Best of ASCO 2009 / GI

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1 Best of ASCO 2009 / GI Santa Monica, CA J. Randolph Hecht, M.D. Professor of Clinical Medicine Director, UCLA GI Oncology Program David Geffen School of Medicine at UCLA

2 Financial Disclosures I have no relevant financial relationships to disclose Hecht

3 Abstracts Practice Changing:» LBA4509 (ToGA Gastric), 4503 (ABC-2 Biliary), 4505 (ESPAC-3 Pancreas), LBA4007, CRA4008 (STAR, PRODIGE Rectal) Not Practice Changing But Interesting:» LBA4 (C0-8 Colon Adjuvant), 4010 (ACCENT Colon), 4506 (CONKO-4 Pancreas) Life Is Too Short:» 4000 (QUASAR), 4001, 4002 (PETACC-3), 4019 (Leuven) Bonus!:» LBA4009 (ACT-2 Anus), 4508 (PROMID Carcinoid)

4 Practice Changing

5 Gastric Cancer 22,000 cases/yr 12,000 deaths/yr US Jemal, et al., CA Cancer J Clin nd most common cause of cancer and death worldwide Risk has fallen 10 fold over past century

6 Molecular Biology p53: 77% EGFR HER2/neu: Bang ASCO % E-cadherin FHIT p16/p27 COX-2

7 HER-2 in Gastric Cancer HER-2 overexpressed in UGI tumors Amplification correlated with poor outcome N=182 Park DI DDS 2006

8 ToGA!

9 Efficacy results from the ToGA trial: a phase III study of trastuzumab added to standard chemotherapy in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer Eric Van Cutsem* Y-K Kang, HC Chung, L Shen, A Sawaki, F Lordick, J Hill, M Lehle, A Feyereislova, Y-J Bang *University Hospital Gasthuisberg, Leuven, Belgium Van Cutsem ASCO 2009

10 ToGA trial design Phase III, randomized, open-label, international, multicenter study 3807 patients screened HER2-positive (22.1%) Stratification factors advanced vs metastatic GC vs GEJ measurable vs non-measurable ECOG PS 0-1 vs 2 capecitabine vs 5-FU HER2-positive advanced GC (n=584) R 5-FU or capecitabine a + cisplatin (n=290) 5-FU or capecitabine a + cisplatin + trastuzumab (n=294) 1 Bang et al; Abstract 4556, ASCO 2009 a Chosen at investigator s discretion GEJ, gastroesophageal junction Van Cutsem ASCO 2009

11 Primary end point: OS Event FC + T FC Events Median OS HR % CI 0.60, 0.91 p value Time (months) No. at risk T, trastuzumab Van Cutsem ASCO 2009

12 Secondary end point: PFS Event FC + T FC Events Median PFS HR % CI 0.59, 0.85 p value Time (months) No. at risk Van Cutsem ASCO 2009

13 Secondary end point: tumor response rate Patients (%) Intent to treat p= F+C + trastuzumab p= F+C 47.3% 41.8% p= % 34.5% 2.4% 5.4% CR PR ORR ORR= CR + PR CR, complete response; PR, partial response Van Cutsem ASCO 2009

14 Conclusions 1. Trastuzumab + chemo is the new SOC for HER-2+ GCs 2. What about esophageal cancer? 3. How do we get trastuzumab? 4. How long? 5. What about lapatanib? LOGIC/ TRIO13: CapeOx +/- lapatanib UGI adenoca 6. Other targets: EGFR, c-met, VEGF

15 ABC

16 Biliary Cancer 9800 cases/year; 3400 deaths/year (Jemal CA 2009) Anecdotal activity with 5-FU, gemcitabine, platins No randomized Ph III trials ABC-1

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19 New Standard of Care

20 Adjuvant Pancreas CONKO-1 Gem > Nothing ESPAC-1 5-FU > Nothing > 5-FU+XRT ESPAC-3 (v2)

21 Neoptolemos ASCO 2009

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24 Conclusions 5-FU = Gem Adjuvant?? XRT All pretty bad

25 Adjuvant Rectal Cancer TME most important Chemoradiation with 5-FU standard of care Preop preferred (dec toxicity, inc sphincter sparing) What does it accomplish? Local control Reduction of distant mets What about other drugs? Irinotecan Oxaliplatin Biological agents

26 Oxaliplatin Improves survival in colon cancer (MOSAIC, C-07) Phase II trials improved pcr rate (5-FU 10-15%, Ox 25-30%) 3 Large Trials STAR ACCORD 12/0405 PRODIGE 2 NSABP R-04 pending

27 STAR STUDY OUTLINE R stage center RT 50.4 Gy FU 225 mg/m 2 /day PVI RT 50.4 Gy FU 225 mg/m 2 /day PVI OXA 60 mg/m 2 weekly x wks T M E FU/LV (bolus or CI, center choice) N = 747 Aschele ASCO 2009

