2013 ASCO CRC Poster Discussion (Old Dog, New Tricks) Weijing Sun, MD, FACP University of Pittsburgh

Bevacizumab in CRC Therapy: Doses, efficacy, maintenance, and impact of ages , 3516, 3517, 3521 S-1 in CRC: the un-replaceable role of fluoropyrimidines in CRC therapy, and equivalence of different analogs : -3518, 3519 Early response is critical and an indicator for the overall outcome: 3520 What can we learn from these studies? What is the potential impact of these studies on clinic practice?

3516: FOLFIRI plus bevacizumab as second-line therapy in patients with metastatic colorectal cancer who have failed first- line bevacizumab plus oxaliplatin-based therapy: the randomized phase III EAGLE study Hiroshi Tamagawa, et al Evaluated the optimal dose of Bevacizumab (2 nd -line): A long-time question since the first day of bevacizumab in clinical practice: 5mg/kg vs. 10 mg/kg vs. 7.5 mg/kg (commonly used in q3wks regimen with XELOX) Evaluated the optimal dose of Bevacizumab (2 nd -line): A long-time question since the first day of bevacizumab in clinical practice: 5mg/kg vs. 10 mg/kg vs. 7.5 mg/kg (commonly used in q3wks regimen with XELOX) Oxaliplatin based CTx + bevacizumab 5mg/kg R Arm A: FOLFIRI + bevacizumab 5mg/kg Arm B: FOLFIRI + bevacizumab 10mg/kg Primary End Point: PFS Secondary end points: Toxicity, RR, TTF, OS, OS from the first-line, duration from the start of the first-line Primary End Point: PFS Secondary end points: Toxicity, RR, TTF, OS, OS from the first-line, duration from the start of the first-line N=367

PFS Hazard ratio: 0.95 (95% CI: ) p= (log-rank test) Median PFS: A = 6.1 month (95% CI: ); B = 6.4 month (95% CI: ) A B Months PFS Probability (%)

Subgroup Analysis of PFS LY metastasisno yes Peritoneal metastasisno yes Age<65 years ≥65 years Pretreatment<180 days ≥180 days CEA<20 ng/mL ≥20 ng/mL CA 19-9<35 ng/mL ≥35 ng/mL Sum of<50 mm target lesions≥50 mm Arm B better 0.99( ) 1.08( ) 0.93( ) 1.31( ) 1.02( ) 1.00( ) 0.75( ) 1.14( ) 1.25( ) 0.82( ) 1.09( ) 0.96( ) 1.22( ) 0.81( ) Arm A better Hazard Ratio (95% CI)

No differences: -dose intense of chemotherapy -subgroup analysis: sex, age, PS, primary site (rectal vs. colon) metastatic characteristics (location, numbers, peritoneal mets), CEA, CA19-9… Arm A (n=180) Arm B (n=187) PR, No. (%)20 (11.1)20 (10.7) p=1.00 SD, No. (%) 127 (70.6)132 (70.6) PD, No. (%) 25 (13.9)22 (11.8) NE, No. (%) 8 ( 4.4)13 ( 7.0)

PFSRR IFL + Placebo6.2 months35 % IFL + Bev. 5 mg/kg10.6 months45% PFSRR FOLFOX4.8 months9.2% FOLFOX + Bev. 10 mg/kg7.2 months21.8% (Bev. 10 mg/kg)(2.8 months)(3.0%) The Potential Impact of Bevacizumab Dose on the CRC Chemotherapy Efficacy First line: AVF 2107g Second line: E3200 PFSRR 5FU/LV5.2 months17 % 5-FU/LV + Bev. 5mg /Kg9.0 months40 % 5-FU/LV + Bev 10 mg /Kg7.2 months24 % Initial Phase II: Kabbinavar

Conclusion No significant difference was found in PFS between Arm A and Arm B. No Surprise - dose of Bevacizumab was based on neither the Tumor mass (size or numbers) nor the biologics (VEGF, or VEGFR levels) of Cancer. However, patients with first-line treatment <180 days, CEA ≥20 ng/mL, sum of target lesions ≥50 mm seem to benefit from bev 10 mg/kg. May make sense as larger tumor burden may be benefit with more Bev. The results from study suggest that the optimal dose of continuous bev as second-line treatment is 5 mg/kg. With the efficacy from this and other studies and cost-effective ration—Agree! No need to have any further debate regarding the appropriate dose of Bevacizumab in CRC therapy (in the 2 nd line setting)

