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2013 ASCO CRC Poster Discussion (Old Dog, New Tricks)

2013 ASCO CRC Poster Discussion (Old Dog, New Tricks). Weijing Sun, MD, FACP University of Pittsburgh. Bevacizum a b in CRC Therapy: Doses , efficacy, maintenance , and impact of ages - 3515 , 3516, 3517, 3521

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2013 ASCO CRC Poster Discussion (Old Dog, New Tricks)

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  1. 2013 ASCO CRC Poster Discussion(Old Dog, New Tricks) Weijing Sun, MD, FACP University of Pittsburgh

  2. Bevacizumabin CRC Therapy: Doses, efficacy, maintenance, and impact of ages - 3515, 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?

  3. Evaluated the optimal dose of Bevacizumab (2nd-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) 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 Arm A: FOLFIRI Hiroshi Tamagawa, et al + bevacizumab 5mg/kg R Oxaliplatin based CTx + bevacizumab 5mg/kg Arm B:FOLFIRI + bevacizumab 10mg/kg N=367 • Primary End Point: PFS • Secondary end points: Toxicity, RR, TTF, OS, • OS from the first-line, duration from the start of the first-line

  4. PFS 100 80 Hazard ratio: 0.95 (95% CI: 0.75-1.21) p=0.676 (log-rank test) Median PFS: A = 6.1 month (95% CI: 5.3-7.0); B = 6.4 month (95% CI: 5.6-7.4) 60 A PFS Probability (%) B 40 20 0 6 12 18 24 30 36 Months

  5. Subgroup Analysis of PFS Hazard Ratio (95% CI) Arm B better Arm A better

  6. 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…

  7. The Potential Impact of Bevacizumab Dose on the CRC Chemotherapy Efficacy Initial Phase II: Kabbinavar First line: AVF 2107g Second line: E3200

  8. 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 2nd line setting)

  9. Alessandro Passardi et al 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

  10. Baseline Characteristics

  11. PFS • A relative small study with diverse CT regimens (60% FOLFOX) • Appeared as ‘NO16966’ Data • No data in 2nd and 3rd line therapy • Will not change current practice = 1.2 months HR = 0.87, 95% CI (0.70-1.08), p = 0.212 OS:20.6 months in both arms [p=0.278, HR 1.18 (0.88-1.58)] RR: 48.9 (CT +B) vs. 47.9 % (p=0.371) HR = 0.87 95% CI (0.70-1.08) p = 0.212

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

  13. 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? OPTIMOX 1 FOLFOX4(n=312) R 6 cycles 12 cycles 6 cycles FOLFOX7 LV5FU2 FOLFOX7(n=313)

  14. PACCE: PFS and OS

  15. CAIRO2

  16. Survivals Grade 3/4 Toxicity (%)

  17. Maintenance PFS(randomized population, from randomization)

  18. CAIRO2: KRAS genotyping (n=501)

  19. Survivals

  20. Maintenance PFS WT KRAS Mut KRAS

  21. Conclusions • The addition of erlotinib to bevacizumabfollowing induction therapywithbevacizumab-basedchemotherapysignificantlyincreases the maintenance PFS. • In contrast to anti-EGFR Mabs, KRAS tumorstatusdoes not select patients withmCRCbenefitingfromerlotinib However: Will the results change the practice? • Bevacizumabalone is not standard, and without clear benefit (SAKK 41/06, abs 3503); and after OPTIMOX 1, 5-FU (or Capecitabine)+ bevacizumabis 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

  22. Bevacizumab 7.5 mg/kg day 1, q21d + Capecitabine 1000 mg/m2 b.i.d. days 1–14, q21d 3521: Results according to age in AVEX, a randomized phase 3 trial of bevacizumab with capecitabine for elderly patients with mCRC Previously untreated mCRC, age 70 yearsN=280 Randomize 1:1 Capecitabine 1000 mg/m2 b.i.d. days 1–14, q21d Stratification factors: • ECOG PS (0–1 vs2) • Geographic region Mark P. Saunders, et al Are elderly patients at increased risk for toxicity secondary to Bevacizumab, and how old is old?

  23. Progression-free and overall survival* A. Progression-free survival B. Overall survival Capecitabine (n=140) Bevacizumab + Capecitabine (n=140) HR=0.79 (95% CI: 0.57–1.09), P=0.182 1.0 1.0 HR=0.53 (95% CI: 0.41–0.69) P<0.001 0.8 0.8 0.6 0.6 OS estimate PFS estimate 0.4 0.4 9.1 mo 0.2 0.2 5.1 mo 20.7 mo 16.8 mo 0.0 0.0 140 99 68 41 23 13 8 2 2 1 0 140 120 95 81 60 44 34 16 12 8 5 140 108 85 62 49 33 19 11 9 6 5 140 82 38 13 6 4 1 1 1 1 0 Time (months) Time (months) Number at risk BEV + cape 0 4 8 12 16 20 24 28 32 36 40 0 4 8 12 16 20 24 28 32 36 40 44 Number at risk BEV + cape 2 Cape 1 Cape *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

  24. Progression-free and overall survival

  25. No major difference of AEs comparing with other Bevacizumab studies

  26. 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-angiogenicagent, (however, data here is only for Bev… ). • Key issue is careful patient selection.

