ASCO 2009 Highlights in Gastrointestinal Malignancies Axel Grothey - - PowerPoint PPT Presentation

ASCO 2009 Highlights in Gastrointestinal Malignancies

Axel Grothey Professor of Oncology Mayo Clinic Rochester

Adjuvant Therapy of Colon Cancer

• LBA 04

NSABP C-08 Wolmark

• 4000

Oncotype QUASAR Kerr

• 4001

PETACC-3 Tejpar

• 4002

PETACC-3 Roth

• 4010

Elderly pts McCleary

History of adjuvant therapy of colon cancer

• 5-FU/lev superior

to surgery alone

• 5-FU/LV superior

to surgery alone

• 5-FU/LV superior to 5-

FU/lev

• 6- and 12-month

treatment cycles equivalent

• Lev unnecessary
• High-dose and low-

dose LV equivalent

• Monthly and weekly

treatment equivalent

• LV5FU2 and

monthly bolus equivalent

1990 1994 1998 2002

Moertel et al. Ann Intern Med. 1995;122:321. Francini et al. Gastroenterol. 1994;106:899. Wolmark et al. Proc Am Soc Clin Oncol. 1996;15:205. Abstract O’Connell et al. J Clin Oncol. 1998;16:295. Haller et al. Proc Am Soc Clin Oncol. 1998;17:256a. Abstract 982. Andre et al. Proc Am Soc Clin Oncol. 2002. Abstract 529.

Beyond 5-FU in the adjuvant setting

Completed studies:

• Oxaliplatin (MOSAIC, NSABP C-07)
• Irinotecan (CALGB 89803, ACCORD-2, PETACC-3)
• Capecitabine (X-ACT)
• Bevacizumab (NSABP C-08)

Ongoing studies:

• CAPOX (XELOXA)
• Bevacizumab (AVANT, E5202)
• Cetuximab in KRAS wt CC (N0147, PETACC-8)

MOSAIC: Study Design

Primary end-point: disease-free survival Secondary end-points: safety, overall survival

n=2246 Enrollment: Oct 1998–Jan 2001 (146 centres; 20 countries)

• Completely resected colon cancer
• Stage II, 40%; Stage III, 60%
• Age 18–75 years
• KPS ≥60
• No prior chemotherapy

R

LV5FU2 FOLFOX4

(LV5FU2 + oxaliplatin 85 mg/m²)

(n=1123) (n=1123)

LV5FU2, Leucovorin 200 mg/m2 iv over 2 hours followed by 5-fluorouracil 400 mg/m2 bolus and 5-fluorouracil 600 mg/m2 iv

• ver 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m2 iv over 2 hours on Day 1

MOSAIC: Disease-free Survival - Final Update

5-year DFS %

HR [95% CI] p-value FOLFOX4 LV5FU2 ITT 73.3 67.4 0.80

[0.68–0.93]

0.003 Stage III 66.4 58.9 0.78

[0.65–0.93]

0.005 Stage II 83.7 79.9 0.84

[0.62–1.14]

0.258 High-risk stage II n=576 82.1 74.9 0.74

[0.52–1.06]

— Low-risk stage II n=323 86.3 89.1 1.22

[0.66–2.26]

—

Data cut-off: June 2006

Δ7.5 Δ7.2

―High-risk‖ Stage II Colon Cancer

• Clinico-pathological parameters (MOSAIC)
• T4 tumors
• Obstruction/perforation
• Lymphatic or vascular invasion
• Undifferentiated histology
• Less than 10 (12) Ln examined
• Molecular parameters
• LOH 18q
• MSS
• Other?

MOSAIC: OS: Stage II and Stage III

Data cut-off: January 2007 FOLFOX4 stage II LV5FU2 stage II FOLFOX4 stage III LV5FU2 stage III

Overall survival (months) Probability

1.0 0.8 0.6 0.4 0.2 0.9 0.7 0.5 0.3 0.1 6 12 18 24 60 30 36 42 48 54 66 96 72 78 84 90 HR [95% CI] Stage II 1.00 [0.71–1.42] Stage III 0.80 [0.66–0.98]

0.1% 4.4%

p=0.996 p=0.029

Andre JCO 2009

Long-term Safety

Data cut-off: January 2007

Peripheral Sensory Neuropathy

Evaluable patients n=811 Grade 0 84.3% Grade 1 12.0% Grade 2 2.8% Grade 3 0.7%

10 20 30 40 50 60 During Tx 6 months 1-year 2-year 3-year 4-year

Grade 1 Grade 2 Grade 3

Andre JCO 2009

Treatment of Colorectal Cancer in Elderly Patients: ACCENT Database

• Median age of diagnosis of CRC in the United States is 71 years
• Previous analyses have shown that elderly patients (≥70 years)

with CRC benefit from treatment with IV fluoropyrimidines in both the adjuvant and metastatic settings