3517: Effectiveness of bevacizumab added to gold standard chemotherapy in metastatic colorectal cancer (mCRC): Final results from the ITACa randomized clinical trial Alessandro Passardi, et al Alessandro Passardi et al

Baseline Characteristics Patient CharacteristicsCT+bevacizumab N=176CT N=194 Age: median years (range)66 (34-83)66 (33-82) Male %6159 Performance Status (ECOG) % Tumor localization % rectum2326 colon7774 Stage at diagnosis % I-III17 IV83 CT regimen % folfox5961 folfiri4139 KRAS % wild type5955 mutant4145 Prior cancer therapy % surgery7675 radiotherapy10 Adjuvant chemotherapy1913

Events / n (%) Median PFS (95% CI) CT + B159 / 176 (90.3)9.6 ( ) CT178 / 194 (91.8)8.4 ( ) HR = % CI ( ) p = = 1.2 months HR = 0.87, 95% CI ( ), p = = 1.2 months HR = 0.87, 95% CI ( ), p = OS: 20.6 months in both arms [p=0.278, HR 1.18 ( )] RR: 48.9 (CT +B) vs % (p=0.371) OS: 20.6 months in both arms [p=0.278, HR 1.18 ( )] RR: 48.9 (CT +B) vs % (p=0.371) CT + BCT Treatment cycles (N) Treatment cycles per patient median (range) 8 (1-43)6 (1-28) Cycles with reduction of CT: N (%) 291 (14.0) 404 (20.8) CT Cumulative dose: median (range) 90 ( ) 87 ( ) -A relative small study with diverse CT regimens (60% FOLFOX) -Appeared as ‘NO16966’ Data -No data in 2 nd and 3 rd line therapy -Will not change current practice -A relative small study with diverse CT regimens (60% FOLFOX) -Appeared as ‘NO16966’ Data -No data in 2 nd and 3 rd line therapy -Will not change current practice PFS

3515: Maintenance therapy with bevacizumab with or without erlotinib in metastatic CRC according to KRAS: Results of the GERCOR DREAM phase III trial. C. Tournigand, et al mFOLFOX7 bevacizumab XELOX2 bevacizumab FOLFIRI bevacizumab Bevacizumab (7.5 mg/kg q3w) + erlotinib (150 mg/d) until PD Bevacizumab (7.5 mg/kg q3w) + erlotinib (150 mg/d) until PD RANDOMIRANDOMIZATZATIONIONRANDOMIRANDOMIZATZATIONION No Prog N=222 N=224 INDUCTION, N=700MAINTENANCE, N=446 Bevacizumab (7.5 mg/kg q3w) until PD Bevacizumab (7.5 mg/kg q3w) until PD REREGGIISSTTRRAATTIIOONNREREGGIISSTTRRAATTIIOONNGISTRATION Primary end point: PFS on maintenance therapy Secondary endpoints : OS, OS from maintenance, Duration without chemotherapy, RR, Survival according to KRAS mutational status Primary end point: PFS on maintenance therapy Secondary endpoints : OS, OS from maintenance, Duration without chemotherapy, RR, Survival according to KRAS mutational status

OPTIMOX 1 FOLFOX4 (n=312) FOLFOX7 (n=313) 6 cycles FOLFOX7 LV5FU2 12 cycles Clinic Chemptherapy Goal: Increasing the efficacy, minimize/delay the toxicity -Optimox 1: maintain the efficacy and decreasing the toxicity with ‘stop and go’ strategy -Biological agents benefit in combination with chemotherapy -VEGF inhibitors vs. EGFR inhibitor(s) and combination? Maintenance? The impacts of Kras status? Clinic Chemptherapy Goal: Increasing the efficacy, minimize/delay the toxicity -Optimox 1: maintain the efficacy and decreasing the toxicity with ‘stop and go’ strategy -Biological agents benefit in combination with chemotherapy -VEGF inhibitors vs. EGFR inhibitor(s) and combination? Maintenance? The impacts of Kras status? R R

PACCE: PFS and OS Ox-CT + BEV (n=410) Ox-CT + BEV + Pmab (n=413) HR (95% CI) PFS (mos)11.1 months9.6 months1.27 ( ) OS ( mos)>24 months19.4 months1.43 ( ) ORR46%45% Iri-CT + BEV (n=115) Iri-CT + BEV + Pmab (n=115) HR (95% CI) PFS (mos) ( ) OS (mos) NR ORR39%43%1.15 (OR)

