomization

Capecitabine

2000 mg/m2 days 1-14

Oxaliplatin

130 mg/m2 day 1

q3w

B

344 Pts., 11 Centers

12 months enrollment, 12 moths F/U


Sox vs cox in mcrc statistical hypothesis

SOX vs COX in mCRC: Statistical hypothesis

  • Non-inferiority study: SOX is non-inferior to COX in PFS

  • The upper limit of 95% CI for HR is <1.4327, non-inferiority margin of 13% in 15 m PFS

  • One-sided test, power 80%, 5 % significance

  • 192 events are required, drop-out rate of 10%, 344 patients required

  • As a general comment non-inferiority studies should not only consider PFS but OS


Sox vs cox in mcrc patients population

SOX vs COX in mCRC: Patients population

  • Adhere to the CONSORT disposition

  • Populations: - intention-to-treat

    - per protocol

    - safety


Sox vs cox in mcrc efficacy data

SOX vs COX in mCRC: Efficacy data

Progression-free Survival

Overall Survival

FA set

HR = 0.760 [0.594, 0.973]

P-value = 0.0286

Median : 7.2 vs. 6.2 m

FA set

HR = 0.897 [0.638, 1.260]

P-value = 0.5298

Median : 20.9 vs. 19.9 m


Sox vs cox in mcrc safety profile

SOX vs COX in mCRC: Safety profile

  • “SOX regimen showed favorable safety profiles compared to COX regimen”


Sox vs cox in mcrc safety profile1

SOX vs COX in mCRC: Safety profile

  • All toxicities but skin more frequent in SOX than COX


Sox vs cox in mcrc critique and implications

SOX vs COX in mCRC: Critique and implications

  • Design:

    • the trial was underpowered to detect non inferiority

    • a margin of 1.43 is a very large margin

    • for NI studies, OS is the more usual primary endpoint

  • Results:

    • Matured results, with trends towards superiority on both PFS and OS

    • Safety: not well defined, grade 2-3-4-5 all together

    • Complete follow-up, safety description and treatment details are needed

    • SOX may be a reasonable option in those countries where S1 is approved


Outline3

Outline

  • New therapeutic options in mCRC:

    • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al

    • A phase III study of SOX (S-1/oxaliplatin) versus COX (capecitabine/oxaliplatin) in mCRC. A 3524. Park, et al

    • Phase II trial of figitumumab in mCRC. A3525. Becerra, et al

  • Maintenance treatment in mCRC:

    • A phase III trial on maintenance treatment with erlotinib + bevacizumabvsbevacizumab in mCRC. A3526. Johnsson, et al

    • A randomized phase II study of maintenance enzastaurin with 5-FU/leucovorin plus bevacizumab in mCRC. A3527. Wolff, et al

  • Predictive/prognostic biomarkers in mCRC:

    • An international consortium study in chemorefractory mCRC patients to assess the impact of FCGR polymorphisms on cetuximab efficacy. A3528. Geva, et al

    • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al


Figitumumab cp 751 871 in mcrc

Figitumumab (CP-751,871) in mCRC


Figitumumab cp 751 871 in mcrc1

Figitumumab (CP-751,871) in mCRC


Cixutumumab imc a12 cetuximab

Cixutumumab (IMC-A12) ± Cetuximab

  • Randomized, phase II study of the IGF-1R MoAbIMC-A12 (cixutumumab), with or without cetuximab, in patients with cetuximab- or panitumumab-refractory mCRC (NCT00503685)1:

    • Negative

    • 1 PR out of 41 patients treated with the combo (not all KRAS wt)

