Moving The Bar in Upper GI Malignancies: A Review of Recent Upper Gastrointestinal Phase III Studies – Clinically Meaningful or

Just Statistically Positive?

Eileen M. O’Reilly, M.D.Associate Member, Associate AttendingMemorial Sloan-Kettering Cancer Center

Associate ProfessorWeill Medical College of Cornell University

Three Perspectives

• Review of Recent Phase III Studies in Upper Gastrointestinal Malignancies– Eileen M. O’Reilly, M.D.

• Health Care Economics in Relation to Upper Gastrointestinal Cancers– Neal J. Meropol, M.D.

• Statistical Review of the benefit: Is it Meaningful?– Donna Niedzwicki, Ph.D.

Agenda/ Goals

• Discuss recent representative positive phase III studies in:– Gastric cancer– Pancreas neuroendocrine cancer– Pancreas adenocarcinoma

• Focus on trial design, results, application

• Cost, statistical considerations – co-speakers

Gastric Cancer

Example of clinically significant and statistically significant phase III trial with utility in a clearly defined patient subset

Rationale for Trastuzumab in Gastric Ca

• Her-2 – transmembrane receptor tyrosine kinase• 10-20% of GC, 20- 30% GE Jn ca are Her-2+• Trastuzumab

– Inhibits Her-2 signaling in Her-2+ tumors– Prevents Her-2 activation– Activates antibody-dependent cellular cytotoxicity

• Trastuzumab has benefit in Her-2 overexpressing GC cell lines and Her-2+ tumors in mice xenografts

Fujimoto, 2007. Gravolos, 2008. Kim, Int J Oncol, 2008. Kasprzyk, PG, Cancer Res, 1992

Bang, Y., et al. Lancet, 2010

ToGA Trial: Gastric CancerRandomized Phase III

Stratification₋ Location: Stomach vs GE junction₋ Measurable vs non-measurable₋ ECOG 0-1 vs 2₋ Fluropyrimidine: 5-FU (800mg/m2 IV d 1-5) vs capecitabine (1000mg/m2 PO BID d 1-14)

N= 3807 screened↓

N= 810 (22%)Her-2 Positive GC

↓N= 594 eligible

N= 294 FU + Cisplatin 80 mg/m2

x 6 cycles + Trastuzumab q 3wks

N= 290 FU + Cisplatin 80 mg/m2

x 6 cycles

RANDOMIZE

Bang, Y., et al. Lancet, 2010

ToGA Design & Endpoints

• Randomized, double-blind, placebo-controlled• Her-2 testing – central lab (Germany)

– Positive: IHC 3+ or FISH+ (> 2) in IHC 0, 1+ or 2+

• Primary endpoint: OS• Secondary endpoints: PFS, TTP, ORR, duration of response,

safety, QoL

• Biostatistical plan– Median OS 10 → 13 mths (HR 0.77)– α level 0.05, 80% power– N= 584

Bang, Y. Lancet, 2010

ToGA: Overall Survival (FISH+ or IHC3+)

Bang, Y. Lancet, 2010

ToGA: Progression-Free Survival

Bang, Y. Lancet, 2010

ToGA Survival: IHC 2+/FISH+ or IHC 3+(Post-hoc Exploratory Analysis)

Bang, Y. Lancet, 2010

Response Rate

CharacteristicF + C

N= 290F + C +

TrastuzumabN= 294

Complete response 2.4% 5.4%

Partial response 32% 42%

Overall response rate 34.5% 47.3%p= 0.0017

Toxicity: Non-Hematologic AE’s

Adverse eventF+C

N= 290F+C + Trastuzumab

N= 294

All Grade 3-4 All Grade 3-4

NauseaVomitingFatigueDiarrheaConstipationAstheniaStomatitisWeight decreaseAbdominal painCardiac AE’s

63%46%28%28%32%18%15%14%14%6%

7%8%2%4%2%3%2%2%1%3%

67%50%35%37%26%19%24%23%16%6%

7%6%4%9%

<1%4%

<1%2%1%1%

AEs occurring in >10% of patients

TOGA Trial: Quality of Life

• EORTC QLQ-C30, gastric cancer specific module STO22– Global health scores increased during and after

chemotherapy in both arms– Disease specific symptoms (dysphagia) improved

both arms– No negative impact in QoL for addition of

trastuzumab

Ruschoff, J. Virchows Arch, 2010

Summary Her-2 Targeting in Esophago-Gastric Cancer

• Her-2 validated target– Survival endpoint substantiated, clinically signficant

• Improved OS, PFS, RR, TTP, QoL, similar safety• Standardized scoring system• Better in high Her-2 expression (IHC 2+ /FISH+ IHC 3+)• Trastuzumab