CAPOX/ Bev CAPOX/BEV/Cet p value n = 368 n = 368 Median PFS (months) (HR; 95% CI) 10.7 ( ) 9.6 ( ) (1.21; ) Median OS (months) (HR; 95% CI) 20.4 ( ) 20.3 ( ) 0.21 (1.15; ) Response rate (CR + PR) 44% 0.88 Disease control rate (CR + PR + SD) 83%81%0.39 CAIRO2

Bev alone (N=228) Bev + erlotinib (N=224) HR [95% CI] P value Maintenance PFS (from randomization) 4.6 [ ] 5.9 [ ] HR 0.76 [ ] PFS (from registration) 9.3 [ ] 10.2 [ ] HR 0.75 [ ] OS (from registration) 27.9 [ ] 28.4 [ ] HR 0.89 [ ] Survivals Bevacizumab N=228 Bevacizumab + Erlotinib N=224 Diarrhea2 (1)20 (9) Skin toxicity0 (0)46 (20) Grade 3/4 Toxicity (%)

Maintenance PFS (randomized population, from randomization) BB + E No. of patients Events Censored 4565 Median maint. PFS HR [95% CI] 0.76 [ ] P value

CAIRO2: KRAS genotyping (n=501) Kras WT (n=305) 61% Kras Mutated Kras Mutated (N=196) 39% p PFS (months) CAPOX +B CAPOX +B+C p OS (months) CAPOX +B CAPOX +B +C p

Survivals Bev alone (N=111) Bev + erlotinib (N=129) HR [95% CI] P value m PFS (from randomization) 5.9 [ ] 6.0 [ ] HR 0.86 [ ] PFS (from registration) 9.7 [ ] 10.9 [ ] HR 0.82 [ ] OS (from registration) 31.5 [ ] 31.8 [ ] HR 0.92 [ ] Bev alone (N=89) Bev + erlotinib (N=91) HR [95% CI] P value Maintenance PFS (from randomization) 4.4 [ ] 4.7 [ ] HR 0.77 [ ] PFS (from registration) 9.9 [ ] 9.8 [ ] HR 0.80 [ ] OS (from registration) 26.9 [ ] 26.3 [ ] HR 1.06 [ ] 0.767

Maintenance PFS

-The addition of erlotinib to bevacizumab following induction therapy with bevacizumab-based chemotherapy significantly increases the maintenance PFS. -In contrast to anti-EGFR Mabs, KRAS tumor status does not select patients with mCRC benefiting from erlotinib However: Will the results change the practice? Bevacizumab alone is not standard, and without clear benefit (SAKK 41/06, abs 3503); and after OPTIMOX 1, 5-FU (or Capecitabine)+ bevacizumab is already the maintenance therapy in many practices (which is supported by CAIRO3, abs 3502). Erlotinib is not indicated in CRC May help future investigation of anti-VEGF mAb + Anti-EGFR TKI in mCRC Conclusions

3521: Results according to age in AVEX, a randomized phase 3 trial of bevacizumab with capecitabine for elderly patients with mCRC Mark P. Saunders, et al Previously untreated mCRC, age  70 years N=280 Capecitabine 1000 mg/m 2 b.i.d. days 1–14, q21d Bevacizumab 7.5 mg/kg day 1, q21d + Capecitabine 1000 mg/m 2 b.i.d. days 1–14, q21d Stratification factors: ECOG PS (0–1 vs 2) Geographic region Randomize 1:1 Are elderly patients at increased risk for toxicity secondary to Bevacizumab, and how old is old?

Progression-free and overall survival * *Overall population. 113 PFS events in the BEV + cape arm; 127 PFS events in the cape arm; 75 OS events in each treatment arm. BEV = bevacizumab; cape = capecitabine; CI = confidence interval; OS = overall survival; PFS = progression-free survival Number at risk BEV + cape Cape Time (months) PFS estimate mo 9.1 mo HR=0.53 (95% CI: 0.41–0.69) P<0.001 Time (months) OS estimate 16.8 mo 20.7 mo HR=0.79 (95% CI: 0.57– 1.09), P=0.182 Number at risk BEV + cape Cape Bevacizumab + Capecitabine (n=140) Capecitabine (n=140) A. Progression-free survivalB. Overall survival

