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/LV superior to 5- • 5-FU/lev superior FU/lev • 6- and 12-month to surgery alone treatment cycles • LV5FU2 and equivalent monthly bolus • Lev unnecessary equivalent • 5-FU/LV superior • High-dose and low- to surgery alone dose LV equivalent • Monthly and weekly treatment 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 n=2246 (n=1123) Enrollment: FOLFOX4 Oct 1998 – Jan 2001 (146 centres; (LV5FU2 + oxaliplatin 85 mg/m²) 20 countries) • Completely resected colon cancer R • Stage II, 40%; Stage III, 60% • Age 18 – 75 years LV5FU2 • KPS ≥60 (n=1123) • No prior chemotherapy Primary end-point: disease-free survival Secondary end-points: safety, overall survival LV5FU2, Leucovorin 200 mg/m 2 iv over 2 hours followed by 5-fluorouracil 400 mg/m 2 bolus and 5-fluorouracil 600 mg/m 2 iv over 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m 2 iv over 2 hours on Day 1

MOSAIC: Disease-free Survival - Final Update 5-year DFS % HR Data cut-off: June 2006 FOLFOX4 LV5FU2 [95% CI] p-value ITT 73.3 67.4 0.80 0.003 [0.68 – 0.93] Stage III 66.4 58.9 0.78 0.005 Δ7.5 [0.65 – 0.93] Stage II 83.7 79.9 0.84 0.258 [0.62 – 1.14] — High-risk stage II 82.1 74.9 0.74 Δ7.2 n=576 [0.52 – 1.06] — Low-risk stage II 86.3 89.1 1.22 n=323 [0.66 – 2.26]

―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 1.0 p=0.996 0.9 0.1% 0.8 p=0.029 0.7 4.4% Probability 0.6 0.5 0.4 FOLFOX4 stage II 0.3 HR [95% CI] LV5FU2 stage II Stage II 1.00 [0.71 – 1.42] 0.2 FOLFOX4 stage III Stage III 0.80 [0.66 – 0.98] 0.1 LV5FU2 stage III 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Overall survival (months) Data cut-off: January 2007 Andre JCO 2009

Long-term Safety 60 Evaluable Peripheral Grade 1 patients n=811 Sensory Grade 2 50 Grade 3 Grade 0 84.3% Neuropathy 40 Grade 1 12.0% 30 Grade 2 2.8% Grade 3 0.7% 20 10 0 During 6 1-year 2-year 3-year 4-year Tx months Data cut-off: January 2007 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 Endpoint* Deaths within HR (95% CI) 6 mos Age Experimental vs Control IV 5-FU/LV Exp vs Ctrl % (p-value) DFS OS TTP <70 0.77 0.81 0.76 0.81 v 0.81 n = 3,977 (0.68,0.86) (0.71,0.93) (0.67,0.86) (p=1.0) ≥ 70 1.04 1.19 0.92 2.57 v 1.37 n = 703 (0.80,1.35) (0.90,1.57) (0.69,1.23) (p=0.25) Interaction of age by 0.016 0.037 0.21 treatment p-value * Values < 1 favor experimental arm 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 Oral Oxaliplatin Irinotecan Age < 70 Overall Age >= 70 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 2.2 Hazard Ratio McCleary, N. ASCO 2009

2009 Update of MOSAIC Trial No benefit in DFS with FOLFOX vs 5-FU/LV for patients > 65 yrs ! Andre JCO 2009

X-ACT: Cape vs Mayo - 5-year DFS (median follow-up 6.8 years) 1.0 5-year n DFS (%) Estimated probability Capecitabine 1,004 60.8 0.8 5-FU/LV 983 56.7 0.6 0.4 HR=0.88 (95% CI: 0.77 – 1.01) NI margin 1.20 0.2 0 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 Months Test of non-inferiority p<0.0001 ITT population Test of superiority p=0.0682 Twelves C, et al. Eur J Cancer Suppl ITT (intent-to-treat) population; NI = non-inferiority 2007;5:1 (Abstract 1LB)