28 Gerard ASCO 2009

29 TUMORS CHARACTERISTICS FU/RT FU/OXA/RT (n=379) (n=368) T stage, % T T T N +, % cm from anal verge median 6 6 TRUS: 33; pelvic CT scan: 261; both 453

30 TOXICITY % of patients FU/RT FU/OXA/RT (n=379) (n=353) p grade III-IV any type 8 24 <.0001 diarrhea 4 15 <.0001 radiation dermatitis grade II-III neurosensory 0.5/0 36/1 <.0001 Tx related deaths 0.3 (1) 0.6 (2)

31 SURGERY patients, % FU/RT (n= 379) FU/OXA/RT (n= 368) Operated LAR APR other 4 5 Median interval 52 days 53 days Deaths < 60 d 0.8 (3) 0.8 (3)

32 pathologic CR patients, % FU/RT FU/OXA/RT (n= 379) (n= 368) p ypt0n (95% cl) (13-20) (13-20)

33 M+ at SURGERY (unplanned / exploratory) patients, n FU/RT FU/OXA/RT (n=379) (n=368) p pm1 11 (3%) 2 (0.5%) liver 6 1 peritoneal 4 1 nodes 1 - cm1 5 - liver 4 - liver+lung 1 - Overall 16 2

34 Oxaliplatin/XRT in Rectal Cancer No improvement in pcr, sphincter sparing Worse toxicity Effect on mets No information on post-op chemo

35 Interesting

36 CRC: Demographics and Presentation Estimated 2008 U.S. incidence (new cases): 148,810 Estimated 2008 U.S. mortality: 49,960 12% stage I * 18.6% stage IV * 24.5% stage II * 12.3% of patients presented with recurrent CRC. *2002 data. 32.6% stage III * American Cancer Society, 2005; Datamonitor, 2003.

37 Adjuvant Therapy of Stage III Disease 5-FU Works!» 5-FU/levamisole NCCTG 31% dec. RFS ECOG 33% improvement OS NCI Consensus 1990» 5-FU/leucovorin NSABP C-04 INT 0089 IMPACT (Pooled)

38 ECOG/INT 0089: Efficacy DFS % of Patients 5-Year 10-Year 5-Year OS 10- Year 5-FU + low-dose LV FU + high-dose LV FU + Lev FU + low-dose LV + Lev P>0.05 in all comparisons except 5-FU + low-dose LV + Lev vs 5-FU + Lev (P<0.05). Haller et al. J Clin Oncol. 2005;23:8671.

39 Combination Chemotherapy 5-FU/Irinotecan» CALBG X C89803» PETACC 3» ACCORD 5-FU/Oxaliplatin» NSABP C-07» MOSAIC

40 MOSAIC: Study Design n=2246 Enrollment: Oct 1998 Jan 2001 (146 centres; 20 countries) Completely resected colon cancer Stage II, 40%; Stage III, 60% Age years KPS 60 No prior chemotherapy R (n=1123) (n=1123) FOLFOX4 (LV5FU2 + oxaliplatin 85 mg/m²) LV5FU2 Primary end-point: disease-free survival Secondary end-points: safety, overall survival LV5FU2, Leucovorin 200 mg/m 2 iv over 2 hours followed by 5-fluorouracil 400 mg/m 2 bolus and 5-fluorouracil 600 mg/m 2 iv over 22 hours on Days 1 and 2, every 14 days; FOLFOX4, LV5FU2 + oxaliplatin 85 mg/m 2 iv over 2 hours on Day 1 De Gramont ASCO 2007

41 Probability MOSAIC Overall Survival: Stage III p= % HR [95% CI] Stage III 0.80 [ ] FOLFOX4 stage III LV5FU2 stage III 0 De Gramont ASCO Overall survival (months)

42 What About Biologic Agents?

43 A phase III trial assessing bevacizumab in stage II and III carcinoma of the colon: Results of NSABP Protocol C-08 N.Wolmark G.Yothers M.J.O Connell S.Sharif N.Atkins T.E.Seay L.Feherenbacher S.O Reilly and C.J.Allegra

44 NSABP C-08 Stage ll + lll Strat: # Pos. N Randomize mff6 mff6 + B

45 NSABP C-08 mff6 q2wk X 6 mo R Bev* q2wk X 1 yr *5mg/K

46 NSABP C-08 DFS % Ev 3yDFS mff6+b mff HR 0.89 P 0.15 Yrs

47 DFS Stage II DFS Stage III Ev 3yDFS mff6+b mff Δ 2.7 Ev 3yDFS mff6+b mff Δ 1.8 HR 0.82 P 0.35 HR 0.90 P 0.25 NSABP C

48 Conclusions There was a transient effect of bevacizumab but NOT clinically significant Awaiting AVANT, what about other trials? (E5202) No evidence for bevacizumab in adjuvant therapy Cetuximab trials pending (PETACC-8; N0147)