Progression-free and overall survival Outcome 70 – 74 years75 – 79 years≥80 years Bev + Cape n=55 Cape n=46 Bev + cape n=57 Cape n=66 Bev + cape n=28 Cape n=28 Median PFS, mos (95% CI) 7.6 (6.0–11.8) 5.0 (4.0–6.5) 9.8 (7.1–11.4) 5.1 (4.1–7.4) 10.5 (5.0–14.5) 5.1 (2.2–7.1) Hazard ratio (95% CI) Log-rank P 0.52 (0.32–0.83) < (0.40–0.89) (0.19–0.71).003 Median OS, months (95% CI) 20.7 (13.7–26.1) 22.2 (9.7–42.7) 19.8 (13.8–27.3) 17.4 (11.9–23.0) 19.7 (7.5–26.9) 12.6 (6.6–17.0) Hazard ratio (95% CI) Log-rank P 0.91 (0.50–1.66) (0.48–1.30) (0.31–1.24).24

AE, % 70 – 74 years75 – 79 years≥80 years Bev + Cape n=54 Cape n=46 Bev + cape n=53 Cape n=64 Bev + cape n=27 Cape n=26 Any AE Grade ≥3 AE SAE Grade 5 AE* AE leading to dose interruption/modification Any AE leading to discontinuation AE, % 70 – 74 years75 – 79 years≥80 years Bev + Cape n=54 Cape n=46 Bev + cape n=53 Cape n=64 Bev + cape n=27 Cape n=26 Bleeding/hemorrhage – Hypertension VTE – Proteinuria 13–424– ATE 4– No major difference of AEs comparing with other Bevacizumab studies

Conclusions A statistically significant improvement in PFS with the addition of bevacizumab to capecitabine (HR, 0.53; P<.001) – Patients grouped according to age (70–74 years, 75–79 years, ≥80 years) had a similar PFS benefit The safety profile was consistent with previously reported data and consistent across age subgroups Suggests that the combination of bevacizumab and capecitabine is an effective and well-tolerated regimen for elderly with good PS -Age is ‘relative’, even with anti-angiogenic agent, (however, data here is only for Bev… ). -Key issue is careful patient selection. -Age is ‘relative’, even with anti-angiogenic agent, (however, data here is only for Bev… ). -Key issue is careful patient selection.

3518: Non-inferiority of S-1 to UFT/LV as adjuvant chemotherapy for stage III colon cancer: A randomized phase III trial (ACTS-CC) Yoshihiko Nakamoto, et al. ACTS-CC study group S-1: 80, 100, 120 mg/day according to BSA in 2 divided doses daily Day 1-28, q6w x 4 cycles (24w) S-1 UFT: mg/day according to BSA LV: 75mg/day in 3 divided doses daily Day 1-28, q5w x 5 cycles (25w) UFT/ LV pStage III Colon Cancer (C-RS) ・ Curatively resected ・ Age: y.o. ・ PS: 0-1 Control arm Test arm Stratification factors ・ LN metastasis (N1/N2) ・ Institution R Primary End Point: 3-yr DFS, Non inferiority margin of HR in DFS: 1.29 Target sample size ： 1,480 pts. with one-sided α=0.05, β=0.20 Primary End Point: 3-yr DFS, Non inferiority margin of HR in DFS: 1.29 Target sample size ： 1,480 pts. with one-sided α=0.05, β=0.20

Biochemical action of S-1 and UFT/LV Effector Modulator ① Modulator ② S-1 CDHP DPD inhibition （ strong ） oteracil Decreasing GI toxicity UFT/LV uracil DPD inhibition （ moderate ） LV Potentiation of TS inhibition DPD ： Dihydropyrimidine dehydro- genase TS ： thymidylate synthetase CDHP ： 5-chloro-2,4-dihydroxypyridine tegafur Prodrug of 5-FU - Potent DPD inhibitory activity - Easy administration (Twice-daily p.o.) - Low price (1/2 of UFT/LV, 1/3 of mFOLFOX6 in Japan)

DFS and OS Median follow-up: 41.3 months ( ) EAS ： n=1, % 80.1% 75.5% 71.8% 86.5% 77.6% 72.5% 66.1% S-1 UFT/LV HR 0.85 [95%CI: ], p= One-sided p< (non- inferiority) No. at risk 0y1y2y3y4y5y S UFT/LV % 96.8% 93.6% 88.3% 98.9% 96.6% 92.7% 86.1% HR 0.86 [95%CI: ] P= No. at risk 0y1y2y3y4y5y S UFT/L V S-1 UFT/LV

Conclusions - Adjuvant chemotherapy using S-1 will be a treatment option for stage III colon cancer in Japan -S-1 for stage III CRC is non-inferior in DFS to that of UFT/LV. - AEs were acceptable, and the completion rate of the protocol Tx. was high. NSABP C-063 yr. DFS5 yr DFS5 yr. OS 5-FU/LV74.5 %68.2 %78.7 % UFT74.5 %67.2 %78.5 % -Might fit in US pts, based on NSABP C-06 data, however, not available in USA

