Is There a New Standard of Care for Adjuvant Therapy in Colon Cancer? When is 3 Months Enough? Jeffrey Meyerhardt, MD, MPH Dana-Farber Cancer Institute Boston, MA 1
Disclosure Ad Board: Genentech Honorarium: Chugai Involvement in IDEA Collaboration Study co-chair of CALGB/SWOG 80702 2
Stage III Colon Cancer 3
Stage III Colon Cancer Cured with Surgery Alone Didn t need chemo 4
Stage III Colon Cancer Recur despite surgery and chemo Chemo didn t help (at least enough) 5
Stage III Colon Cancer Cured because they got adjuvant therapy after surgery FOLFOX/CAPOX Fluoropyrimidine Only ones that benefit from chemo (as measured by cure) 6
Stage III Colon Cancer These people all get side effects from chemotherapy The goals of reducing total treatment from 6 to 3 months are to reduce side effects, burdens of therapy, and costs for all these patients 7
Stage III Colon Cancer The key issue in trying to reduce therapy from 6 to 3 months is not to compromise these people from being cured 8
Basic Schema for IDEA 3 months Stage III colon cancer patients who underwent surgery R 1:1 Investigator s choice FOLFOX or CAPOX 6 months Shi et al ASCO 2017 9
IDEA Trials Summary Trial Regimen(s) Stage III Colon Cancer Patients * Enrolling Country TOSCA CAPOX or FOLFOX4 2402 Italy SCOT CAPOX or mfolfox6 3983 UK, Denmark, Spain, Australia, Sweden, New Zealand IDEA France CAPOX or mfolfox6 2010 France C80702 mfolfox6 2440 US, Canada HORG CAPOX or FOLFOX4 708 Greece ACHIEVE CAPOX or mfolfox6 1291 Japan *Only stage III colon cancer patients were included in the pooled primary analysis Shi et al ASCO 2017 10
Patient Characteristics by Study Patient Characteristics TOSCA (N=2402) SCOT (N=3983) IDEA France (N=2010) C80702 (N=2440) HORG (N=708) ACHIEVE (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% 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% Median follow-up time, m 62 37 51 35 48 37 * 1% of PS 2 in IDEA France and C80702 trials Shi et al ASCO 2017 11
Patient Characteristics by Duration and Regimen FOLFOX CAPOX Patient characteristics 3m Arm 6m Arm 3m Arm 6m Arm (N=3870) (N=3893) (N=2554) (N=2517) Median Age, years 64 64 65 65 ECOG PS * 0 77% 77% 82% 81% 1 22% 22% 18% 19% T Stage T1-2 13% 14% 13% 12% T3 68% 67% 63% 63% T4 19% 19% 24% 25% N Stage N1 72% 73% 71% 71% * N2 28% 27% 29% 29% 1% of PS 2 in FOLFOX treated patients Shi et al ASCO 2017 12
Adverse Events FOLFOX CAPOX Adverse Events 3m Arm 6m Arm p-value 1 3m Arm 6m Arm p-value 1 Overall G2 G3-4 Neurotoxicity G2 G3-4 Diarrhea G2 G3-4 32% 38% 14% 3% 11% 5% 32% 57% 32% 16% 13% 7% <.0001 41% 24% <.0001 12% 3% <.0001 10% 7% 48% 37% 36% 9% 13% 9% 1 Chi-squared test for trend; Total of 19 grade 5 events; Adverse events only collected on first 617 patients enrolled to SCOT trial <.0001 <.0001 0.0117 Shi et al ASCO 2017 13
Neuropathy measured by patient questionnaire over time by treatment duration: SCOT Trial Iveson et al ASCO 2017 14