• This analysis reviewed the efficacy of newer therapies in older

patients

• Patient population was derived the ACCENT database
• 10,499 pts <70 years, 2,170 pts ≥70 years
• 6 phase III trials compared IV FU to combinations with

irinotecan, oxaliplatin, or oral FU (capecitabine and UFT/LV) in stage II/III colon cancer

• Endpoints were overall survival (OS), disease free survival

(DFS), and time to recurrence (TTR)

• Folprecht. J Clin Oncol. 2008;26:1443-1451.
• McCleary. ASCO 2009. Abstract 4010.

Elderly Patients: Efficacy of FOLFOX Pooled Analysis C-07/MOSAIC

* Values < 1 favor experimental arm

Age Endpoint* HR (95% CI) Experimental vs Control IV 5-FU/LV Deaths within 6 mos Exp vs Ctrl % (p-value) DFS OS TTP <70 n = 3,977 0.77 (0.68,0.86) 0.81 (0.71,0.93) 0.76 (0.67,0.86) 0.81 v 0.81 (p=1.0) ≥ 70 n = 703 1.04 (0.80,1.35) 1.19 (0.90,1.57) 0.92 (0.69,1.23) 2.57 v 1.37 (p=0.25) Interaction

• f age by

treatment p-value 0.016 0.037 0.21

McCleary, ASCO 2009, Abstract 4010

Treatment of Colorectal Cancer in Elderly Patients: ACCENT Database

• Limitations of study
• ACCENT does not track:
• Toxicity
• Dose intensity
• Co-morbidity
• These data do not contradict earlier

studies showing the benefit of adjuvant therapy with 5-FU/LV vs. surgery alone in elderly patients

• McCleary. ASCO 2009. Abstract 4010.

Forest Plots of Hazard Ratios – DFS

0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2

Hazard Ratio

Age < 70 Age >= 70 Oxaliplatin Oral Irinotecan Overall

McCleary, N. ASCO 2009

2009 Update of MOSAIC Trial

Andre JCO 2009

No benefit in DFS with FOLFOX vs 5-FU/LV for patients > 65 yrs !

X-ACT: Cape vs Mayo - 5-year DFS (median follow-up 6.8 years)

5-year n DFS (%) Capecitabine 1,004 60.8 5-FU/LV 983 56.7

1.0 0.8 0.6 0.4 0.2 6 42 48 78 96 Months HR=0.88 (95% CI: 0.77–1.01) NI margin 1.20 12 18 24 30 36 54 60 66 72 84 90

ITT population

Estimated probability

ITT (intent-to-treat) population; NI = non-inferiority Twelves C, et al. Eur J Cancer Suppl 2007;5:1 (Abstract 1LB)

102

Test of non-inferiority p<0.0001 Test of superiority p=0.0682

Chemo/ radiotherapy-naïve stage III colon cancer Bolus 5-FU/LV Mayo Clinic or Roswell Park CAPOX Capecitabine 1,000mg/m2 b.i.d. days 1–15 Oxaliplatin 130mg/m2 day 1 q3w

Schmoll HJ, et al. J Clin Oncol 2007;25:4217–23

XELOXA: phase III trial of CAPOX in the adjuvant setting

• Primary endpoint: disease-free survival

n=944 n=942 R A N D O M I S A T I O N

duration of therapy: 24 weeks

Trial open 4/03 – 10/04 Final data at ESMO 2009

Adjuvant Trials in Colon Cancer with Cetuximab (KRAS wild-type!)

Stage III colon cancer (N=2400)

PETACC 8

FOLFOX4 6m FOLFOX4 6m + Cetuximab 6m Stage III colon cancer (N=3600)

Intergroup N0147

mFOLFOX6 6m mFOLFOX6 6m + Cetuximab 6m

Adjuvant Trials in Colon Cancer with Bevacizumab

Stage II/III colon cancer (N=3450) XELOX 6m + Bevacizumab 12m FOLFOX4 6m + Bevacizumab 12m

AVANT

FOLFOX4 6m Stage II/III colon cancer (N=2710) 25% Stage II mFOLFOX6 6m mFOLFOX6 6m + Bevacizumab 12m

NSABP C-08

Reported at ASCO2009

NSABP C-08

R

mFOLFOX6 q2wk X 6 mo BEV* q2wk X 1 yr *5mg/kg

N=2710 pts 25% stage II

Wolmark et al ASCO 2009

NSABP C-08 Accrual

mFF6 mFF6+B

Randomized Lost / Ineval Analysis 1356 18 1338 1354 16 1334

Wolmark et al ASCO 2009

mFF6 mFF6+B < 60 yr

58.3 58.2

Male

49.8 49.9

Stage II (0)