1 Reidy et al, J Clin Oncol 2010


Dalotuzumab mk 0646 cetuximab

Dalotuzumab (MK-0646) + Cetuximab

Amended for KRaswild type; N=344 patients

  • Negative: inferior PFS & OS for experimental arms

  • Biomarker sub-analysis in progress

DJ Watkins et al. Clinical Science Symposium. A#3501. J ClinOncol 2011

ClinicalTrials.gov


Pmab vs pmab amg479 vs pmab amg102

PmabvsPmab+ AMG479 vsPmab + AMG102

Part 1 (Phase 1b)a

Part 2 (Phase 2)b

Part 3 (Phase 2)c

Panitumumab+ Rilotumumab(AMG 102) Q2W

R

A

N

D

O

M

I

Z

E

R

A

N

D

O

M

I

Z

E

Panitumumab+ Rilotumumab(AMG 102) Q2W

Rilotumumab (AMG 102) Q2W

Panitumumab+ Ganitumab(AMG 479) Q2W

Amgen Trial 20060447

NCT00788957

Ganitumab (AMG 479) Q2W

Panitumumab+ Placebo Q2Wd

C Eng et al. Clinical Science Symposium. A#3500. J ClinOncol 2011

ClinicalTrials.gov


Anti igf1r moabs in mcrc clinical implications

Anti-IGF1R MoAbs in mCRC: clinical implications

  • Two large phase II studies negative

  • Two randomized phase II/III studies negative

  • No further development in mCRC permited unless a dependence/predictive signature is characterized

    • Ligands IGF-1 & -2

    • IGF1R

    • IGFBPs


Outline4

Outline

  • New therapeutic options in mCRC:

    • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al

    • A phase III study of SOX (S-1/oxaliplatin) versus COX (capecitabine/oxaliplatin) in mCRC. A 3524. Park, et al

    • Phase II trial of figitumumab in mCRC. A3525. Becerra, et al

  • Maintenance treatment in mCRC:

    • A phase III trial on maintenance treatment with erlotinib + bevacizumabvsbevacizumab in mCRC. A3526. Johnsson, et al

    • A randomized phase II study of maintenance enzastaurin with 5-FU/leucovorin plus bevacizumab in mCRC. A3527. Wolff, et al

  • Predictive/prognostic biomarkers in mCRC:

    • An international consortium study in chemorefractory mCRC patients to assess the impact of FCGR polymorphisms on cetuximab efficacy. A3528. Geva, et al

    • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al


Act maintenance tx in mcrc study design

ACT: maintenance tx in mCRC. Study design

  • Primary objective:

    • PFS

  • Secondary objectives:

    • OS

    • ORR 1sttx

    • Safety

FOLFIRI / FOLFOX / XELIRI / XELOX

(Investigator´s choice)

+ bev (2.5 mg/kg*w)

18 weeks

PD

Curative surgery

  • Statistical design:

  • mPFS 3  5 m, HR 0.6

  • Power 90%, p<.05 (2s)

  • 168 events, 240 pts planned

  • Power 80%, 126 events

  • Stratification:

  • OXL-based chemo

  • Objective response

CR PR SD

Bev (7.5 mg/kg) q3w

Erlo (150 mg p.o.) qd

Bev(7.5 mg/kg) q3w


Act maintenance tx in mcrc results

ACT: maintenance tx in mCRC. Results

1.00

  • Bev + Erlotinibvs Bev: mPFS 4.2  5.9; HR 0.81, p=0.24

  • Combined treatment more toxic but manageable

  • ACT2 study: - KRAS WT: Bev + erlotinibvs Bev

    - KRAS MT: Bev + low dose CPC vs Bev

Estimated probability

0.75

0.50

HR 0.81 (0.57-1.15) p=0.24

0.25

0.00

0

5

10

15

20

Months


Enzastaurin maintenance tx in mcrc study design

Enzastaurin: maintenance tx in mCRC. Study design

FOLFIRI / FOLFOX

(Investigator´s choice)

+ bev (2.5 mg/kg*w)

12 weeks

  • Primary objective:

    • PFS

  • Secondary objectives:

    • OS

    • Safety

PD

  • Statistical design:

  • mPFS 5.5  7.5 m

  • Power 60%, p<.2 (1s)

  • Stratification:

  • OXL-based chemo

  • Objective response

CR PR SD

  • Enzaustarin:

  • Oral serine/threoninekinase

  • inhibitor targeting PKCβ

ENZ

+ 5FU/LV + Bev

Placebo +

5FU/LV + Bev

Enzastaurin 1125 mg/day gTID (125 mg tablets) on Day 1 of Cycle 1 (loading dose) and 500 mg/day given BID thereafter


