1. Treating and Supporting Patients with Advanced Cancer Neal J. Meropol, M.D. Fox Chase Cancer Center Philadelphia, PA June 1, 2009 Colorectal Cancer Poster Discussion

2. How do we improve outcomes? Toxicity Efficacy GOALS How measured?What endpoints? Refine treatment New treatment Improve selection

3. Topics for Consideration Refine treatment –De Gramont (oxaliplatin) –Grothey (oxaliplatin) –Mitchell (panitumumab) –Tebbutt (capecitabine, bevacizumab, mitomycin) New treatment –Earhart (picoplatin) Improve selection –McLeod (Thymidylate synthase genotyping)

4. Copyright ©2008 American Association for Cancer Research Teicher, B. A. Clin Cancer Res 2008;14:1610-1617 Platinum Structures

5. De Gramont et al. (#4024) The problem: uncertain benefit of oxaliplatin reintroduction following holiday The solution: define characteristics predictive of benefit Eligible patients had received oxaliplatin previously for metastatic disease Endpoints: PFS and OS upon reintroduction based on interval and prior response N=330

6. De Gramont: Conclusions PFS and OS on reintroduction –associated with induction response –associated with induction PFS –associated with length of holiday Response rate with reintroduction –associated with length of holiday Comment –most favorable subgroups have prolonged interval from progression to death, suggesting differences in underlying biology –be prepared to reintroduce oxaliplatin in those patients who can tolerate it

7. Grothey et al. (#4025) The problem: oxaliplatin-induced neuropathy The solution: calcium and magnesium infusions Adjuvant treatment with FOLFOX +/- Ca/Mg Endpoints: CTCAE, oxaliplatin-specific neuropathy scale, and symptom questionnaire N=102

8. Potential Mechanism of Ca/Mg Neuroprotection Na + Membrane Extracellular Intracellular ATP Ca ++ Oxaliplatin Oxalate Dach- Platinum Mg ++

9. Grothey et al: Conclusions Ca/Mg reduced cumulative symptoms including –numbness, shirt buttoning, tingling, muscle cramps Consistent with other measures (e.g. CTCAE) No difference in acute neuro symptoms (except muscle cramps reduced) with Ca/Mg Comment –These encouraging data require further confirmation –difficult to interpret PRO measures, given low response rate, incomplete validation

10. Mitchell et al. (#4027) The problem: EGFR antibody-induced skin toxicity The solution: prophylactic treatment Metastatic colorectal cancer s/p fluoropyrimidine/oxaliplatin, initiating treatment with panitumumab plus FOLFIRI or irinotecan Randomize to prophylactic vs. reactive skin toxicity management Intervention: moisterizers, sunscreen, topical steroid, doxycycline Outcomes: CTCAE, Dermatology Life Quality Index N=95

11. Lacouture. Nature Reviews Cancer 6: 803–812, 2006 Epidermis Basement membrane Dermis Hypodermis Skin Structure

12. The Intervention Skin moisturizer – apply to face, hands, feet, neck, back, and chest daily in the morning upon rising Sunscreen (PABA free, SPF > 15, UVA/UVB protection) – apply to exposed skin areas before going outdoors Topical steroid (1% hydrocortisone cream) – apply to face, hands, feet, neck, back, and chest at bedtime Doxycycline 100 mg po BID Per investigator discretion, a reactive skin treatment could be initiated at any time

13. Mitchell: Conclusions During first 6 weeks, prophylactic group had –less grade 2+ skin tox (29% vs. 62%), and less grade 3 (6% vs. 21%) –More favorable derm-related QOL at weeks 3 (1.3 vs. 4.2 units) and 7 (2.0 vs. 2.6 units) –less grade 3+ diarrhea (15% vs. 32%), dehydration (6% vs. 17%), and neutropenia (8% vs. 26%)