24.9 24.9

Stage III (1-3)

45.4 45.5

Stage III (4+)

29.7 29.6

NSABP C-08 Patient Characteristics

Wolmark et al ASCO 2009

<0.001 <0.001 <0.0001 <0.0001 P 1.7 0.3

Wound Comp

2.7 0.8

Proteinuria

11.1 6.3

Pain

12 1.8

Hypertension

mFF6+B mFF6

Allegra et al JCO May 4, 2009

Median Duration of Bev = 11.5 months NSABP C-08 Grade 3+ Toxicities Increased with Bevacizumab (%)

NSABP C-08 – DFS

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 20 40 60 80 100

Ev 3yDFS mFF6+B 291 77.4 mFF6 312 75.5

HR 0.89 P 0.15

Wolmark et al ASCO 2009

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 60 70 80 90 100

NSABP C-08 – DFS

Ev 3yDFS mFF6+B 291 77.4 mFF6 312 75.5

HR 0.89 P 0.15

Wolmark et al ASCO 2009

NSABP C-08 HR over Time

0.0004 0.004 0.02 0.05 0.08

Wolmark et al ASCO 2009

NSABP C-08

1.0 1.5 2.0 2.5 3.0 Ev mFF6+B 216 mFF6 190

HR 1.07 P 0.48 Event-free at 1 Yr

0.0 0.5 1.0 60 70 80 90 100

DFS at 1 Yr

Ev 1yDFS mFF6+B 75 94.3 mFF6 122 90.7

HR 0.60 P 0.0004

∆ 3.6

Time-Treatment Interaction P = 0.001

Wolmark et al ASCO 2009

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 60 70 80 90 100

NSABP C-08 – DFS

Ev 3yDFS mFF6+B 291 77.4 mFF6 312 75.5

HR 0.89 P 0.15

Scans?

Wolmark et al ASCO 2009

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 20 40 60 80 100

Ev 3yDFS mFF6+B 40 87.4 mFF6 47 84.7

HR 0.82 P 0.35 DFS Stage II

Δ 2.7

0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 20 40 60 80 100

Ev 3yDFS mFF6+B 251 74.2 mFF6 265 72.4

HR 0.90 P 0.25 DFS Stage III

Δ 1.8

NSABP C-08

Wolmark et al ASCO 2009

mFF6 mFF6+B P Recurrence (N) 248 227 NS Death (N) 146 132 NS Second Ca (N) 46 47 NS 2yS Post Rec (%) 41 37 NS Rec Mult Sites (%) 18 18 NS Sites of Rec – – NS

NSABP C-08 Status at 36 mo Med Follow-up

Wolmark et al ASCO 2009

Stage II and Stage III Colon Cancers Are Different Diseases!

ACCENT Database: Time from Recurrence to Death by Stage

Log Rank P-Value = <0.0001 20 40 60 80 100 1 2 3 4 5 6 7 8 Time (Years) % Alive Stage II (N=1153) Stage III (N=4550) Total (N=5703)

O’Connell, et al. JCO 2008

Molecular Marker (%) Stage II (n = 420) Stage III (n = 984) P Value p53 overexpression 30 37 .01 SMAD4 loss 9 13 .02 Thymidylate synthase 43 29 .0001 Telomerase 40 48 .06 MSI-H 22 12 .0001 18q LoH 63 70 .04 KRAS 36 37 .67 BRAF 8 8 .90

PETACC 3: Stage-Specific Molecular Markers

• PETACC 3: 5-FU/LV + irinotecan vs 5-FU/LV in stage II/III CC
• Translational study in 1404 pts with suitable biopsy material

Roth AD, et al. GI Cancers Symposium 2009. Abstract 288; ASCO 2009.

Defective MMR - Colon cancer

• Characterized by presence of MSI & loss of

MLH1, MSH2, MSH6 or PMS2 expression

• ~15% of Sporadic CC, >90% loss of MLH1
• Clinical Correlations: Right sided, Female,