Non-inferiority Hypothesis Testing Statistical Conclusions Under Different Scenarios 3m TRT better Superiority 6m TRT better Non-inferiority Not proven Inferiority Hazard Ratio 1.0 1.12 Non-Inferiority Margin TRT: treatment Piaggio et al. JAMA 2012;308(24):2594-2604 15
Percent Without Event N Patients At risk 100 90 80 70 60 50 40 30 20 10 0 Primary DFS Analysis (mitt) Duration 3-yr DFS 3m 74.6 % 6m 75.5 % 3-yr DFS diff. = -0.9%, 95% CI, (-2.4 to 0.6%) HR 1.07 (1.00 1.15) Duration 3 Months 6 Months 0 1 2 3 4 5 6 Years from Randomization 6424 5446 4464 3000 1609 826 321 6410 5530 4477 3065 1679 873 334 Shi et al ASCO 2017 16
Differences in Usage of CAPOX v FOLFOX TOSCA (N=2402) SCOT (N=3983) IDEA France (N=2010) C80702 (N=2440) HORG (N=708) ACHIEVE (N=1291) Chemotherapy CAPOX 35% 67% 10% 0% 58% 75% FOLFOX 65% 33% 90% 100% 42% 25% * 1% of PS 2 in IDEA France and C80702 trials Shi et al ASCO 2017 17
Percent Without Event Percent Without Event DFS Comparison by Regimen FOLFOX CAPOX 100 N Pts At risk 90 80 70 60 50 40 30 20 10 0 Duration 3-yr DFS 3m 73.6 % 6m 76.0 % 3-yr DFS diff. = -2.4% 95% CI, (-4.3 to -0.5%) HR 1.16 (1.06 1.26) Duration 3 Months 6 Months 0 1 2 3 4 5 6 Years from Randomization 3870 3227 2561 1825 1121 633 291 3893 3308 2633 1880 1150 666 309 100 90 80 70 60 50 40 30 20 10 0 Duration 3-yr DFS 3m 75.9 % 6m 74.8 % 3-yr DFS diff. = 1.1% 95% CI, (-1.3 to 3.5%) Duration 3 Months 6 Months HR 0.95 (0.85 1.06) 0 1 2 3 4 5 6 Years from Randomization 2554 2219 1903 1175 488 193 30 2517 2222 1844 1185 529 207 25 Interaction p-value = 0.0051 Shi et al ASCO 2017 18
DFS Comparison by Regimen and Study FOLFOX CAPOX Patients 3m arm Patients 6m arm HR (3m/6m) Favors 3m Favors 6m Patients 3m arm Patients 6m arm HR (3m/6m) Favors 3m Favors 6m TOSCA 770 792 1.14 TOSCA 424 416 0.92 SCOT 662 672 1.21 SCOT 1330 1319 0.94 IDEA France 895 914 1.27 IDEA France 107 94 0.97 HORG 148 148 0.87 HORG 206 206 1.12 ACHIEVE 163 159 1.08 ACHIEVE 487 482 0.92 C80702 1232 1208 1.10 Overall 3870 3893 1.16 Overall 2554 2517 0.95 0.5 1 1.12 1.5 Hazard Ratio 0.5 1 1.12 1.5 Hazard Ratio Shi et al ASCO 2017 19
Treatment Compliance in IDEA FOLFOX CAPOX Treatment Compliance 3m Arm 6m Arm 3m Arm 6m Arm Total no. weeks received treatment Median (Q1-Q3) Reached the planned last cycle 1 Dose intensity %, Mean (Standard Deviation) 12 (12-12) 24 (20-24) 12 (12-12) 24 (18-24) 90% 71% 86% 65% 5FU 2 D 1.2% 92.4 (22.7) 81.6 (26.6) D~11% --- --- Capecitabine --- --- 91.2 (23.5) 78.0 (29.4) Oxaliplatin D 1.6% 91.4 (19.9) 72.8 (25.6) 89.8 (21.7) 69.3 (28.3) 1 1% of patients assigned to 3m treatment (both FOLFOX and CAPOX) received > 3m of treatment; 2 combining infusion and bolus D~20% Shi et al ASCO 2017 20
Potential Reasons for Treatment Interaction In the first 4 weeks of CAPOX, the dose of oxaliplatin received is 260 mg/m 2. However, with FOLFOX it is 170 mg/m 2 More continuous 5-FU is better However There is no indication of differences in metastatic CRC eg. N01966 Bias by indication who gets CAPOX may have factors that are favorable associated with outcome 21
