Duration of Adjuvant Therapy for Colon Cancer Anthony F. Shields, - PowerPoint PPT Presentation

Duration of Adjuvant Therapy for Colon Cancer Anthony F. Shields, M.D., Ph.D. Karmanos Cancer Institute Wayne State University Detroit, Michigan

Adjuvant Therapy for Colon Cancer Standard therapy after surgery for: Stage III with + nodes Stage II with high risk features (T4, obstruction, perforation) Also considered for: Stage II without added risk factors Stage IV resected metastatic disease Options: FOLFOX, CAPOX, Capecitabine, 5FU

Observed 5-year Survival by TN Category LL Gunderson, J Clin Oncol , 2010

MOSAIC 2007: Stage III Adjuvant • Study now presented with > 5 years follow-up • 6.6% DFS benefit maintained HR = 0.8, p = 0.003 Prob OS 5FU FOLFOX p 6 years Overall 76% 78.6% 0.057 Stage II 86.8% 86.9% 0.996 Stage III 68.6% 73% 0.029

MOSAIC 2009: Stage III Adjuvant Peripheral Sensory Neuropathy T. Andre et al., J Clin Oncol , 2009

12 Weeks of ci 5-FU vs 6 Months of 5-FU/LV 5 Year 12 wks 6 HR RFS (%) Ci 5-FU months (95% CI) 5-FU/ p-value LV 0.8 (0.62-1.04) RFS 73.3 66.7 p=0.10 OS 0.79 (0.61-1.03) OS 75.7 71.5 p=0.08 Likelihood of ci 5-FU being inferior: P<0.005 N=801 Chau et al., Ann Oncol 2005

Duration of Adjuvant Chemotherapy for Stage III Colon Cancer A. Grothey, A.F. Sobrero, A.F. Shields, T. Yoshino, J. Paul, J. Taieb, J. Souglakos, Q. Shi, R. Kerr, R. Labianca, J.A. Meyerhardt, D. Vernerey, T. Yamanaka, I. Boukovinas, J.P. Meyers, L.A. Renfro, D. Niedzwiecki, T. Watanabe,* V. Torri, M. Saunders, D.J. Sargent,* T. Andre, and T. Iveson – SCOT (UK, Denmark, Spain, Australia, Sweden, New Zealand), TOSCA (Italy), Alliance/SWOG 80702 (US, Canada), IDEA France , ACHIEVE (Japan), HORG (Greece) • Total of 12,834 patients with stage III disease included in analysis

Study Overview • Objective: 3 months Reduce side-effects of therapy without giving up (too much) anti- cancer efficacy of therapy Stage III FOLFOX * Colon Patients R Cancer or CAPOX * • Non-inferiority design: As agreed upon by patient advocates and oncologists, 6 months shorter duration of therapy should 12,834 patients not sacrifice more than 12% of benefit of adjuvant therapy * Investigator’s choice, In statistical terms: upper 95% no randomization confidence interval of Hazard Ratio (HR) of disease free survival (DFS) should not exceed 1.12

Non-inferiority Hypothesis Testing Statistical Conclusions Under Different Scenarios 3m TRT better 6m TRT better Superiority One-sided Type I Error Rate Non-inferiority = 0.025 Power = 90% Require 3390 DFS Events Not proven Inferiority Hazard Ratio 1.0 1.12 Non-Inferiority Margin TRT: treatment Piaggio et al. JAMA 2012;308(24):2594-2604

Patient Characteristics by Study TOSCA SCOT IDEA France C80702 HORG ACHIEVE Patient Characteristics (N=2402) (N=3983) (N=2010) (N=2440) (N=708) (N=1291) Median Age, years 64 65 64 61 67 66 ECOG PS * 0 95% 71% 74% 71% 82% 96% 1 5% 29% 25% 28% 18% 4% T Stage T1-2 13% 12% 12% 18% 8% 15% T4 12% 29% 18% 15% 14% 28% T3 75% 59% 70% 67% 78% 57% T4 12% 29% 18% 15% 14% 28% N Stage N1 73% 69% 75% 73% 67% 74% N2 27% 31% 25% 27% 33% 26% Chemotherapy CAPOX 35% 67% 10% 0% 58% 75% Median follow-up FOLFOX 65% 33% 90% 100% 42% 25% CAPOX 35% 67% 10% 0% 58% 75% 62 37 51 35 48 37 * 1% of PS 2 in IDEA France and C80702 trials Median follow-up 62 37 51 35 48 37 time, m time, m