  27. pStageIII Colon Cancer (C-RS) 3518: Non-inferiority of S-1 to UFT/LV as adjuvant chemotherapy for stage III colon cancer: A randomized phase III trial (ACTS-CC) ・Curatively resected ・Age: 20 - 80 y.o. ・PS: 0-1 R Stratification factors 　 ・ LN metastasis(N1/N2) 　 ・ Institution Yoshihiko Nakamoto, et al. ACTS-CC study group Test arm Control arm S-1 UFT/ LV UFT: 300-600 mg/day according to BSA LV: 75mg/day in 3 divided doses daily Day 1-28, q5w x 5 cycles (25w) S-1: 80, 100, 120 mg/day according to BSA in 2 divided doses daily Day 1-28, q6w x 4 cycles (24w) 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

  28. Biochemical action of S-1 and UFT/LV tegafurProdrug of 5-FU - Potent DPD inhibitory activity - Easy administration (Twice-daily p.o.) - Low price (1/2 of UFT/LV, 1/3 of mFOLFOX6in Japan) DPD： Dihydropyrimidinedehydro- genase TS： thymidylate synthetase CDHP： 5-chloro-2,4-dihydroxypyridine

  29. DFS and OS EAS：n=1,518 Median follow-up: 41.3 months (1.8-52.2) 98.8% 96.8% 93.6% S-1 88.3% 88.2% 98.9% 80.1% 96.6% 92.7% 75.5% UFT/LV 86.1% 71.8% 86.5% S-1 77.6% 72.5% 66.1% UFT/LV HR 0.86 [95%CI: 0.62-1.19] P=0.3600 HR 0.85 [95%CI: 0.70-1.03], p=0.1003 One-sided p<0.0001 (non-inferiority)

  30. Conclusions - 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. - Adjuvant chemotherapy using S-1 will be a treatment option for stage III colon cancer in Japan - Might fit in US pts, based on NSABP C-06 data, however, not available in USA

  31. 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 mCRC 1st line Age: 20 - 80 PS: 0-1 Non-inferiority n=512 R • Stratification factors: • With vs. without adjuvant chemotherapy • Institutions Test arm Control arm mFOLFOX6+Bev (n=256) L-OHP: 85 mg/m2 d1 Bev: 5 mg/kg d1 l-LV: 200mg/m2 d1 5-FU: 400mg/m2 bolus d1 5-FU: 2,400mg/m2 46 hr civ d1,2 repeated every 2 wks SOX+Bev (n=256) L-OHP: 130 mg/m2 d1 Bev: 7.5 mg/kg d1 S-1: 80, 100, 120 mg*/body d1-14 repeated every 3 wks *According to body surface area, BSA < 1.25 m2, 1.25=<BSA <1.5, BSA >=1.5

  32. PFS and OS mFOLFOX6+Bev : 30.9 M (95% CI:28.6-33.1) SOX+Bev : 29.6 M(95% CI:25.8- …) OS PFS HR=1.021 (95% CI:0.847-1.232) mFOLFOX6+Bev : 10.2 M (95% CI:9.5-11.3) SOX+Bev: 10.2 M(95% CI:9.4-11.1) HR=1.052 (95% CI:0.805-1.376 Median follow-up duration: 23.4 M (0.3 to 37.8) mFOLFOX6+Bev SOX+Bev mFOLFOX6+Bev SOX+Bev

  33. Subgroup analysis of PFS(FAS) No. of pts Sub-group P value for interaction mFOLFOX6+Bev better SOX+Bevbetter D.Takahari, et al. ASCO 2013; Abstract #3519

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

  35. 15 Studies: N9741, OPTIMOX 1, FOCUS, AVF2192g, AVF2107g, HORG, HORIZON H, FOCUS 2, NO16966, OPTIMOX 2, PACCE, MAX, Macco, PRIME, HORIZON IH Dirkje W Sommeijer, et al, the ARCAD Group 3520: Prognostic value of early objective tumor response (EOTR) to 1stline systemic therapy in mCRC: Individual patient data (IPD) meta-analysis of randomized trials from the ARCAD (Aide et Recherche en Cancérologie Digestive) database

  36. OS and PFS EOTR at 6 weeks EOTR at 12 weeks EOTR at 8weeks PFS PFS PFS

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

  38. 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: • Early response vs. Duration of response • Tumor biology • Early response brings more treatment options (resection, local-regional therapy, more lines of therapy), improved quality of life.

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