Is There a New Standard of Care for Adjuvant Therapy in Colon Cancer? When is 3 Months Enough?

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1 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

2 Disclosure Ad Board: Genentech Honorarium: Chugai Involvement in IDEA Collaboration Study co-chair of CALGB/SWOG

3 Stage III Colon Cancer 3

4 Stage III Colon Cancer Cured with Surgery Alone Didn t need chemo 4

5 Stage III Colon Cancer Recur despite surgery and chemo Chemo didn t help (at least enough) 5

6 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

7 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

8 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

9 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

10 IDEA Trials Summary Trial Regimen(s) Stage III Colon Cancer Patients * Enrolling Country TOSCA CAPOX or FOLFOX Italy SCOT CAPOX or mfolfox UK, Denmark, Spain, Australia, Sweden, New Zealand IDEA France CAPOX or mfolfox France C80702 mfolfox US, Canada HORG CAPOX or FOLFOX4 708 Greece ACHIEVE CAPOX or mfolfox Japan *Only stage III colon cancer patients were included in the pooled primary analysis Shi et al ASCO

11 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 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 * 1% of PS 2 in IDEA France and C80702 trials Shi et al ASCO

12 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 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

13 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% < % 24% < % 3% < % 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 < Shi et al ASCO

14 Neuropathy measured by patient questionnaire over time by treatment duration: SCOT Trial Iveson et al ASCO

15 Non-inferiority Hypothesis Testing Statistical Conclusions Under Different Scenarios 3m TRT better Superiority 6m TRT better Non-inferiority Not proven Inferiority Hazard Ratio Non-Inferiority Margin TRT: treatment Piaggio et al. JAMA 2012;308(24):

16 Percent Without Event N Patients At risk 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 ( ) Duration 3 Months 6 Months Years from Randomization Shi et al ASCO

17 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

18 Percent Without Event Percent Without Event DFS Comparison by Regimen FOLFOX CAPOX 100 N Pts At risk 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 ( ) Duration 3 Months 6 Months Years from Randomization 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 ( ) Years from Randomization Interaction p-value = Shi et al ASCO

19 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 TOSCA SCOT SCOT IDEA France IDEA France HORG HORG ACHIEVE ACHIEVE C Overall Overall Hazard Ratio Hazard Ratio Shi et al ASCO

20 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 (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

21 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

22 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:

23 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):

24 DFS Comparison by Stage Patients 3m Arm Patients 6m Arm HR (3m/6m) Favors 3m Favors 6m Interaction P-value N stage N1 N T stage T1/T2 T3 T Hazard Ratio Shi et al ASCO

25 DFS Comparison by Stage, cont. N stage N1 N2 Patients 3m Arm Patients 6m Arm HR (3m/6m) Favors 3m Favors 6m Interaction P-value 0.44 T stage T1/T2 T3 T Risk Group T1-3 N1 T4 or N Hazard Ratio Shi et al ASCO

26 Percent Without Event Percent Without Event DFS Comparison by Risk Groups T1-3 N1 (58.7%) T4 or N2 (41.3%) 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 Years from Randomization N Patients At risk 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 Years from Randomization Interaction p-value = 0.11 Shi et al ASCO

27 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 N Patients At risk Years from Randomization 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 ( ) Years from Randomization 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 ( ) yr DFS 3m 85.0 % 6m 83.1 % 3-yr DFS 3m 64.1% 6m 64.0 % T1-3, N1 CAPOX Years from Randomization Not Proven Noninferior HR 0.85 ( ) T4 or N2 CAPOX HR 1.02 ( ) Years from Randomization N Patients At risk Duration 3 Months 6 Months Shi et al ASCO

28 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 SCOT IDEA France CALGB HORG ACHIEVE I 2 =12.8 Q test, P=0.331 Meta Analysis Favours A Favors 3 mo Favours B Favors 6 mo 28

29 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 SCOT IDEA France CALGB HORG ACHIEVE I 2 =24.9 Q test, P=0.247 Meta Analysis Favours A Favors 3 mo Favours B Favors 6 mo 29

30 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 SCOT IDEA France HORG ACHIEVE I 2 =0.0 Q test, P=0.937 Meta Analysis Favours A Favors 3 mo Favours B Favors 6 mo 30

31 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 SCOT IDEA France HORG ACHIEVE I 2 =35.4 Q test, P=0.186 Meta Analysis Favours A Favors 3 mo Favours B Favors 6 mo 31

32 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 ( ) 64.1 ( ) 83.1 ( ) 64.0 ( ) 0.85 ( ) 1.02 ( ) 81.9 ( ) 61.5 ( ) 83.5 ( ) 64.7 ( ) 1.10 ( ) 1.20 ( ) 83.1 ( ) 62.7 ( ) 83.3 ( ) 64.4 ( ) 1.01 ( ) 1.12 ( ) Non-inferior Not proven Inferior Non-inferiority of 3 months compared with 6 months of adjuvant therapy 32

33 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

34 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 ( ) (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 / / months p= / / 1721 Duration 3-yr RF % HR (95% CI) / / months ( ) 6 months 91.2 Ref High risk stage II 98 / / yr RFS diff. = % (-9.7% -1.7%) Overall 739 / / Hazard ratio 34

35 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

36 Only data from SCOT Rectal Cancer Variable Category Disease Site Colon 3 month arm DFS/Patients 633 / month arm DFS/Patients 628 / m better 6m better Noninferiority boundary p= Rectum 106 / / 547 Overall 739 / / 3030 P-values are for homogeneity of the duration effect over the variable categories Hazard ratio only patients without preop chemort Iverson et al ASCO

37 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

38 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

39 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

40 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

41 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