Early stage, Better prognosis

• Tumors: Poorly differentiated, Signet-ring-

cell, Lymphocytic infiltration, near diploid

• dMMR cells resistant to 5-FU1,2

1Carethers, 1999; 2Arnold 2003

Defective MMR vs MSI

• Microsatellites (MS) = small DNA segments that consist of

repetitive nucleotides of generally 100-200 base pairs

• prone to replication errors which can change their length
• DNA mismatch repair (MMR) proteins consist of hMLH1, hMSH2,

hMSH6, hPMS2, hMSH3, and hMLH3

• MMR proteins can be deficient due to
• mutations of genes (e.g. HNPCC/Lynch) – 5% of CRC
• methylation of promoter region – 15-20% of sporadic CRC
• Test method for dMMR phenptype:
• Analysis of MS lengths using 5 specific DNA markers
• MSI-H: MSI in at least 2 of 5 markers, MSI-L: MSI in only 1

marker, MSS: no instability detected

• IHC for MMR proteins: MLH1, MSH2 most important (>90%)

Pooled data (N=1027)

Trial Treatment N % Stage II % dMMR 784852 5FU/LEV 117 30% 14% INT 0035 5FU/LEV 215 50% 18% 874651 5FU/LV 66 19% 12% GIVIO 5FU/LV 183 52% 16% FFCD 5FU/LV 154 66% 19% NCIC 5FU/LV 292 61% 15% Total 1027 52% 16%

Sargent ASCO 2008

DFS/OS in Stage II dMMR Patients (N=102)

HR: 2.80 (0.98-8.97) p=0.05

5-yr DFS

Untreated 87% Treated 72% Sargent ASCO 2008 HR: 3.15 (1.07-9.29) p=0.03 Untreated 93% Treated 75%

5-yr OS

N = 55 N = 47

PETACC 3: Stage-Specific Prognostic Values

Roth AD, et al. ASCO 2009.

Marker Stage II (n=420) Stage III (n=984)

HR P HR P MSI (Hi vs Stable) 0.3 0.004 0.7 0.06 18qLOH 2.1 0.03 1 0.91 SMAD4 (any loss) 1.4 0.21 1.6 <0.0001 hTERT (High) 1.4 0.32 1.5 0.01 p53 (High) 1.0 0.98 1.3 0.03 TS (High) 0.5 0.03 0.7 0.02 KRAS (Mutated) 1.1 0.84 1.0 0.72 BRAF(Mutated) 0.9 0.90 1.2 0.28

P values from the Wald test in a univariate Cox regression HR = hazard ratio

PETACC 3: Multivariate Analysis Stage II

Roth AD, et al. ASCO 2009.

Markers HR [95% CI] P value T4 v. T3 2.58 [1.56 - 4.28] 0.00024 MSI-H v. MSS 0.28 [0.10 - 0.72] 0.0089 18qLOH 1.37 [0.67 - 2.77] 0.38

93 85

72 83 64 44 8

Percentage of Patients (%)

p < .001

10 20 30 40 50 60 70 80 90 100 Stage I Stage IIA Stage IIB Stage IIIA Stage IIIB Stage IIIC Stage IV

O’Connell et al., 2004.

(T3N0) (T1–2N0) (T4N0) (T1–2N1) (T3–4N1) (T

anyN2)

(M1)

5-Year Relative Survival By AJCC Stage

• MSI as a suppressor of lymph node and

distant metastasis?

*Br J Cancer. 2009 100(2):266-73. Frequency Analysis

Stage II Stage III Stage IV MSI-H

22% (86/395) 12% (104/859) 3.5% *

PETACC 3: Detailed Analysis of MSI

Tejpar, et al. ASCO 2009. (abstract 4001)

HR MSI H (95% CI) 5FU (n= 625) 5FU/iri (n= 608) Both arms

Stage II (n= 391) RFS 0.228 (0.05-0.955) P= 0.043 0.296 (0.091-0.968) P=0.044 0.265(0.107- 0.661) P= 0.0044 OS 0.18 (0.02-1.34) P= 0.095 0.143 (0.02-1.06) P=0.057 0.159( 0.039- 0.659) P=0.011 Stage III (n= 842) RFS 0.596 (0.344-1.03) P=0.064 0.815 (0.478-1.39) P=0.45 0.693 (0.473-1.02) P= 0.06 OS 0.515 (0.261-1.02) P=0.055 0.939 (0.515-1.71) P=0.84 0.699 (0.446- 1.09 ) P= 0.12 Both stages * P are stage corrected RFS 0.501 (0.300-0.837) P=0.0083 0.642 (0.394-1.05) P=0.076 0.569 ( 0.400 -0.811) P=0.0018 OS 0.437(0.229-0.833) P= 0.012 0.676 (0.380-1.20) P= 0.18 0.548 (0.357-0.842) P=0.006

Results: Prognostic impact of MSI

Tejpar, et al. ASCO 2009. (abstract 4001)

Colon Cancer Technical Feasibility

Development Studies

Surgery Alone

NSABP C-01/C-02 (n=270) CCF (n = 765)

Selection of Final Gene List & Algorithm Development Studies

Surgery + 5FU/LV

NSABP C-04 (n=308) NSABP C-06 (n=508)

Clinical Validation Study – Stage II Colon Cancer QUASAR (n>1200) Test prognostic, but not predictive!