3519: A randomized phase III trial of S-1/oxaliplatin (SOX) plus bevacizumab versus 5-FU/l-LV/oxaliplatin (mFOLFOX6) plus bevacizmab in patients with metastatic colorectal cancer: the SOFT study. D. Takahari, et al SOFT Study Group Stratification factors: With vs. without adjuvant chemotherapy Institutions n=512 mFOLFOX6+Bev (n=256) L-OHP: 85 mg/m 2 d1 Bev: 5 mg/kg d1 l-LV: 200mg/m 2 d1 5-FU: 400mg/m 2 bolus d1 5-FU: 2,400mg/m 2 46 hr civ d1,2 repeated every 2 wks SOX+Bev (n=256) L-OHP: 130 mg/m 2 d1 Bev: 7.5 mg/kg d1 S-1: 80, 100, 120 mg*/body d1-14 repeated every 3 wks mCRC 1st line Age: PS: 0-1 *According to body surface area, BSA =1.5 Non-inferiority Control arm Test arm R

PFS and OS mFOLFOX6+Bev SOX+Bev mFOLFOX6+Bev : 10.2 M (95% CI: ) SOX+Bev: 10.2 M (95% CI: ) PFS HR=1.021 (95% CI: ) Best overall response mFOLFOX6+Bev (n=233) No. of pts * SOX+Bev (n=234) No. of pts * p value NE1621 RR (%) DCR (%) R0 resection rate2224 R0-R (%)22 (8.6%)24 (9.4 %) mFOLFOX6+Bev : 30.9 M (95% CI: ) SOX+Bev : 29.6 M (95% CI:25.8- …) Median follow-up duration: 23.4 M (0.3 to 37.8) mFOLFOX6+Bev SOX+Bev OS HR=1.052 (95% CI:

SexMale Female Age<65 65 ≦ Primary lesionColon Rectosigmoid Rectum Histologytub1,2 por1,2 Other History of surgery for No colorectal cancer Yes History of adjuvant No therapy for CRC Yes Target lesions No Yes Liver metastases No Yes Lung metastases No Yes BSA(m 2 )< ≦ < ≦ SOX+Bev better mFOLFOX6+Bev better P value for interaction Sub-group No. of pts Subgroup analysis of PFS(FAS) D.Takahari, et al. ASCO 2013; Abstract #3519

Conclusions SOX + Bev can replace with mFOLFOX6 + Bev as a first-line treatment for mCRC in Japan with a more convenient regimen D.Takahari, et al. ASCO 2013; Abstract #3519

3520: Prognostic value of early objective tumor response (EOTR) to 1 st line systemic therapy in mCRC: Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD ( Aide et Recherche en Cancérologie Digestive) database Dirkje W Sommeijer, et al, the ARCAD Group 15 Studies: N9741, OPTIMOX 1, FOCUS, AVF2192g, AVF2107g, HORG, HORIZON H, FOCUS 2, NO16966, OPTIMOX 2, PACCE, MAX, Macco, PRIME, HORIZON IH 15 Studies: N9741, OPTIMOX 1, FOCUS, AVF2192g, AVF2107g, HORG, HORIZON H, FOCUS 2, NO16966, OPTIMOX 2, PACCE, MAX, Macco, PRIME, HORIZON IH

OS and PFS EOTR at 6 weeksEOTR at 12 weeks EOTR at 8weeks PFS

EOTR at 6, 8, 12 weeks, overall response rate and PFS and OS (adjusting with age, gender, PS, Mets in liver and lung) PFS OS

Discussion -Clinic investigation: EORT warrants further consideration as a potential surrogate endpoint to detect early signals for future trials, particularly randomized studies. - Clinic Practice: EORT as a ‘clinic surrogate prognostic factor’ in mCRC treatment -Questions: a)Early response vs. Duration of response b)Tumor biology c)Early response brings more treatment options (resection, local-regional therapy, more lines of therapy), improved quality of life. -Clinic investigation: EORT warrants further consideration as a potential surrogate endpoint to detect early signals for future trials, particularly randomized studies. - Clinic Practice: EORT as a ‘clinic surrogate prognostic factor’ in mCRC treatment -Questions: a)Early response vs. Duration of response b)Tumor biology c)Early response brings more treatment options (resection, local-regional therapy, more lines of therapy), improved quality of life.