Disease-free Survival among Patients Receiving Fluorouracil plus Leucovorin or Capecitabine HR 0.87 [0.75 to 1.00]; P=0.05 Twelves C et al. N Engl J Med 2005;352:2696-2704. 22
6 months of bolus 5-FU/LV vs 12 weeks of protracted venous infusion 5-FU as adjuvant treatment in colorectal cancer Chau et al. Ann Oncol. 2005;16(4):549-557. 23
DFS Comparison by Stage Patients 3m Arm Patients 6m Arm HR (3m/6m) Favors 3m Favors 6m Interaction P-value N stage N1 N2 4583 1798 4585 1769 1.07 1.07 0.44 T stage T1/T2 T3 T4 849 4219 1320 841 4181 1335 1.07 1.04 1.16 0.36 0.5 1 1.12 1.5 Hazard Ratio Shi et al ASCO 2017 24
DFS Comparison by Stage, cont. N stage N1 N2 Patients 3m Arm 4583 1798 Patients 6m Arm 4585 1769 HR (3m/6m) 1.07 1.07 Favors 3m Favors 6m Interaction P-value 0.44 T stage T1/T2 T3 T4 849 4219 1320 841 4181 1335 1.07 1.04 1.16 0.36 Risk Group T1-3 N1 T4 or N2 3744 2634 3727 2622 1.01 1.12 0.11 0.5 1 1.12 1.5 Hazard Ratio Shi et al ASCO 2017 25
Percent Without Event Percent Without Event DFS Comparison by Risk Groups T1-3 N1 (58.7%) T4 or N2 (41.3%) 100 90 80 70 60 50 40 30 20 10 Duration 3-yr DFS 3m 83.1 % 6m 83.3 % 3-yr DFS diff. = -0.2% 95% CI, (-1.9 to 1.5%) Duration 3 Months 6 Months 0 0 1 2 3 4 5 6 Years from Randomization N Patients 3744 3313 2796 1934 1064 527 211 At risk 3727 3336 2788 1949 1081 566 221 100 90 80 70 60 50 40 30 20 10 Duration 3-yr DFS 3m 62.7 % 6m 64.4 % 3-yr DFS diff. = -1.7% 95% CI, (-4.3 to 0.9%) Duration 3 Months 6 Months 0 0 1 2 3 4 5 6 Years from Randomization 2634 2099 1640 1044 531 292 107 2622 2151 1655 1094 586 301 110 Interaction p-value = 0.11 Shi et al ASCO 2017 26
Percent Without Event Percent Without Event Percent Without Event Percent Without Event DFS Comparison by Risk Group and Regimen in IDEA N Patients At risk 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 100 N Patients At risk Years from Randomization 2311 2013 1642 1198 751 411 195 2308 2030 1669 1215 745 433 203 90 80 70 60 50 40 30 20 10 3-yr DFS 3m 81.9 % 6m 83.5 % 3-yr DFS 3m 61.5 % 6m 64.7 % Inferior Not Proven T1-3, N1 FOLFOX HR 1.10 (0.96 1.26) 0 0 1 2 3 4 5 6 Years from Randomization 1523 1189 900 612 360 216 94 1531 1242 937 648 396 228 103 P interaction N = Patients 0.11 At risk comparing T1-3 N1 100 T4 or N2 90 to T4 or N2 80 FOLFOX HR 1.20 (1.07 1.35) 100 90 80 70 60 50 40 30 20 10 70 60 50 40 30 20 10 3-yr DFS 3m 85.0 % 6m 83.1 % 3-yr DFS 3m 64.1% 6m 64.0 % T1-3, N1 CAPOX 0 0 1 2 3 4 5 6 Years from Randomization 1433 1300 1154 736 313 116 16 1419 1306 1119 734 336 133 18 Not Proven Noninferior HR 0.85 (0.71 1.01) T4 or N2 CAPOX HR 1.02 (0.89-1.17) 0 0 1 2 3 4 5 6 Years from Randomization N Patients 1111 910 740 432 171 76 13 At risk 1091 909 718 446 190 73 7 Duration 3 Months 6 Months Shi et al ASCO 2017 27
