Gastrointestinal Colorectal Cancer Poster Discussion Session #3523 - #3528

Gastrointestinal Colorectal CancerPoster Discussion Session

#3523 - #3528

Josep Tabernero, MDVall d’Hebron University Hospital

Barcelona, Spain

Disclosure

• Consutant or Advisory Role:– Amgen– Biogen Idec– Bristol-Myers Squibb– Merck-Serono KGaA– Novartis– Onyx– Pfizer– Roche– Sanofi-Aventis

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 + bevacizumab vs

bevacizumab 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)

Ir vs IrCsnon-inferior efficacy

primary endpoint PFS at 12 wks

IrPanirinotecan + panitumumab

IrCsirinotecan + ciclosporin

Iririnotecan alone

target n = 1125(494 accrued by end of May 2008)

confirmed aCRC, measurable diseaseprogression during/after prior FP ± oxali

no prior irinotecanWHO PS 0-2

Ir vs IrPansuperior efficacy

primary endpoint OS

PICCOLO: amendment from June 2008

Ir vs IrCsnon-inferior efficacy

primary endpoint PFS at 12 wks

IrPanirinotecan + pan’mab

IrCsirinotecan + c’sporin

Iririnotecan alone

Ir vs IrPansuperior efficacy

primary endpoint OS

Iririnotecan alone

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

target total n = 1200 (including 494 accrued under previous design)

eligibility as before

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 NRAS12-13,61 and BRAF

HR=0.91 [0.73, 1.14], p=0.44460 patients, 312 events

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

IrIrPan

Overall Survival; KRAS-wt

PICCOLO: Ir vs. IrPan – Efficacy analysis

HR=0.78 [0.64, 0.95], p=0.01460 patients, 399 events

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

IrIrPan

Progression-free Survival; KRAS-wt

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

PICCOLO: Clinical implications – 2nd line mCRC

Study N Pre OXL (%) PFS (m) PFS HR, p OS (m) OS HR, p

Ir + Ab Ir Ir + Ab Ir

2005-181 582 67 5.9 3.9 0.73; p .004 14.5 12.5 0.85, p .12

PICCOLO 460 95 5.5 4.7 0.78; p .01 10.4 10.5 0.91, p .44

EPIC (all KRAS) 1298 100 4.0 2.6 0.69; p .0001 10.7 10 0.98, p .71

D Morton, et al. for the FOxTROT Collaborative Group. ASCO 2011, Abstract #3568A Sobrero et al. EPIC study, J Clin Oncol 2008; 26:2311-2319; M Peeters et al. J Cin Oncol 2010; 28:4706-4713










Seymour, et al

Stra

tific

atio

n

Ran

dom

izat

ion

S-180 mg/m2 days 1-14

Oxaliplatin130 mg/m2 day 1

q3w

Capecitabine2000 mg/m2 days 1-14

Oxaliplatin130 mg/m2 day 1

q3w

A

B

344 Pts., 11 Centers12 months enrollment, 12 moths F/U

PrimarySite

Prior Adjuvant Treatment

Measurable or

Evaluable Disease

SOX vs COX in mCRC: Study design

Primary objective: • PFS

Secondary objectives:• OS• ORR• QoL• Safety

• 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: Statistical hypothesis

SOX vs COX in mCRC: Patients population

• Adhere to the CONSORT disposition• Populations: - intention-to-treat

- per protocol

- safety

SOX COX Total

Total N 172 173 345

Full analysis 168 165 333

Safety 169 166 335

PP analysis 164 163 327

SOX vs COX in mCRC: Efficacy data

FA setHR = 0.760 [0.594, 0.973]P-value = 0.0286Median : 7.2 vs. 6.2 m

FA setHR = 0.897 [0.638, 1.260]P-value = 0.5298Median : 20.9 vs. 19.9 m

SOX COX Odds; pORR 47% 34% 1.776; 0.012

DCR 88% 85% 1.299; 0.4216

Overall SurvivalProgression-free Survival

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

SAEs ≥Grade 2 SOX N=169 COX N=166HB 25 14ANC 77 68PLT 80 47CONSTITUTIONAL 55 39SKIN 16 24N/V 72 49DIARRHEA 35 27LIVER FUNCTION 47 22NEUROPATHY 62 50