Development and Validation of an 18-Gene RT- PCR Colon Cancer Assay

Validation of Analytical Methods

761 genes 375 genes 18 genes

ASCO 2009

Kerr et al., ASCO 2009, abstr. 4000

% of Patients

QUASAR: OS in patients with ―no clear indication for chemo‖ (mostly stage II) 5-FU/LV vs surgery alone

P = .02

5-year OS, Observation = 77.4% vs Chemotherapy = 80.3% Relative risk = 0.83 (95% CI, 0.71-0.97)

Years

QUASAR group, Lancet 2007

1 2 3 4 5 6 7 8 9 10 20 40 60 80 100

Observation (n=1622) Chemotherapy (n=1617)

5-yr OS difference: 2.9%

QUASAR: Evaluable Stage II Colon Cancer Patients

Parent QUASAR study n=3,239 Patients with collected blocks n=2,197 (68%) Confirmed stage II n=1,490 (69%) Final evaluable population n=1,436

54 excluded (3.6%): 29 synchronous tumors 8 insufficient tissue 7 identifier queries 6 RNA quality/quantity 4 ineligible histology 707 cases stage III and rectal cancer

Kerr et al., ASCO 2009, abstr. 4000

QUASAR: Pre-Specified Primary Endpoint: Recurrence Risk Is there a significant relationship between the risk

• f recurrence and the pre-

specified continuous Recurrence Score in stage II colon cancer patients randomized to surgery alone?

STROMAL FAP INHBA BGN CELL CYCLE Ki-67 C-MYC MYBL2 REFERENCE ATP5E GPX1 PGK1 UBB VDAC2 GADD45B

RECURRENCE SCORE Calculated from Tumor Gene Expression

Kerr et al., ASCO 2009, abstr. 4000

22%

(16%-29%)

18%

(13%-24%)

12%

( 9% -16%)

Kaplan-Meier Estimates (95% CI)

• f Recurrence Risk at 3 years

QUASAR Results: Recurrence Risk in Pre-specified Recurrence Risk Groups (n=711)

Comparison of High vs. Low Recurrence Risk Groups using Cox Model: HR = 1.47 (p=0.046)

Years

Recurrence Risk Group Hig h Intermediate Low

Proportion Event Free

0.0 0.2 0.4 0.6 0.8 1.0 1 2 3 4 5

Recurrence Risk Group Range

• f RS

Proportion of patients Low <30 43.7% Intermediate 30-40 30.7% High ≥41 25.6%

Kerr et al., ASCO 2009, abstr. 4000

QUASAR Results: Prediction of Differential 5FU/LV Benefit for Treatment Score

• Continuous Treatment Score and Treatment Benefit

with 5FU/LV – Treatment Score by Treatment Interaction for RFI: interaction p = 0.19

• Selected Secondary Analyses

– Treatment Score by Treatment Interaction not significant when adjusted for prognostic covariates – Treatment Score by Treatment Interaction not significant for DFS (interaction p=0.12) or OS (interaction p=0.15)

Kerr et al., ASCO 2009, abstr. 4000

QUASAR RESULTS: Recurrence Score, T Stage, and MMR Deficiency are Key Independent Predictors of Recurrence in Stage II Colon Cancer

Multivariate Analysis

Kerr et al., ASCO 2009, abstr. 4000

QUASAR Results: Recurrence Score, T Stage, and MMR Deficiency are Key Independent Predictors

• f Recurrence in Stage II Colon Cancer

0% 5% 10% 15% 20% 25% 30% 35% 40% 45%

10 20 30 40 50 60 70 Recurrence Score Risk of recurrence at 3 years

T3 and MMR deficient (11%) T4 stage (13%) T3 and MMR proficient (76%)

Kerr et al., ASCO 2009, abstr. 4000

Decision Algorithm in Adjuvant Therapy

Resected Colon Ca Stage II Stage III FOLFOX High-Risk dMMR No therapy! 5-FU/LV or Capecitabine

* *

*pts not considered candidates for oxaliplatin

T4 and/or <12 LNs Low-Risk Intermed. Risk yes yes no no

?

Oncotype Colon ?

Neo-Adjuvant Therapy of Rectal Cancer

• 4007

ACCORD-2 Gerard

• 4008

STAR Aschele

• 4014

AIO Hofheinz

Addition of Oxaliplatin to Fluoropyrimidine-based Neoadjuvant Radio-Chemotherapy

• Locally advanced rectal cancer
• High rates of distant metastases (30-35%)
• Positive circumferential resection margin in 10-

30% of ―resectable‖ tumors

• Oxaliplatin
• Improves the efficacy of FU-based

chemotherapy

• Radiosensitizing properties in experimental

models

• Promising activity with preoperative

radiotherapy and fluorouracil

• Aschele. ASCO 2009. Abstract CRA4008.