14. Mitchell: Comment This small data set provides encouragement that the natural history of panitumumab skin toxicity can be modified by an intensive prophylactic intervention Unclear what components of the intervention are responsible for benefit Uncertain of the clinical significance of unit changes in DLQI (scale range 0-30) The differences in non-skin-related adverse events raises the possibility of unmeasured variables accounting for the observed results Further study is definitely warranted: placebo-control

15. Tebbutt et al. (#4023) The problem: irinotecan and oxaliplatin may be too toxic for some patients The solution: develop less toxic regimens Previously untreated patients with metastatic CRC Patients deemed “suitable” for capecitabine monotherapy Phase III randomized trial of AGITG –capecitabine vs. capecitabine/bevacizumab vs. capecitabine/bevacizumab/mitomycin Primary endpoint: PFS N = 471

16. Tebbutt: Results No significant tox differences (after controlling for treatment duration), except bev-associated tox No significant impairment in QOL with multiagent regimens CCBCBMCB vs. CCBM vs. C RR (%)313846NSp=0.006 PFS (mo) 5.78.58.4 HR 0.63, p<0.0001 HR 0.59, p<0.0001 OS (mo)19.118.416.5 HR 0.86, p=0.2 HR 1.00, p>0.9

17. Tebbutt: Comments Results consistent with prior studies showing benefit of adding bevacizumab to fluoropyrimidines Uncertain contribution of mitomycin; trend towards inferior survival raises concern for “burning bridges” Sequential (rather than combination) chemotherapy is a valid option for initial therapy – the challenge remains to better define which patients will benefit most from each approach

18. Earhart et al. (#4026) The problem: platinum-induced neurotoxicity The solution: new platinum structure Randomized phase II trial of FOLPI vs. FOLFOX Initial treatment of metastatic colorectal cancer Endpoints –RECIST; CTCAE, FACT-neurotox, neurologist N=101

19. Earhart: Conclusions Picoplatin associated with: –less neurotoxicity –more hematologic toxicity and alopecia –lower response rate (22% vs. 28%), but equivalent PFS –more frequently death as reason for discontinuation (5 vs. 1) Comment –response rate (28%) and PFS (7.0 months) lower than expected with FOLFOX –suggest: expand phase II experience before moving to phase III

20. McLeod et al. (#4026) The problem: not all patients are equally likely to benefit from fluoropyrimidines The solution: evaluate TYMS polymorphisms as a potential classifier

21. Rectal cancer: T3/T4, N0-2, M0-1 “Tandem phase II study” TYMS genotype-directed neoadjuvant therapy –*2/*2, *2/*3, *2/*4 (“good risk”) – 5FU plus radiation –*3/*3, *3/*4 (“bad risk”) – 5FU/irinotecan plus radiation Endpoints: downstaging, pathologic CR rates N=135

22. McLeod: Conclusions 27% considered “bad risk” Grade 3-4 diarrhea higher with irinotecan (42% vs. 21%) “Good Risk” N=90 “Bad Risk” N=31 Downstaging64.4%64.5% Path CR20%45%

23. McLeod: Comment TS is an appropriate target for developing a classifier Genotyping provides a more attractive platform than gene expression or immunohistochemistry Genotype-directed studies are feasible Impressive pCR rate in “bad risk” group Do these results warrant a prospective randomized trial with TS-polymorphism-based treatment assignment in rectal cancer? –Not quite yet

24. Why not yet? pCR rate appears low for “good risk” patients Similar results observed in unselected patients treated with XRT/capecitabine/irinotecan (56% T downstage) and XRT/capecitabine/oxaliplatin (58% T downstage) (RTOG0247, Wong et al. ASCO 2008) Is FP/irinotecan optimal strategy for “bad risk”? We have an opportunity: –“Prospective” analysis of banked specimens from R04 –FP/XRT +/- oxaliplatin

25. Summary We’re making real progress in the treatment of colorectal cancer We need new drugs, but still have a lot to learn about how best to use what we have Patient-reported outcomes are critical to understanding treatment impact We need to think strategically about allocation of finite research resources – our clinical research 401K –New drugs? Patient selection? Toxicity minimization? Where should we set the bar?