SOX vs COX in mCRC: Safety profile

• All toxicities but skin more frequent in SOX than COX

SAEs ≥Grade 2 SOX N=169 COX N=166HB 25 14ANC 77 68PLT 80 47CONSTITUTIONAL 55 39SKIN 16 24N/V 72 49DIARRHEA 35 27LIVER FUNCTION 47 22NEUROPATHY 62 50

SOX vs COX in mCRC: Safety profile

• 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

SOX vs COX in mCRC: Critique and implications










Seymour, et al

Figitumumab

Human IgG2 anti-IGF1R MoAb2 cohorts: (A) 20 mg/Kg q2w; (B) 30 mg/Kg q3w

Endpoint 6-month OS

Secondary endpoints

PFS, OS, ORR, PK, safety, ADA levelsp-fIGF-1

Statistics H0 p=0.45; H1 p>0.45; sample size calculation not well defined (85 + 83 = 168 patients)

Patients Refractory mCRC; 76% ≥3 systemic txNo comments on previous anti-EGFR tx

Molecular selection

No molecular selection

Figitumumab (CP-751,871) in mCRC

Results mPFS: 1.4 monthsmOS: 5.6 – 5.8 monthsORR: 0%

Biomarker Trend of longer mOS in pts with ↑ p-fIGF-1 levelsNo data on how cut-off was established <1 vs ≥1 ng/mL (mean, median, quartile?)

Safety Most common AEs: anorexia, astheniaMost common grade 3/4 AEs: hyperglycemia, asthenia

Figitumumab (CP-751,871) in mCRC

Cixutumumab (IMC-A12) ± Cetuximab

• Randomized, phase II study of the IGF-1R MoAb IMC-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

Amended for KRas wild type; N=344 patients

ClinicalTrials.gov

• Negative: inferior PFS & OS for experimental arms• Biomarker sub-analysis in progress

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

Pmab vs Pmab + AMG479 vs Pmab + AMG102

ClinicalTrials.gov

RANDOMIZE

RANDOMIZE

Amgen Trial 20060447 NCT00788957

Part 2 (Phase 2)bPart 1 (Phase 1b)a Part 3 (Phase 2)c

Panitumumab + Rilotumumab(AMG 102) Q2W

Panitumumab + Ganitumab(AMG 479) Q2W

Panitumumab + Placebo Q2Wd

Rilotumumab (AMG 102) Q2W

Ganitumab (AMG 479) Q2W

Panitumumab + Rilotumumab(AMG 102) Q2W

Eventsn/N (%)

Median Months(95% CI)

Panitumumab + Placebo (n = 48) 36/48 (75) 3.7 (2.5-5.3)Panitumumab + Ganitumab (n = 46) 36/46 (78) 5.3 (2.7-5.7)

Hazard ratio = 0.89 (95% CI: 0.56-1.42)

Patie

nts

with

Prog

ress

ion-

Free

Surv

ival

(%)

Patients at risk:Panitumumab + Placebo: 48 43 30 24 19 19 7 6 3 2 1 1 0

Panitumumab + Ganitumab: 46 44 30 27 24 22 11 8 1 1 1 1 0

1009080706050403020100

0 1 2 3 4 5 6 7 8 9 10 11 12Months

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

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– …










Seymour, et al

ACT: maintenance tx in mCRC. Study design

FOLFIRI / FOLFOX / XELIRI / XELOX(Investigator´s choice)+ bev (2.5 mg/kg*w)

18 weeks

Bev (7.5 mg/kg) q3wBev (7.5 mg/kg) q3wErlo (150 mg p.o.) qd

CR PR SD

PDCurative surgery

Stratification:•OXL-based chemo•Objective response


Secondary objectives:• OS• ORR 1st tx• Safety

Statistical design:mPFS 3 5 m, HR 0.6Power 90%, p<.05 (2s)168 events, 240 pts plannedPower 80%, 126 events

• Bev + Erlotinib vs Bev: mPFS 4.2 5.9; HR 0.81, p=0.24• Combined treatment more toxic but manageable• ACT2 study: - KRAS WT: Bev + erlotinib vs Bev

- KRAS MT: Bev + low dose CPC vs Bev

Events Median PFS (mos, 95% CI)

Bev + erlo 62 5.93 (4.30-6.37)