– FDA approved for GC (10/ 2010): Her-2 overexpressing– EMEA approval: IHC3+ or IHC2+/FISH+– NICE (UK): IHC3+ only

Pancreas Neuroendocrine Tumors (PNET’s)

Examples of trials statistically challenging to design; full clinical impact remains to be seen but benefits appear meaningful

Pancreas Neuroendocrine Tumors (PNET’s)

• Rare malignancies– 1.3% of all pancreas malignancies– 2-4 per million– 1,000 yr new diagnoses US, rising incidence

• Variable natural history, median OS with metastases > 2 yrs

• FDA drug approvals– 1982 Streptozotocin (+/- 5FU, doxorubicin)– 1998 Somatostatin (symptomatic NET’s)

Yao, JC. Ann Surg Oncol, 2007. Moertel, CG. NEJM, 1980. Jensen, RT. Cancer, 2008

Everolimus (RAD001)

• mTOR serine-threonine kinase– Central regulator of protein synthesis– Autocrine activation via IGF-1 in PNET’s

• Antiproliferative effect on PNET cell lines by binding to FKBP-12

• Prior activity demonstrated in PNET’s

von Wichert, G. Cancer Res, 2000. Yao, JC. J Clin Oncol, 2008. Yao, JC. J Clin Oncol, 2010

Yao, JC. NEJM, 2011

RADIANT-3: Phase III Everolimus vs Placebo

Randomization 1: 1Stratification₋ Prior chemotherapy Y vs N₋ WHO performance status 0 vs 1-2Option for cross-over from placebo arm on POD

N= 410 PNET‘sWell-differentiated

Low-intermediate gradePOD within 12 mthsMeasurable disease

WHO performance 0-2N= 203 Placebo

N= 207 Everolimus 10mg daily

RANDOMIZE

Yao, CJ. NEJM, 2011

RADIANT-3 Design & Endpoints

• Randomized, double-blind, placebo-controlled• Primary endpoint: PFS

– Local, central, independent RECIST (1.0) reviews• Secondary endpoints:

– OS, ORR, duration response, safety

• Biostatistical plan– 33% reduction in risk of POD/death (HR 0.67)

prolonging mPFS from 6 → 9 mths– N= 282 progression-free events; 92.6% power, 1-sided

significance 2.5%, estimated 10% lost to follow-up– N= 392

Demographic Information

CharacteristicEverolimus

N= 207PlaceboN= 203

SexMale / Female 53% / 47% 58% / 42%

Age, years (median) 58 (23-87) 57 (20- 82)

Prior somatostatin (on study) ~50% (~40%) ~50% (~40%)

WHO performance status012

139 (67%)62 (30%)

6 (3%)

133 (66%)64 (32%)

6 (3%)

HistologyWell differentiatedModerately differentiated

170 (82%)35 (17%)

171 (84%)30 (15%)

Time from initial diagnosis > 2 yrs 118 (57%) 127 (63%)

Yao, JC. NEJM, 2011

RADIANT-3: PFS & Response

Characteristic EverolimusN= 207

PlaceboN= 203

PFS events (%) 109 (53%) 165 (81%)

Censored data (%) 98 (47%) 38 (19%)

Median PFS months 11 mths 4.6 mths

HR 0.35 (0.27- 0.45), p< 0.001

Median duration exposure 38 weeks 16 weeks

Response rate 5% 2%

Stable disease 73% 51%

Yao, JC. NEJM, 2011

Progression-Free and Overall Survival and

Overall Survival.

Yao JC et al. N Engl J Med 2011;364:514-523.

Progression-Free Survival

Overall Survival

Yao, JC. NEJM, 2011

RADIANT-3: Toxicity

Adverse event, %

EverolimusN= 204

PlaceobN= 203

All Grade 3-4 All Grade 3-4

StomatitisRashDiarrheaFatigueInfectionsNauseaAnemiaLow plateletsPneumonitisHyperglycaemiaCough

131 (64%)99 (49%)69 (34%)64 (31%)46 (23%)41 (20%)35 (17%)27 (13%)35 (17%)27 (13%)22 (11%)

14 (7%)1 (<1%)7 (3%)5 (2%)5 (2%)5 (2%)

12 (6%)8 (4%)5 (2%)11 (5%)

-

34 (17%)21 (10%)20 (10%)29 (14%)12 (6%)

37 (18%)6 (3%)

1 (<1%)-

9 (4%)4 (2%)

---

1 (<1%)1 (<1%)

----

4 (2%)-

AEs occurring in >10% of patients

Everolimus in PNET’s

• 65% risk reduction in POD/(death)• Mostly grade 1-2 side effects• Mature survival data pending• Benefit in subpopulations (further data poster

discussion session 6/6)• Long-term use question• Combination therapy?