Oxaliplatin in Neoadjuvant Radio- Chemotherapy for Rectal Cancer

Author N Chemo RT Grade 3- 4 toxicity Pathological CR rate Aschele (STAR)

379

5-FU 225 mg/m2/d 50.4 Gy in 28 fractions

8% 16%

368

5-FU 225 mg/m2/d Oxaliplatin 60 mg/m2/w x 6 50.4 Gy in 28 fractions

24% 15%

Gerard (ACCORD)

295

Capecitabine 800 mg/m2 bid 45 Gy in 25 fractions

11% 14%

292

Capecitabine 800 mg/m2 bid 5 of 7 d Oxaliplatin 50 mg/m2/w 50 Gy in 25 fractions

25% 19%

• Aschele. ASCO 2009. Abstract CRA4008. Gerard. ASCO 2009; Abstract LBA4007.

Log-rank: p=0.303

AIO Study – Rtx + Cape or 5-FU: Disease free survival

Preliminary data

• Hofheinz. ASCO 2009. Abstract 4014.

50.4 Gy + N Pts

197 195

Median follow-up: 1.6 years

Neoadjuvant Therapy of Rectal Cancer – ASCO 2009

• Capecitabine had activity similar to 5-FU
• Addition of oxaliplatin did not improve response
• Increased toxicity
• Oxaliplatin does not appear to be a

radiosensitizer in these studies

• Implications for ongoing NSABP R-04?
• Cape vs ci 5-FU +/- oxaliplatin plus Rtx
• Primary EP: local disease control
• Accrual: 1260/1600 pts

Other GI Malignancies

• 4503

GemCis Biliary Valle

• 4505

ESPAC-3 Neoptolemos

• 4506

LMWH in PC Riess

• 4509

ToGA Van Cutsem

Trastuzumab plus Chemotherapy in Advanced HER2+ Gastric Cancer: ToGA

Van Cutsem et al. J Clin Oncol 2009; 27(suppl):798s (LBA4509) Bang et al. J Clin Oncol 2009; 27(suppl): 215s (abstract 4556)

Rationale: A subpopulation of gastric cancers overexpress HER2

Stratification by

• Gastric vs GEJ
• Advanced vs metastatic
• 5-FU vs capecitabine

5-FU 800 mg/m2/d infusional d1-5 q3w X 6 Capecitabine 1000 mg/m2 bid d1-14 q3w X 6 Cisplatin 80 mg/m2 q3w X 6 Trastuzumab 6 mg/kg q3w to PD (8 mg/kg loading) 5-FU or Capecitabine (investigator discretion) + Cisplatin + Trastuzumab (n=294) 5-FU or Capecitabine (investigator discretion) + Cisplatin (n=290) (n = 584) HER2+ GC (n = 810, 22%)

R

Screen 3807 GC patients for HER2 expression

Primary endpoint: OS

ToGA: Main patient selection criteria

Exclusion criteria

• Previous adjuvant chemotherapy within 6 months
• Chemotherapy for advanced disease
• Congestive heart failure or baseline LVEF <50%
• Creatinine clearance <60 mL/min

IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; LVEF, left ventricular ejection fraction

Inclusion criteria

• Adenocarcinoma of stomach or GEJ
• Inoperable locally advanced and/or metastatic disease
• Measurable (RECIST), or non-measurable evaluable disease
• HER2-positive tumor (centrally assessed)

– IHC 3+ and/or FISH+

• Adequate organ function and ECOG performance status ≤2
• Written informed consent

Van Cutsem et al. ASCO 2009 (LBA4509)

Patient demographics and baseline characteristics

Characteristic F+C n=290 F+C + trastuzumab n=294 Sex, % Male / Female 75 / 25 77 / 23 Age, median (range) years 59.0 (21-82) 61.0 (23-83) Weight, median (range) kg 60.3 (28-105) 61.5 (35-110) Region, n (%) Asia C/S America Europe Other 166 (56) 26 (9) 95 (32) 9 (3) 158 (53) 27 (9) 99 (33) 14 (5) Type of GC (central assessment) Intestinal Diffuse Mixed 74.2a 8.7a 17.1a 76.8b 8.9b 14.3b Prior gastrectomy 21.4 24.1

Highest recruitment was from Korea, Japan, China and Russia F, fluoropyrimidine; C, cisplatin an=287; bn=293