Enzastaurin rationale in mcrc

Enzastaurin: rationale in mCRC

  • Suppresses signaling via PKCβand PI3K/AKT

    • Inhibits phosphorylation of downstream signal proteins, including GSK3b

  • Suppresses tumor growth, proliferation, and angiogenesis

  • Inhibits multiple PKC isoforms

    • Highly selective for PKCβ: IC50=0.006 mM

    • IC50 (mM): PKCa=0.039, PKCg=0.83, PKCe=0.110

    • Promotes apoptosis

  • Promotes apoptosis

  • Preclinical activity: only HCT-116, synergistic over bevacizumab, no evaluation with 5FU

Enzastaurin

A Novel, AcyclicBisindolylmaleimide


Enzaustarin maintenance tx in mcrc results

Enzaustarin: maintenance tx in mCRC. Results

  • mPFS from randomization 5.8 vs 8.1 m; HR=1.35, 95% CI: 0.84-2.16; p=0.9 (1s)

  • mPFS from start of first-line therapy 8.9 vs 11.3 m; HR=1.39, 95% CI: 0.86-2.23; p=0.9 (1s)

  • Low grade toxicity, but pulmonary embolism (7%) and G 3/4 thrombosis in 18%

  • Safety or activity interaction?

PFS Time From Randomization (Months)


Maintenance treatment in mcrc

Maintenance treatment in mCRC

  • Unmet need

  • Several approaches being evaluated

    • Targeted therapies:

      • Bevacizumab: MACRO, CAIRO-3, DREAM (+ erlotinib), AIO-ML21768

      • Cetuximab: MACRO-2

      • Other targeted therapies

    • Less complex/toxic chemotherapy

  • The concept is valid and feasible


Outline5

Outline

  • New therapeutic options in mCRC:

    • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al

    • A phase III study of SOX (S-1/oxaliplatin) versus COX (capecitabine/oxaliplatin) in mCRC. A 3524. Park, et al

    • Phase II trial of figitumumab in mCRC. A3525. Becerra, et al

  • Maintenance treatment in mCRC:

    • A phase III trial on maintenance treatment with erlotinib + bevacizumabvsbevacizumab in mCRC. A3526. Johnsson, et al

    • A randomized phase II study of maintenance enzastaurin with 5-FU/leucovorin plus bevacizumab in mCRC. A3527. Wolff, et al

  • Predictive/prognostic biomarkers in mCRC:

    • An international consortium study in chemorefractory mCRC patients to assess the impact of FCGR polymorphisms on cetuximab efficacy. A3528. Geva, et al

    • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al


Fcgr polymorphisms on cetuximab efficacy

FCGR polymorphisms on cetuximab efficacy

FcRIIa 131 histidine (H)/arginine (R)

FcRIIIa 158 valine (V)/phenylalanine (F)

Breast cancer

FcRIIa 131 histidine (H)/arginine (R)

FcRIIIa 158 valine (V)/phenylalanine (F)

NHL

A Musolino et al. J ClinOncol 2008;26:1789-1796;

WK Weng et al. J ClinOncol 2003;21:3940-3947


Fcgr polymorphisms on cetuximab efficacy1

FCGR polymorphisms on cetuximab efficacy

Colon cancer

  • Limited series available: 39 and 69 patients

  • FcRIIIa and FcRIIa polymorphisms predictive independently of KRAS mutation status

FcRIIIa 158 valine (V)/phenylalanine (F)

FcRIIa 131 histidine (H)/arginine (R)

FcRIIIa 158 valine (V)/phenylalanine (F)

FcRIIa 131 histidine (H)/arginine (R)

FcRIIa 131 histidine (H)/arginine (R)

W Zhang et al. J ClinOncol 2007;25:3712-3718;

F Bibeau et al. J ClinOncol 2009; 27:1122-1129


Fcgr polymorphisms on cetuximab efficacy european consortium

FCGR polymorphisms on cetuximab efficacyEuropean Consortium

  • Characteristics:

    • Largest series: KRAS WT 591 patients, KRAS MT 261 patients

    • Homogeneous population treated with cetuximab and irinotecan in the refractory setting

  • Results:

    • No correlation between FCGRIIa & IIIaSNPs and efficacy in unselected patients and KRAS WT population

    • In the KRAS MT population potential benefit in FCGRIIIa SNPs FF vs non-FF:

      • DCR 61.5% vs 47.9%, p=0.049 (Fisher's Exact Test, 2-sided)

      • Increase in OS: mOSFF 39 w vs non-FF 31 w, p=0.005

    • Hypothesis: ADCC in the non-sensitive population by signal transduction inhibition (KRAS MT)?