PNETs and Sunitinib

• PNET’s– Angiogenesis key role in development PNET’s– High VEGF expression correlated with poorer prognosis– Express PDGFR, c-KIT, VEGFR2, VEGFR3, EGF

• Sunitinib– Broad spectrum oral tyrosine kinase inhibitor

VEGFR 2, 3, c-kit, PDGF, FLT– Activity in preclinical model RIP1-Tag2 transgenic mouse model

of NET – decreased endothelial cell density, pericytes on vessels– Phase I, II clinical activity in NET’s observed

Couvelard, A. Br J Can, 2005. Zhang, J. Can, 2007. Pietras, K. J Clin Oncol, 2005. Faivre, S. J Clin Oncol, 2006. Kulke, MH. J Clin Oncol, 2008

Raymond, E. NEJM, 2011

Randomized Phase III Sunitinib vs PlaceboSUN 1111

Randomization 1: 1, balanced by country/regionNo other stratification factors used

N= 171 PNET‘s

Well-differentiatedPOD within 2-12 mthsMeasurable disease

ECOG performance 0-1 N= 85 Placebo

N= 86 Sunitinib 37.5 mg PO daily

RANDOMIZE

Raymond, E. NEJM, 2011

Phase III Sunitinib vs Placebo Design & Endpoints

• Randomized, double-blind, placebo-controlled• Primary endpoint: PFS• Secondary endpoints:

– ORR, duration response, OS, safety

• Biostatistical plan– N= 340 pts – 260 events, 90% power

50% increase PFS (placebo arm: 5.1 months)– 2-sided log-rank– Interim analysis after N= 130 events

Study Conduct

• 6/07- 4/09 N= 171 accrued from 42 centers, 11 countries

• 2/09 Data Safety Monitoring Committee– N= 154 accrued (340 planned)– Recommended discontinuation of trial

• High rate of progression (49 on placebo, 24 on sunitinib); deaths in control arm (15 on placebo, 5 on S)

• Delayed progression in sunitinib arm

Demographic Information

CharacteristicSunitinib

N= 86PlaceboN= 85

Sex, %Male / Female 49% / 51% 47% / 53%

Age, years (median) 56 (25-84) 57 (26-78)

ECOG performance status01

53 (62%)33 (38%)

41 (48%)43 (51%)

TumorNon-functioningFunctioning

42 (49%)25 (28%)

44 (52%)21 (24%)

Ki67 ≤ 5% (where available) 23 (63%) 20 (56%)Time from initial diagnosis

(median) 2.4 years 3.2 years

Raymond, E. NEJM, 2011

Sunitinib vs Placebo: Endpoints

CharacteristicSunitinib

N= 86PlaceboN= 85

PFS events (%) 30 (35%) 51 (60%)

Censored data (%) 56 (65%) 34 (40%)

Estimated median PFS 11.4 mths 5.5 mths

HR 0.42 (0.26- 0.66), p< 0.001

# Deaths at study termination 9 (10%) 21 (25%)

Censored data (%) 77 (90%) 64 (75%)

Median overall survival NR NR

Response rate (%) 8 (9%) - (0%)

Stable disease (%) 54 (63%) 51 (60%)

Raymond, E. NEJM, 2011

Overall Survival: Sunitinib vs Placebo1.0

0.8

0.6

0.4

0.2

0

Pro

po

rtio

n o

f p

atie

nts

0 5 10 15 20 25

86 60 38 16 3 085 61 33 12 3 0

Number at risk

SunitinibPlacebo

Time (months)

Sunitinib

Placebo

HR=0.42 (95% CI 0.19, 0.89)

P=0.02

Raymond, E. NEJM, 2011

Sunitinib vs Placebo: Toxicity

Adverse event

SunitinibN= 83

PlaceobN= 82

All Grade 3-4 All Grade 3-4

DiarrheaNauseaAstheniaVomitingFatigueNeutropeniaHypertensionHand-FootStomatitisRashPlatelets

49 (59%)37 (45%)28 (34%)28 (34%)27 (32%)24 (29%)22 (26%)19 (23%)18 (22%)15 (18%)14 (17%)

4 (5%)1 (1%)4 (5%)

-4 (5%)

10 (12%)14 (10%)

5 (6%)3 (4%)

-3 (4%)

32 (39%)24 (29%)25 (30%)29 (14%)22 (27%)

3 (4%)4 (5%)2 (2%)2 (2%)4 (5%)4 (5%)

2 (2%)1 (1%)3 (4%)2 (2%)7 (8%)

-1 (1%)