Bev 67 4.23 (3.77-4.83)

Est

imat

ed p

roba

bilit

y

0.00

0.25

0.50

0.75

1.00

0 5 10 15 20Months

HR 0.81 (0.57-1.15) p=0.24

ACT: maintenance tx in mCRC. Results

Enzastaurin: maintenance tx in mCRC. Study designFOLFIRI / FOLFOX

(Investigator´s choice)+ bev (2.5 mg/kg*w)

12 weeks

Placebo +5FU/LV + Bev

ENZ+ 5FU/LV + Bev

CR PR SD

PD

Stratification:•OXL-based chemo•Objective response


Secondary objectives:• OS• Safety

Statistical design:mPFS 5.5 7.5 mPower 60%, p<.2 (1s)

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

Enzaustarin:Oral serine/threonine kinaseinhibitor targeting PKCβ

Enzastaurin: rationale in mCRC

EnzastaurinA Novel, Acyclic

Bisindolylmaleimide

• Suppresses signaling via PKCβ and 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

♦ 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?

Enzaustarin: maintenance tx in mCRC. Results

PFS Time From Randomization (Months)

• 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

Maintenance treatment in mCRC










Seymour, et al

FCGR polymorphisms on cetuximab efficacyFcRIIIa 158 valine (V)/phenylalanine (F) FcRIIa 131 histidine (H)/arginine (R)

Breast cancer

A Musolino et al. J Clin Oncol 2008;26:1789-1796;WK Weng et al. J Clin Oncol 2003;21:3940-3947

FcRIIa 131 histidine (H)/arginine (R) FcRIIIa 158 valine (V)/phenylalanine (F)

NHL

FCGR polymorphisms on cetuximab efficacy

W Zhang et al. J Clin Oncol 2007;25:3712-3718;F Bibeau et al. J Clin Oncol 2009; 27:1122-1129

FcRIIa 131 histidine (H)/arginine (R)

FcRIIIa 158 valine (V)/phenylalanine (F) FcRIIa 131 histidine (H)/arginine (R)

FcRIIIa 158 valine (V)/phenylalanine (F) FcRIIa 131 histidine (H)/arginine (R)

Colon cancer

♦ Limited series available: 39 and 69 patients♦ FcRIIIa and FcRIIa polymorphisms predictive independently of KRAS mutation status

• 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 & IIIa SNPs 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: mOS FF 39 w vs non-FF 31 w, p=0.005

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

FCGR polymorphisms on cetuximab efficacyEuropean Consortium










Seymour, et al

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 NRAS12-13,61 and BRAF

IrPan better Ir better

*Adjusted HRs, 95% CIs

KRAS wt: 460 pts, 399 eventsHR=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

NRAS mut: 21 pts, 19 eventsHR=2.18 (0.74, 6.39)

KRAS146 mut: 17 pts, 15 eventsHR=0.56 (0.13, 2.48)

Any mut: 99 pts, 91 eventsHR=1.38 (0.89, 2.13)

All wt: 264 pts, 229 events; HR=0.70 (0.53, 0.91), p=0.01

BRAF mut: 63 pts, 59 events; HR=1.47 (0.85, 2.56)

PICCOLO: PFS by molecular populations

IrPan better Ir better

*Adjusted HRs, 95% CIs

KRAS wt: 460 pts, 312 eventsHR=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

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

NRAS mut: 21 pts, 15 eventsHR=4.59 (1.19, 17.67)

KRAS146 mut: 17 pts, 14 eventsHR=1.32 (0.30, 5.81)

Any mut: 99 pts, 80 eventsHR=2.03 (1.26, 3.28)

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

PICCOLO: OS by molecular populations

HR=2.03 [1.26, 3.28] p<0.0199 patients, 80 events

Any Mutation

IrIrPan

BRAF mut

HR=2.03 [1.13, 3.64] p=0.01763 patients, 53 events

IrIrPan

PICCOLO: OS by molecular populations

• 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

PICCOLO: molecular populations. Clinical implications

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

Acknowledgments• Thanks to the authors for providing all the

presentations and answers to my queries• Special thanks to:

– Daniel Sargent– Andres Cervantes– Sabine Tejpar

Gastrointestinal Colorectal Cancer Poster Discussion Session #3523 - #3528

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