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Colorectal Discussion Beyond Progression: Is this progress?

Colorectal Discussion Beyond Progression: Is this progress?. Alan P. Venook, MD University of California, SF. Disclosures. Roche / Genentech, Regeneron and Sanofi have provided me with background information

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Colorectal Discussion Beyond Progression: Is this progress?

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  1. Colorectal DiscussionBeyond Progression: Is this progress? Alan P. Venook, MD University of California, SF

  2. Disclosures • Roche / Genentech, Regeneronand Sanofihave provided me with background information • I have served on Data Safety Monitoring Boards related to studies with Bevacizumab and Brivanib • I helped design the original CRC Bevacizumab trial and prescribe Bevacizumab • I had no involvement in the Afliberceptor Brivanibtrials nor have I ever prescribed the drugs • Thanks to Drs. Arnold, Allegra and Siu being timely • Thanks to Lee Ellis and Napo Ferrara for trying to educate me about VEGF biology PRESENTED BY:

  3. Colorectal abstracts • Review data (briefly) • Mechanism of action (minimal) • Clinical impact • Research implications • Next steps PRESENTED BY:

  4. Theme: Beyond Progression • TML – BEV* beyond progression • Initiated by AIO; completed by Roche / Genentech • VELOUR - 2nd line Aflibercept in pts PD on Bev • Regeneron / Sanofi • CO.20 – Cetuximab +/- Brivanib • NCIC + AGITG * BEV = Bevacizumab PRESENTED BY:

  5. Themes: Beyond Progression • TML – Bev beyond progression OS IMPROVED • Initiated by AIO; completed by Roche / Genentech • VELOUR - 2nd line Aflibercept in pts PD on Bev • Regeneron/ SanofiSAME BENEFIT +/- PRIOR BEV • CO.20 – Cetuximab +/- BrivanibCLOSE BUT NOT QUITE • NCIC + AGITG PRESENTED BY:

  6. SWOG 0600/iBET: A Phase III of Irinotecan and Cetuximab With or Without Bevacizumabin Patients With mCRC That Progressed During First-Line TherapyGold, Grothey et al.. Second line R A N D O M I Z E mCRC KRAS wild-type previously treated with Bevacizumab and oxaliplatin- based CT (n=1260) Bevacizumab 5 mg/kg + (FOLFIRI or Irinotecan + Capecitabine) PD Cetuximab + (FOLFIRI or Irinotecan + Capecitabine) CT + dual biologic arm removed • Primary endpoint: OS • Secondary endpoints: PFS, objective tumor response, tolerability, and safety • June 2007

  7. BRiTERegistry: BevacizumabRegimens: Investigation Treatment Effects Grothey et al, ASCO, 2007 • A longer median OS in the BBP subgroup was observed compared with the No BBP subgroup (Table 4). • A longer survival beyond 1st PD was observed in the BBP subgroup versus the No BBP subgroup. Median OS: 19.9 v. 31.8 mos OS Beyond PD: 9.5 v. 19.2 mos

  8. SWOG 0600/iBET: A Phase III of Irinotecan and Cetuximab With or Without Bevacizumabin Patients With mCRC That Progressed During First-Line TherapyGold, Grothey et al.. Second line R A N D O M I Z E mCRC KRAS wild-type previously treated with Bevacizumab and oxaliplatin- based CT (n=1260) Bevacizumab 5 mg/kg + (FOLFIRI or Irinotecan + Capecitabine) PD Cetuximab + (FOLFIRI or Irinotecan + Capecitabine) N = 68 CT + dual biologic arm removed • Primary endpoint: OS • Secondary endpoints: PFS, objective tumor response, tolerability, and safety • June 2007 – October 2010