XELOXA: phase III trial of CAPOX in the adjuvant setting R CAPOX A n=944 Capecitabine 1,000mg/m 2 b.i.d. days 1 – 15 N Oxaliplatin 130mg/m 2 day 1 q3w D O Chemo/ M radiotherapy-naïve duration of therapy: 24 weeks I stage III S colon cancer A Bolus 5-FU/LV T Mayo Clinic or Roswell Park I n=942 O Trial open N 4/03 – 10/04 Final data at • Primary endpoint: disease-free survival ESMO 2009 Schmoll HJ, et al. J Clin Oncol 2007;25:4217 – 23

Adjuvant Trials in Colon Cancer with Cetuximab ( KRAS wild-type!) PETACC 8 FOLFOX4 6m Stage III colon cancer (N=2400) FOLFOX4 6m + Cetuximab 6m Intergroup N0147 mFOLFOX6 6m Stage III colon cancer (N=3600) mFOLFOX6 6m + Cetuximab 6m

Adjuvant Trials in Colon Cancer with Bevacizumab AVANT FOLFOX4 6m Stage II/III colon XELOX 6m + cancer (N=3450) Bevacizumab 12m FOLFOX4 6m + Bevacizumab 12m NSABP C-08 mFOLFOX6 6m Stage II/III colon Reported at cancer (N=2710) ASCO2009 25% Stage II mFOLFOX6 6m + Bevacizumab 12m

NSABP C-08 mFOLFOX6 q2wk X 6 mo R 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 1356 1354 Lost / Ineval 18 16 Analysis 1338 1334 Wolmark et al ASCO 2009

NSABP C-08 Patient Characteristics 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 Wolmark et al ASCO 2009

NSABP C-08 Grade 3+ Toxicities Increased with Bevacizumab (%) mFF6 mFF6+B P 1.8 12 <0.0001 Hypertension 6.3 11.1 <0.0001 Pain 0.8 2.7 <0.001 Proteinuria Wound Comp 0.3 1.7 <0.001 Median Duration of Bev = 11.5 months Allegra et al JCO May 4, 2009

Wolmark et al ASCO 2009 NSABP C-08 – DFS 100 80 60 40 Ev 3yDFS mFF6+B 291 77.4 HR 0.89 20 mFF6 312 75.5 P 0.15 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Wolmark et al ASCO 2009 NSABP C-08 – DFS 100 90 80 Ev 3yDFS 70 mFF6+B 291 77.4 HR 0.89 mFF6 312 75.5 P 0.15 60 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Wolmark et al ASCO 2009 NSABP C-08 HR over Time 0.08 0.05 0.02 0.004 0.0004

Event-free at 1 Yr DFS at 1 Yr 100 90 Time-Treatment Interaction P = 0.001 80 Ev 1yDFS Ev mFF6+B 75 94.3 ∆ 3.6 HR 1.07 mFF6+B 216 mFF6 122 90.7 70 mFF6 190 P 0.48 HR 0.60 NSABP C-08 P 0.0004 60 0.0 0.5 1.0 1.0 1.5 2.0 2.5 3.0 Wolmark et al ASCO 2009

Wolmark et al ASCO 2009 NSABP C-08 – DFS 100 90 80 Scans? Ev 3yDFS 70 mFF6+B 291 77.4 HR 0.89 mFF6 312 75.5 P 0.15 60 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

Wolmark et al ASCO 2009 DFS Stage III DFS Stage II 100 100 80 80 60 60 Ev 3yDFS Ev 3yDFS Δ 2.7 mFF6+B 40 87.4 mFF6+B 251 74.2 Δ 1.8 40 40 mFF6 47 84.7 mFF6 265 72.4 HR 0.90 HR 0.82 20 20 P 0.25 P 0.35 NSABP C-08 0 0 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5

NSABP C-08 Status at 36 mo Med Follow-up 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 Wolmark et al ASCO 2009

Stage II and Stage III Colon Cancers Are Different Diseases!

ACCENT Database: Time from Recurrence to Death by Stage 100 Stage II (N=1153) Stage III (N=4550) 80 Total (N=5703) % Alive 60 Log Rank P-Value = 40 <0.0001 20 0 0 1 2 3 4 5 6 7 8 Time (Years) O’Connell, et al. JCO 2008