Outline6

Outline

  • New therapeutic options in mCRC:

    • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al

    • A phase III study of SOX (S-1/oxaliplatin) versus COX (capecitabine/oxaliplatin) in mCRC. A 3524. Park, et al

    • Phase II trial of figitumumab in mCRC. A3525. Becerra, et al

  • Maintenance treatment in mCRC:

    • A phase III trial on maintenance treatment with erlotinib + bevacizumabvsbevacizumab in mCRC. A3526. Johnsson, et al

    • A randomized phase II study of maintenance enzastaurin with 5-FU/leucovorin plus bevacizumab in mCRC. A3527. Wolff, et al

  • Predictive/prognostic biomarkers in mCRC:

    • An international consortium study in chemorefractory mCRC patients to assess the impact of FCGR polymorphisms on cetuximab efficacy. A3528. Geva, et al

    • Addition of panitumumab to irinotecan: Results of PICCOLO in mCRC. A3523. Seymour, et al


Piccolo ir vs irpan analysis populations1

PICCOLO: Ir vs. IrPan – Analysis populations

Primary analysis population (red circle, n=460): KRAS12-13,61-wt, unpretreated

“Double wild-type” (n=384): confirmed to also be BRAF-wt

“All wild-type” (n=265): wt at KRAS12-13,61 KRAS146 NRAS12-13,61and BRAF


Piccolo pfs by molecular populations

PICCOLO: PFS by molecular populations

KRAS wt: 460 pts, 399 events

HR=0.78 (0.64, 0.95), p=0.01

Double wt : 348 pts, 304 events;

HR=0.73 (0.58, 0.92), p=0.01

All wt: 264 pts, 229 events;

HR=0.70 (0.53, 0.91), p=0.01

BRAFmut: 63 pts, 59 events;

HR=1.47 (0.85, 2.56)

NRAS mut: 21 pts, 19 events

HR=2.18 (0.74, 6.39)

KRAS146mut: 17 pts, 15 events

HR=0.56 (0.13, 2.48)

Anymut: 99 pts, 91 events

HR=1.38 (0.89, 2.13)

*Adjusted HRs, 95% CIs

IrPanbetterIr better


Piccolo os by molecular populations

PICCOLO: OS by molecular populations

KRAS wt: 460 pts, 312 events

HR=0.91 (0.73, 1.14), p=0.44

Double wt : 348 pts, 230 events; HR=0.87 (0.67, 1.13), p=0.30

All wt: 264 pts, 171 events; HR=0.86 (0.63, 1.16), p=0.32

BRAFmut: 63 pts, 53 events; HR=2.03 (1.13, 3.64)

NRAS mut:21 pts, 15 events

HR=4.59 (1.19, 17.67)

KRAS146mut: 17 pts, 14 events

HR=1.32 (0.30, 5.81)

Anymut:99 pts, 80 events

HR=2.03 (1.26, 3.28)

*Adjusted HRs, 95% CIs

IrPanbetterIr better


Piccolo os by molecular populations1

PICCOLO: OS by molecular populations

Ir

IrPan

Ir

IrPan

BRAF mut

HR=2.03 [1.13, 3.64] p=0.017

63 patients, 53 events

Any Mutation

HR=2.03 [1.26, 3.28] p<0.01

99 patients, 80 events


Piccolo molecular populations clinical implications

PICCOLO: molecular populations. Clinical implications

  • Patients with BRAF-mut tumors had a poor prognosis and in this study appeared to be further harmed by the addition of panitumumab

  • Overall, 99/460 (22%) patients with KRAS12-13,61-wt tumors had activating mutations in the RAS/RAF pathway, and had significant OS detriment with panitumumab: HR=2.03 (1.26-3.28).

  • International Academic/Pharma collaboration is required to evaluate/corroborate this results in randomized studies

  • Example: European consortium1

  • Potential implications in patient’s profile

W De Roock et al. Lancet Oncol 2010;11:753-762


Acknowledgments

Acknowledgments

  • Thanks to the authors for providing all the presentations and answers to my queries

  • Special thanks to:

    • Daniel Sargent

    • Andres Cervantes

    • Sabine Tejpar


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