FOLFOX, High Risk(T4 or N2) Study name Statistics for each study Hazard ratio and 95% CI Hazard Lower Upper ratio limit limit p-value TOSCA 1.020 0.767 1.356 0.891 SCOT 1.100 0.851 1.422 0.467 IDEA France 1.440 1.140 1.819 0.002 CALGB 1.300 1.030 1.640 0.027 HORG 0.890 0.521 1.522 0.670 ACHIEVE 1.130 0.690 1.850 0.627 1.203 1.069 1.354 0.002 0.1 0.2 0.5 1 2 5 10 I 2 =12.8 Q test, P=0.331 Meta Analysis Favours A Favors 3 mo Favours B Favors 6 mo 28
FOLFOX, Low Risk(T1-3N1) Study name Statistics for each study Hazard ratio and 95% CI Hazard Lower Upper ratio limit limit p-value TOSCA 1.230 0.943 1.605 0.127 SCOT 1.400 0.948 2.067 0.090 IDEA France 1.150 0.889 1.488 0.288 CALGB 0.890 0.684 1.157 0.385 HORG 0.670 0.326 1.375 0.275 ACHIEVE 1.220 0.561 2.654 0.616 1.100 0.960 1.260 0.172 0.1 0.2 0.5 1 2 5 10 I 2 =24.9 Q test, P=0.247 Meta Analysis Favours A Favors 3 mo Favours B Favors 6 mo 29
XELOX, High Risk(T4 or N2) Study name Statistics for each study Hazard ratio and 95% CI Hazard Lower Upper ratio limit limit p-value TOSCA 0.940 0.631 1.401 0.761 SCOT 1.040 0.876 1.235 0.654 IDEA France 0.870 0.401 1.886 0.724 HORG 0.890 0.519 1.527 0.672 ACHIEVE 1.100 0.785 1.541 0.579 1.021 0.892 1.170 0.759 0.1 0.2 0.5 1 2 5 10 I 2 =0.0 Q test, P=0.937 Meta Analysis Favours A Favors 3 mo Favours B Favors 6 mo 30
XELOX, Low Risk(T1-3N1) Study name Statistics for each study Hazard ratio and 95% CI Hazard Lower Upper ratio limit limit p-value TOSCA 0.920 0.621 1.363 0.677 SCOT 0.750 0.577 0.975 0.032 IDEA France 1.100 0.578 2.093 0.772 HORG 1.310 0.799 2.148 0.284 ACHIEVE 0.600 0.350 1.029 0.064 0.847 0.708 1.014 0.070 0.1 0.2 0.5 1 2 5 10 I 2 =35.4 Q test, P=0.186 Meta Analysis Favours A Favors 3 mo Favours B Favors 6 mo 31
3 yr DFS rate (%) and HR by risk group and regimen Regimen CAPOX FOLFOX CAPOX / FOLFOX Combined 3 yr DFS, % (95% 3 yr DFS, % (95% 3 yr DFS, % (95% CI) HR CI) HR CI) (95% CI) (95% CI) 3 m 6 m 3 m 6 m 3 m 6 m HR (95% CI) Risk group Low-risk (T1-3 N1) High-risk (T4 and / or N2) 85.0 (83.1-86.9) 64.1 (61.3-67.1) 83.1 (81.1-85.2) 64.0 (61.2-67.0) 0.85 (0.71-1.01) 1.02 (0.89-1.17) 81.9 (80.2-83.6) 61.5 (58.9-64.1) 83.5 (81.9-85.1) 64.7 (62.2-67.3) 1.10 (0.96-1.26) 1.20 (1.07-1.35) 83.1 (81.8-84.4) 62.7 (60.8-64.4) 83.3 (82.1-84.6) 64.4 (62.6-66.4) 1.01 (0.90-1.12) 1.12 (1.03-1.23) Non-inferior Not proven Inferior Non-inferiority of 3 months compared with 6 months of adjuvant therapy 32
IDEA Clinical Consensus: Risk-based approach to adjuvant chemotherapy in stage III colon cancer Risk group Recommended duration of adjuvant therapy T1-3 N1 3 months 6 months (~60% of stage III) T4 and/or N2 (Or other high-risk factors) Duration of therapy determined by - tolerability of therapy - patient preference - assessment of risk of recurrence - Regimen (CAPOX vs FOLFOX) Shi et al ASCO 2017 33