Van Cutsem et al. ASCO 2009 (LBA4509)

Events 167 182

ToGA: Primary end point: OS

Time (months)

294 290 277 266 246 223 209 185 173 143 147 117 113 90 90 64 71 47 56 32 43 24 30 16 21 14 13 7 12 6 6 5 4 1

No. at risk

11.1 13.8 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Event FC + T FC HR 0.74 95% CI 0.60, 0.91 p value 0.0046 Median OS 13.8 11.1

T, trastuzumab

Van Cutsem et al. ASCO 2009 (LBA4509)

Events 226 235

ToGA: Secondary end point: PFS

2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Event

294 290 258 238 201 182 141 99 95 62 60 33 41 17 28 7 21 5 13 3 9 3 8 2 6 2 6 1 6 1 4 2

5.5 6.7

No. at risk

0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Time (months) FC + T FC HR 0.71 95% CI 0.59, 0.85 p value 0.0002 Median PFS 6.7 5.5

Van Cutsem et al. ASCO 2009 (LBA4509)

ToGA: Efficacy: OS by HER2 status

Subgroup

Median OS (months)

All

11.1 13.8 vs

Pre-planned analysis

IHC0/FISH+ IHC1+/FISH+ IHC2+/FISH+ IHC3+/FISH+ IHC3+/FISH- 7.2 10.2 10.8 12.3 17.7 10.6 8.7 12.3 17.9 17.5

Exploratory analysis

IHC0 or 1+/FISH+ IHC2+/FISH+ or IHC3+ 8.7 11.8 10.0 16.0 vs vs 0.2 0.4 0.6 1 2 3 4 5 vs vs vs vs vs 0.92 1.24 0.75 0.58 0.83 0.48, 1.76 0.70, 2.20 0.51, 1.11 0.41, 0.81 0.20, 3.38

Hazard ratio 95% CI

0.74 0.60, 0.91 1.07 0.65 0.70, 1.62 0.51, 0.83 Risk ratio Favors T Favors no T 584 61 70 159 256 15 131 446

N

Van Cutsem et al. ASCO 2009 (LBA4509)

11 3

ToGA: OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)

1.0 0.8 0.6 0.4 0.2 0.0 36 34 32 30 28 26 24 22 20 18 16 14 12 10 8 6 4 2 Time (months) 11.8 16.0 FC + T FC Events 120 136 HR 0.65 95% CI 0.51, 0.83 Median OS 16.0 11.8 Event 0.1 0.3 0.5 0.7 0.9

218 198 4 5 3 12 4 20 11 228 218 196 170 170 141 142 112 122 96 100 75 84 53 65 39 51 28 1

No. at risk

39 20 28 13 Van Cutsem et al. ASCO 2009 (LBA4509)

ToGA: Efficacy Outcome

Fluoropyrimidine + Cisplatin + Trastuzumab (n = 294) Fluoropyrimidine + Cisplatin (n = 290) HR [95% CI] P Value OS 13.8 months 11.1 months 0.74 [0.60-0.91] .0046 PFS 6.7 months 5.5 months 0.71 [0.59-0.85] .0002 ORR 47% 34.5% .0017 CR 5% 2% .0599 PR 42% 32% .0145

• Preplanned subgroup analysis indicated improved OS benefit with

increasing HER2 expression by IHC

• Exploratory analysis of IHC2+/FISH+ and IHC3+ cohort demonstrated a

4 month increase in OS with trastuzumab (HR [95% CI], 0.65 [0.51-0.83])

Van Cutsem et al. ASCO 2009 (LBA4509)

ToGA: Select Grade 3/4 Toxicities*

Van Cutsem et al. ASCO 2009 (LBA4509)

Fluoropyrimidine + Cisplatin + Trastuzumab (n = 294) Fluoropyrimidine + Cisplatin (n = 290) Hematologic Neutropenia 27% 30% Anemia 12% 10% Nonhematologic Diarrhea 9% 4% Nausea 7% 7% Asymptomatic LVEF drops (< 50%) 6% 1%

*2 deaths due to cardiac events in each arm

Gemcitabine ± Cisplatin in Advanced Biliary Tract Cancer: Phase III UK ABC-02 Trial

• Primary endpoint: OS
• Secondary endpoints including: PFS, toxicity

Eligibility criteria:

• No prior systemic

therapy

• Adequate biliary

drainage Stratification by

• Site of primary
• LA vs metastatic
• Prior therapy

Cisplatin 25 mg/m2 + Gemcitabine 1000 mg/m2 d 1, 8 q21d for 8 cycles (n=204) Gemcitabine 1000 mg/m2 d 1, 8, 15 q28d for 6 cycles (n=206) (n = 410) R A N D O M I Z E