49 Impact of older age on the efficacy of newer adjuvant therapies in >12,500 patients with stage II / III colon cancer: Findings from the ACCENT Database N. Jackson McCleary, J.A. Meyerhardt, E. Green, G. Yothers, A. de Gramont, E. Van Cutsem, M. O Connell, C.J. Twelves, L.B. Saltz, D.J. Sargent for the ACCENT collaborative group

50 Treatment of Colorectal Cancer in Elderly Patients Metastatic setting» Folprecht JCO N=2,692 (22% 70 yrs) 4 trials of irinotecan-based therapy Improved PFS, trend to improved OS for elderly w/addition of irinotecan» Goldberg JCO N=3,742 (16% 70 yrs) 4 trials of oxaliplatin-based therapy Similar survival benefit and toxicity in age subgroups

51 Treatment of Colorectal Cancer in Elderly Patients Adjuvant setting» Sargent NEJM 2001 N=3351 (15% 70 yrs) 7 trials of 5-FU + levamisole/leucovorin v surgery No significant interaction observed between age and efficacy of treatment

52 The Adjuvant Colon Cancer End Points (ACCENT) Group Established in 2003 A collection of individual patient data from trials in the US, Canada, Australia and Europe Original objective - to validate DFS as a surrogate endpoint in adjuvant colon cancer trials O'Connell MJ, et al. JCO 2008; Sargent DJ, et al. JCO 2007; Sargent DJ, et al. JCO 2005

53 Efficacy oxaliplatin-based therapy Age <70 n = 3,977 Endpoint HR (95% CI) Experimental v Control IV 5-FU/LV DFS * OS * TTR * 0.77 (0.68,0.86) 0.81 (0.71,0.93) 0.76 (0.67,0.86) Deaths within 6 mo Exp v Control % (p-value) 0.81 v 0.81 (p=1.0) 70 n = (0.80,1.35) 1.19 (0.90,1.57) 0.92 (0.69,1.23) 2.57 v 1.37 (p=0.25) Interaction of age by treatment p-value * Values < 1 favor experimental arm

54 Conclusions No great rationale for difference with oxaliplatin Why difference between metastatic and adjuvant setting? Hypothesis generating Incorporate in new trials

55 CONKO-4 Trial (4506) Enoxaparin in Advanced Pancreatic Cancer Why?» VTE common in APC»? Therapeutic effect 312 pts svte: 14.5% vs. 5% No change in TTP, OS

56 Conclusions Enoxaparin reduces DVT Is this is worth NNT? No effect on outcome

57 Life Is Too Short Biomarkers Prognostic: How will the patient do? Predictive: Will a specific treatment work? Some markers are both: HER-2 in breast cancer Some markers are only one: KRAS in CRC

58 Life Is Too Short 4000: Oncotype Dx in Stage II CRC Used QUASAR samples and data to validate Recurrence and treatment scores (Prognostic/Predictive) But: Low recurrence score 12% rec rate, high 22% not useful Treatment score not predictive 4001/2: Biomarkers from PETACC-3 Failed adjuvant irinotecan trial MSI progrognostic, Stage II? From III 4019: Retrospective analysis of predictive markers for cetuximab EREG and AREG Already shown (Khambata-Ford JCO 2007)

59 BONUS!!

60 Treatment of Anal Cancer 5-FU/MMC+XRT standard, but high RR with platins in phase II trials RTOG 98-11(Ajani JAMA 2008) Induction chemo, 5-FU/Cis+XRT vs. Standard 5- FU/MMC+XRT

61 RTOG FU/Cis/XRT 5FU/MMC/XRT RFS 54% 60% OS 70% 75% Colostomy rate 19% 10% Ajani 2008

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66 Anal Cancer 2009 MMC and cisplatin are equivalent Induction therapy is bad What about other agents? Oxaliplatin, cetuximab Hard to do studies

67 Carcinoids Slow growing neuroendocrine tumors Often, though not always hormonally active No standard of care for oncologic treatment Octreotide approved for carcinoid syndrome Rare responses but? increased stable disease

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71 Conclusion Octreotide should be the new standard of care for carcinoids What about after progression Other new agents: small molecule VEGFR TKIs, RAD001

72 Best of ASCO 2009 Try to get trastuzumab for HER-2 gastric No oxaliplatin rectal cancer No adjuvant bevacizumab 5-FU OK (barely) pancreatic adjuvant Cisplatin can substitute for MMC in anal cancer Octreotide delays progression in carcinoids

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