Stage II Colon Stage II Colon Cancer In SCOT high risk stage II point estimate HR <1 (Iverson et al ASCO 2017) In TOSCA stage II HR 1.41 (1.05-1.89) (Sobrero et al ASCO 2017) Variable Category 3 month arm Events/Patients 6 month arm Events/Patients 3m better 6m better 6 months STAGE II N-stage 0 98 / 559 101 / 555 3 months p= 0.935 1 343 / 1726 346 / 1721 Duration 3-yr RF % HR (95% CI) 2 298 / 750 295 / 754 3 months 85.5 1.41 (1.05-1.89) 6 months 91.2 Ref High risk stage II 98 / 559 101 / 555 3-yr RFS diff. = - 5.7 % (-9.7% -1.7%) Overall 739 / 3035 742 / 3030 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 Hazard ratio 34
Stage II Colon Cancer Could 3 months chemo in stage II be inferior Sample size smaller and less stable estimate Incomplete nodal staging Is stage 2 different biologically and 6 months is necessary In MOSAIC, high risk stage II, 5 yr overall survival 87.5 v 87.% (FU/LV v FOLFOX) 10 yr overall survival 71.7% v 75.4% 35
Only data from SCOT Rectal Cancer Variable Category Disease Site Colon 3 month arm DFS/Patients 633 / 2484 6 month arm DFS/Patients 628 / 2483 3m better 6m better Noninferiority boundary p= 0.463 Rectum 106 / 551 114 / 547 Overall 739 / 3035 742 / 3030 P-values are for homogeneity of the duration effect over the variable categories 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3 Hazard ratio only patients without preop chemort Iverson et al ASCO 2017 36
How Am I Using These Data For a patient with T4 or N2 disease, I recommend 6 months FOLFOX Patients who have T1-3, N1 disease, I recommend 3 months of CAPOX 37
Adding to the Unanswered Questions Designing the next adjuvant colon cancer trial Stage III MSI-H Colon Cancer R PI: Frank Sinicrope Arm 1: mfolfox6 + Atezolizumab for 12 cycles*, then Atezolizumab only for additional 6 months Arm 2: mfolfox6 alone for 12 cycles* Adjuvant Therapy for Rectal Cancer Chemoradiation Surgery 8 cycles of FOLFOX 38
Adding to the Unanswered Questions TNT for rectal cancer approaches FOLFOX x 8 XRT + Capecitabine Surgery Locally Advanced Rectal Cancer R FOLFOX x 8 XRT + Capecitabine + Veliparib Surgery FOLFOX x 8 XRT + Capecitabine + Pembrolizumab Surgery 39
Cured with Surgery Alone Stage III Colon Cancer Recur despite surgery and chemo Ultimately need to stop giving any of these people chemotherapy IDEA and the 6 trials did not help these people we need to find new strategies. 40
Conclusions IDEA was the largest international effort in GI cancer and should change practice One size does not fit all stage III patients We hoped for a simple answer answer is not simple but colon cancer is not simple Public funding of 6 international trials was essential Amazing colleagues in IDEA - Qian Shi, Alberto F. Sobrero, Anthony F. Shields, Takayuki Yoshino, James Paul, Julien Taieb, Ioannis Souglakos, Rachel Kerr, Roberto Labianca, Franck Bonnetain, Toshiaki Watanabe, Ioannis Boukovinas, Lindsay A. Renfro, Axel Grothey, Donna Niedzwiecki, Valter Torri, Thierry Andre, Daniel J. Sargent, Timothy Iveson, Irene Floriani 41