Primary Outcomes Analysis 100 100 Duration Duration 3 Months 3 Months 90 90 6 Months 6 Months 80 80 70 70 Percent Without Event 60 60 Duration 3-yr DFS 50 50 DFS HR = 1.07 40 40 3m 74.6 % 95% CI, 1.00 to 1.15 30 30 6m 75.5 % 20 20 3-yr DFS diff. = -0.9%, 10 10 95% CI, (-2.4 to 0.6%) 0 0 0 0 1 1 2 2 3 3 4 4 5 5 6 6 Years from Randomization Years from Randomization N Patients 6424 5446 4464 3000 1609 826 321 At risk 6410 5530 4477 3065 1679 873 334

Adverse Events FOLFOX CAPOX p-value 1 6m Arm p-value 1 Adverse Events 3m Arm 6m Arm 3m Arm Overall 32% 32% G2 41% 48% <.0001 <.0001 38% 57% G3-4 24% 37% Neurotoxicity G2 14% 36% 32% 12% <.0001 <.0001 G3-4 3% 9% 16% 3% Diarrhea 13% G2 11% 13% 10% <.0001 0.0117 9% G3-4 5% 7% 7% 1 Chi-squared test for trend; Total of 19 grade 5 events; adverse events only collected on first 617 patients enrolled to SCOT trial

Neuropathy (PSN) Time Course: Japanese Study 1 0.9 0.8 Average PSN Grade 0.7 0.6 0.5 0.4 0.3 6 mo 0.2 0.1 3 mo 0 M M M M M M M M M M M M M M M M M 2 5 8 1 4 7 0 3 6 0 1 2 3 4 5 6 9 1 1 1 2 2 2 3 3 3 Time from Randomization Ø At 36 mo: Ø Grade 2-3 2.8% in 6 mo arm 0% in 3 mo arm Ø ANY Grade 24.3% in 6 mo arm 9.7% in 3 mo arm

Analysis of Risk Groups by Regimen • Large difference in overall prognosis observed between (T1-3 N1) and (T4 or N2) cancers – 3 year DFS ∆ 20% Ø Analysis of 3m vs 6m adjuvant therapy for these groups • Two different adjuvant regimens used, FOLFOX and CAPOX – Preplanned analysis of 3m vs 6m based on regimen

DFS Comparison by Regimen FOLFOX CAPOX 100 100 100 100 Duration Duration Duration Duration 3 Months 3 Months 3 Months 3 Months 90 90 90 90 6 Months 6 Months 6 Months 6 Months 80 80 80 80 70 70 70 70 Percent Without Event Percent Without Event Percent Without Event Percent Without Event 60 60 60 60 Duration 3-yr DFS Duration 3-yr DFS 50 50 50 50 40 40 3m 75.9 % 40 40 3m 73.6 % 30 30 30 30 6m 74.8 % 6m 76.0 % 20 20 20 20 3-yr DFS diff. = 1.1% 3-yr DFS diff. = -2.4% 10 10 10 10 95% CI, (-1.3 to 3.5%) 95% CI, (-4.3 to -0.5%) 0 0 0 0 0 0 1 1 2 2 3 3 4 4 5 5 6 6 0 0 1 1 2 2 3 3 4 4 5 5 6 6 Years from Randomization Years from Randomization Years from Randomization Years from Randomization N Pts 2554 2219 1903 1175 488 193 30 3870 3227 2561 1825 1121 633 291 At risk 2517 2222 1844 1185 529 207 25 3893 3308 2633 1880 1150 666 309 Interaction p-value = 0.0051