Valle et al. ASCO 2009 (abstract 4503)

UK ABC-02 Trial: Select Grade 3/4 Adverse Events

Valle et al. ASCO 2009 (abstract 4503)

Gem + Cis (n = 159) Gem (n = 165) Hematologic Neutropenia 36 (23%) 29 (18%) Leukopenia 24 (15%) 18 (11%) Nonhematologic Any 102 (64%) 108 (65.5%) Elevated Bilirubin 17 (11%) 21 (13%) Elevated ALT 15 (10%) 28 (18%) Elevated AST 12 (8%) 17 (11%) Fatigue 29 (19%) 27 (17%)

No significant differences between arms

UK ABC-02 Trial: Efficacy

Gemcitabine + Cisplatin (n = 148) Gemcitabine (n = 132) P Value (HR [95%CI]) ORR 38 (26%) 21 (16%) NR CR 1 (< 1%) 1 (< 1%) NR PR 37 (25%) 20 (15%) NR SD 79 (53%) 73 (55%) NR CBR (CR + PR +SD) 117 (79%) 94 (71%) .256 (n = 204) (n = 206) PFS 8.4 months 6.5 months .003 (0.72 [0.57-0.90]) OS 11.7 months 8.3 months .002 (0.70 [0.54-0.89])

Valle et al. ASCO 2009 (abstract 4503)

ABC-02 Results: Progression-free survival (ITT)

Treatment arm Gem Gem + Cis Number of patients n=206 n=204 PFS events n(%) 155 (75.2) 135 (66.2)

Median PFS (mo) 6.5 8.4 Log rank p value 0.003 Hazard ratio (95% CI) 0.72 (0.57, 0.90)

Valle et al. ASCO 2009 (abstract 4503)

ABC-02 - Results: Overall Survival (ITT)

Treatment arm Gem Gem + Cis Number of patients n=206 n=204 Deaths n(%) 141 (68.5) 122 (59.8)

Median survival (mo) 8.3 11.7 Log rank p value 0.002 Hazard ratio (95% CI) 0.70 (0.54, 0.89)

Valle et al. ASCO 2009 (abstract 4503)

ABC-02 - Overall Survival Exploratory sub-group analysis

Valle et al. ASCO 2009 (abstract 4503)

CONKO-001 Gemcitabine as Adjuvant Therapy in Resected PC

Gem Obs Gemcitabine 1000 mg/m²: d1, 8, 15; q 4 weeks Observation: d1; q 4 weeks

R a n d

• m

i z a t i

• n

Follow up every 8 weeks

Gem

Ultrasound

after week 8

Ultrasound

after week 16

CT Scan

after week 32

Obs

Gem

Obs

Gem

Obs

Gem

Obs

Gem

Obs

Gem

Obs

CA 19-9 CA 19-9 CA 19-9 CA 19-9 CA 19-9 CA 19-9

4 weeks 4 weeks 4 weeks 4 weeks 4 weeks 4 weeks

CA 19-9

Oettle et al., JAMA 2007

CONKO-001 ASCO 2008 Update

Neuhaus et al., ASCO 2008 months

84 72 60 48 36 24 12 100% 75% 50% 25% 0%

Gemcitabine mOS: 22.8 mos

(95% CI, 18.5-27.2)

Observation mOS: 20.2 mos

(95% CI, 17.7-22.8)

P = 0.005

OS Rate (%)

Obs GEM 1yr 72.5 72.0 3yrs 19.5 36.5 5yrs 9.0 21.0

ESPAC-3: Adjuvant bolus 5-FU/LV vs Gemcitabine in Pancreatic Cancer

Neoptolemos et al. ASCO 2009 (abstract 4505)

ESPAC-3: Adjuvant bolus 5-FU/LV vs Gemcitabine in Pancreatic Cancer

Neoptolemos et al. ASCO 2009 (abstract 4505)

ESPAC-3: Adjuvant bolus 5-FU/LV vs Gemcitabine in Pancreatic Cancer

Neoptolemos et al. ASCO 2009 (abstract 4505)

CONKO-4: LMWH vs Observation in metastatic PC

Riess et al. ASCO 2009 (abstract 4506)

CONKO-4: LMWH vs Observation in metastatic PC

Riess et al. ASCO 2009 (abstract 4506)

CONKO-4: LMWH vs Observation in metastatic PC

Riess et al. ASCO 2009 (abstract 4506)

CONKO-4: LMWH vs Observation in metastatic PC

Riess et al. ASCO 2009 (abstract 4506)

CONKO-4: LMWH vs Obs. in mPC

Riess et al. ASCO 2009 (abstract 4506)