----

AEs occurring in >10% of patients

Summary: Sunitinib in PNET’s

• EMEA approved 12/10; FDA approved 05/11 • Concerns about study design

– Small trial, N= 171– Only 28% of 260 planned PFS events – inflated

effect?– Several unplanned analyses– High cross-over rate – Side effects of sunitinib

Integration of Therapy in PNET

• Everolimus, sunitinib – new options in rare malignancy• What’s the best time to start therapy?• Which therapy first?• Toxicity profile• How to sequence with other systemic/regional

treatment approaches?• Combination of targeted medications?• Role of systemic chemotherapy, e.g., temozolomide +

capecitabine

Pancreas Adenocarcinoma

Example of statistically significant phase III trial but clinically limited therapeutic impact

Moore, M. J Clin Oncol, 2007

NCI PA.3 Phase IIIGemcitabine/Erlotinib vs Gemcitabine/Placebo

Randomization 1: 1Stratification Locally advanced vs M1 Center PS 0-1 vs 2

N= 569 LA or M1 Untreated Pancreas Adenoca

N= 284 Gemcitabine + Placebo

N= 285 Gemcitabine + Erlotinib

(100mg, 150mg)

RANDOMIZE

PA.3 Study Design & Endpoints

• Randomized phase III, double-blind, placebo-controlled

• Primary: OS• Secondary: PFS, RR, duration response, safety,

QoL, correlative EGFR• Biostatistics

– Designed to detect HR 0.75– Minimum of 381 deaths, 80% power, 2-sided 5%– N= 450

CharacteristicG + Erlotinib

N= 285G + Placebo

N= 284

Median overall survival 6.24 mths 5.91 mths

HR. 0.82 (0.69- 0.99), p= 0.038

1-year overall survival 23% 17%Progression-free survival 3.75 mths 3.55 mths

HR 0.77 (0.64- 0.92), p= 0.004

Disease control rate 57.5% 49.2%

PA.3 Results

Moore, MJ. J Clin Oncol, 2007

Moore, MJ. J Clin Oncol, 2007

PA.3 Toxicity

Adverse event

G + ErlotinibN= 282

G + PlaceboN= 280

All Grade 3-4 All Grade 3-4

DiarrheaFatiguePneumonitisInfectionRashStomatitis

56%89%2.1%43%72%23%

6%15%

-17%6%

<1%

41%86%0.4%34%29%29%

2%15%

-16%1%1%

AEs occurring in >10% of patients

Moore, MJ. J Clin Oncol, 2007

Exploratory: Rash and Outcome

Miskad, R. J Clin Oncol, 2007

Summary: Gemcitabine + Erlotinib

• Solid rationale in pancreas adenoca• Statistically significant improved OS, PFS and disease

control• Targeted group – subset with ≥ grade 2 rash• FDA approval in 11/05• Concern relates to the clinical import of results

– Modest effect, higher rates of rash, diarrhea, infection, stomatitis

– Cost effectiveness analyses – limited value• Perspective of FOLFIRINOX

Gemcitabine

FOLFIRINOX

FOLFIRINOX vs Gemcitabine: Overall Survival

Number at riskGemcitabineFOLFIRINOX

171 134 89 48 28 14 7 6 3 3 2 2 2171 146 116 81 62 34 20 13 9 5 3 2 2

1 .0 0

0 .7 5

0 .5 0

0 .2 5

0 .0 0

Pr o

ba

bili

ty

M o n th s0 3 6 9 1 2 1 5 1 8 2 1 2 4 2 7 3 0 3 3 3 6

Median 11.1 mths

Median 6.8 mths

HR= 0.57P < 0.0001

Conroy TJ. NEJM, 2011

CharacteristicFOLFIRINOX

N= 171Gemcitabine

N= 171

Median survival 11.1 mths 6.8 mthsHR. 0.57 (0.45- 0.73), p< 0.001

1-Year overall survival 48% 21%Progression-free survival 6.4 mths 3.3 mths

HR 0.47 (0.37- 0.59), p< 0.001

Overall response rate 32% 9.4%Stable disease 39% 42%Rate of disease control 70% 51%

FOLFIRINOX vs Gemcitabine

Conroy, T. NEJM, 2011

Phase III Trials in Upper GI Malignancies:Clinically Meaningful or Statistically Significant?

• Practice changing results in some cases– Trastuzumab, FOLFIRINOX

• Statistically significant: Erlotinib• We don’t fully now yet: Everolimus, sunitinib • Drug approvals in rare diseases – PNET• New FDA precedent: PFS in diseases with long hx• Era of cost constraints: all agents palliative, all

expensive and all have added toxicity• Future – strength of rationale for agent, robustness

of earlier phase results, trial design