DFS Comparison by Risk Group and Regimen 100 100 100 100 Duration Duration Duration Duration 3 Months 3 Months 3 Months 3 Months 90 90 90 90 6 Months 6 Months 6 Months 6 Months 80 80 80 80 Percent Without Event Percent Without Event Percent Without Event Percent Without Event LOW RISK 70 70 70 70 60 60 60 60 T1-3, N1 T1-3, N1 50 50 50 50 FOLFOX CAPOX 40 40 40 40 30 30 30 30 3 yr DFS, 3 m Rx: -1.6 3 m Rx: +1.9 (-0.8 to 4.6) 20 20 20 20 (-3.8 to 0.6) 10 10 10 10 0 0 0 0 0 0 1 1 2 2 3 3 4 4 5 5 6 6 0 0 1 1 2 2 3 3 4 4 5 5 6 6 Years from Randomization Years from Randomization Years from Randomization Years from Randomization 2311 2311 2013 2013 1642 1642 1198 1198 751 751 411 411 195 195 1433 1433 1300 1300 1154 1154 736 736 313 313 116 116 16 16 2308 2308 2030 2030 1669 1669 1215 1215 745 745 433 433 203 203 1419 1419 1306 1306 1119 1119 734 734 336 336 133 133 18 18 100 100 100 100 Duration Duration Duration Duration 3 Months 3 Months 3 Months 3 Months 90 90 90 90 HIGH RISK 6 Months 6 Months 6 Months 6 Months 80 80 80 80 Percent Without Event Percent Without Event Percent Without Event Percent Without Event 70 70 70 70 60 60 60 60 T4 or N2 50 50 50 50 FOLFOX T4 or N2 40 40 40 40 CAPOX 30 30 30 30 3 m Rx: -3.2 (-6.6 to 0.2) 3 m Rx: 0.1 (-3.9 to 4.1) 20 20 20 20 10 10 10 10 0 0 0 0 0 0 1 1 2 2 3 3 4 4 5 5 6 6 0 0 1 1 2 2 3 3 4 4 5 5 6 6 Years from Randomization Years from Randomization Years from Randomization Years from Randomization 1523 1523 1189 1189 900 900 612 612 360 360 216 216 94 94 1111 1111 910 910 740 740 432 432 171 171 76 76 13 13 1531 1531 1242 1242 937 937 648 648 396 396 228 228 103 103 1091 1091 909 909 718 718 446 446 190 190 73 73 7 7

Regimen CAPOX/FOLFOX CAPOX FOLFOX 3 yr DFS rate (%) Combined and HR by Regimen and 3 yr DFS, % 3 yr DFS, % 3 yr DFS, % Risk Group (95% CI) (95% CI) HR (95% CI) HR HR (95% CI) (95% CI) (95% CI) 3 m 6 m 3 m 6 m 3 m 6 m Low-risk 85.0 83.1 0.85 81.9 83.5 1.10 83.1 83.3 1.01 (T1-3 N1) (83.1-86.9) (81.1-85.2) (0.71-1.01) (80.2-83.6) (81.9-85.1) (0.96-1.26) (81.8-84.4) (82.1-84.6) (0.90-1.12) ~60% Risk Group High-risk (T4 and / or 64.1 64.0 1.02 61.5 64.7 1.20 62.7 64.4 1.12 N2) (61.3-67.1) (61.2-67.0) (0.89-1.17) (58.9-64.1) (62.2-67.3) (1.07-1.35) (60.8-64.4) (62.6-66.4) (1.03-1.23) ~40% Risk P-value Interaction Test: 75.9 74.8 0.95 73.6 76.0 1.16 Groups Regimen: 0.0051 (74.2-77.6) (73.1-76.6) (0.85-1.06) (72.2-75.1) (74.6-77.5) (1.06-1.26) Combined Risk Group: 0.11 Non-inferior Not Proven Inferior

Predicted 5-yrs DFS with Surgery Alone, 5FU, Oxaliplatin x 3 or 6 months 1 0.9 0.8 0.7 0.6 OXA6 0.5 OXa3 0.4 Surg+FUFA Surgalone 0.3 0.2 0.1 0 a b a b a b a b a b a b a b a b 1 2 1 2 1 2 1 2 1 2 1 2 1 2 1 2 N N N N N N N N N N N N N N N N A. Sobrero 1 1 1 1 2 2 2 2 3 3 3 3 4 4 4 4 T T T T T T T T T T T T T T T T