  9. TML – Treatment Multiple Lines Standard second-line CT (oxaliplatin or irinotecan-based) until PD Bev + standard first-line CT (either oxaliplatin oririnotecan-based)(n=820) PD Randomize 1:1 Bev (2.5 mg/kg/wk) + standard second-line CT (oxaliplatin or irinotecan-based) until PD Cross-over: Oxaliplatin →Irinotecan Irinotecan→ Oxaliplatin Primary endpoint Overall survival from randomization Statistics: Designed to detect 30% (HR 0.77) improvement in median OS (90% power, 2-sided 5%) Study conducted in 220 centres in Europe and Saudi Arabia

  10. TML features and findings • Very select patient population • Tolerant of long-term Bev, not curable • PFS 1st line > 3 months • Responses infrequent (4-5%) • Median 4 months additional Bev • Chemotherapy backbone did not matter • BEV beyond PD improves OS 1.4 months (HR = 0.81) PRESENTED BY:

  11. TML: missing in abstract presentation • Impact of subsequent treatment • KRAS status • Only 40% received anti-EGFR • BRAF status • Primaries in place ? • OS from diagnosis, not randomization The word: BIOMARKER PRESENTED BY:

  12. What else does TML teach us? • Affirms the limited utility of Registry studies regarding interventions and outcomes: • BRITE: 9.5 v. 19.2 OS beyond PD • TML: 9.8 v. 11.2 BRiTE findings not replicated; the publication*could be cited as an example of the pitfalls of Registry data *Grothey et al, JCO, 2008 PRESENTED BY:

  13. Aflibercept • Fusion protein of key domains from human VEGF receptors 1 and 2 with human IgG Fc¹ • Blocks all human VEGF-A isoforms, VEGF-B, and placental growth factor (PlGF)² • High affinity – binds VEGF-A and PlGF more tightly than native receptors • Holash J et al. Proc Natl Acad Sci USA. 2002;99:11393-11398. • Tew WP et al. Clin Cancer Res. 2010;16:358-366.

  14. VELOUR – VEGF-trap with irinotecan in coLOrectal cancer after failURe of oxaliplatin Aflibercept 4 mg/kg IV, day 1 + FOLFIRI q2 weeks R A N D O M I Z E 600 Metastatic Colorectal Cancer 1:1 Disease Progression Death • Stratification factors: • ECOG PS (0 vs 1 vs 2) • Prior bevacizumab (Y/N) Placebo IV, day 1 + FOLFIRI q2 weeks 600 OS: 12.06 v 13.5 HR = 0.817 p =0.0032

  15. Consistency of OS and PFS With and Without Prior Bevacizumab Response rate 8.4 11.7 12.4 23.3 • Interactionbetween “treatment arm” and “prior bevacizumab” factor was not significant at the 2-sided 10% level (P=0.57 for OS; P=0.2 for PFS)

  16. NCIC CTG CO.20: Schema 1° endpoint: Overall Survival Total sample size: 750 Trial: 2008 - 2011 Median follow-up: updated analysis: 34 months (694 deaths) 1:1 Brivanib + Cetuximab n = 376 RANDOMI Z E Placebo + Cetuximab n = 374 Stratify by Center and ECOG 0/1 versus 2

  17. What do we learn from NCI CTG CO.20? • PFS improvement does not mean OS as well • The study was powered such that 0.7 mos would not be statistically significant • TML & VELOUR were powered differently • 1.4 mos OS benefit Ask yourselves: is 1.4 mos clinically significant ? PRESENTED BY:

  18. Colorectal abstracts • Review data (briefly) • Mechanism of action (minimal) • Clinical Impact • Research Implications • Next steps PRESENTED BY:

  19. Anti-VEGF mechanism of action: evolving Difficult to explain mechanism of VEGF inhibition beyond progression when we are not sure of the mechanism(s) of action in the first place Courtesy Lee Ellis, MD Ellis, Hicklin. Nat Rev Ca 2008

  20. Colorectal abstracts • Review data (briefly) • Mechanism of action (minimal) • Clinical Impact • Research Implications • Next steps PRESENTED BY:

  21. Clinical Impact -- Regulatory • Drugs likely to be approved by FDA • Aflibercept in 2nd line metastatic CRC w/ FOLFIRI • Regorafenib in “refractory” metastatic colorectal cancer • Label addition for old drug • Bevacizumab beyond progression • Drug with uncertain future • Brivanib awaits other maturing trials (will not discuss further since may never be available) PRESENTED BY:

  22. Clinical Impact – Precision Medicine ?Current Practice Pattern in US While we say CONTINUUM OF CARE, in practice: • FOLFOX / BEV 1st line until neurotoxicity +/- PD, • Then KRAS status: • (FOLF) Irinotecan +/- EGFR Ab • FOLFOX + EGFR • Not established • Regorafenib • Aflibercept • Clinical Trial PRESENTED BY:

  23. Clinical Impact: Whither FOLFOX / BEV? Hurwitz, et al. NEJM, 2004 = 4.7 mos

  24. Clinical Impact: Whither FOLFOX / BEV? History Lesson Hurwitz data: BEV a difference-maker with IFL IN RETROSPECT: • BEV approved “with FU regimen”; FOLFOX > IFL • FOLFOX / BEV: 2nd-line in BEV naïve patients • Subsequent studies: no increase RR, marginal OS • Although not limited by neurotoxicity, FOLFIRI less popular as backbone BY DEFAULT: FOLFOX / BEV 1st-line metastatic CRC PRESENTED BY:

  25. Clinical Impact – Paradigm shift?Current Practice Pattern in US While we say CONTINUUM OF CARE, in practice: • FOLFOX / BEV 1st line until neurotoxicity +/- PD, • Then KRAS status: • (FOLF) Irinotecan +/- EGFR Ab • FOLFOX + EGFR • Not established • Regorafenib • Aflibercept • Clinical Trial BEV beyond PD PRESENTED BY:

  26. Clinical Impact – Paradigm shiftAnti-VEGF therapy: Interpreting TML If TML correctly predicts that continuing 1st-line BEV beyond PD improves outcomes in 2nd-line: • Why would that not apply for 3rd line ? • For subsequent line(s) ? • For EGFR Ab’s in KRAS wt patients? • Should we be stopping BEV before elective surgery? • What toxicities justify stopping BEV? • Treatment Holidays? • Are Aflibercept and Regorafenib extensions of this effect? PRESENTED BY:

  27. Clinical Impact: Anti-VEGF therapy What do we tell our patients? WHY: • Once initiated, discontinuing anti-VEGF therapy may lead to a small survival disadvantage • Anti-VEGF therapy works in subsequent lines as well FOREVER: • In fact, it may be a mistake to discontinue anti-VEGF therapy at any time and that effects all the decisions we will make over the course of your disease WHEN? • So while anti-VEGF therapy is a standard 1st line treatment, it may make more sense to use it in 2nd and subsequent lines rather than up-front PRESENTED BY:

  28. Colorectal abstracts • Review data (briefly) • Mechanism of action(minimal) • Clinical Impact • Research Implications • Next steps PRESENTED BY:

  29. Implications: from Clinical Care to Research • Is FOLFOX / BEV the optimal 1st line choice? • Can we distinguish BEV v. Aflibercept ? • Is Regorafenib different ? • Have we reached the ceiling with VEGF as a target? • What about EGFR antibodies? When? • Should we revisit dual antibodies? WHO BENEFITS and WHO DOES NOT? PRESENTED BY:

  30. Put some “precision” into Precision Medicine • Treating many patients to help few • Missed opportunity and added toxicities • Paucity of biomarkers for colorectal cancer: • KRAS: who does NOT benefit from EGFR inhibition • MSI: who may not need chemotherapy • BRAF: who does very poorly overall • Need to inform choice of treatment by biomarkers if at all possible PRESENTED BY:

  31. Colorectal abstracts • Review data (briefly) • Mechanism of action (minimal) • Clinical Impact • Research Implications • Next steps PRESENTED BY:

  32. CALGB/SWOG # 80405 Shameless advertising: clinical and correlative results expected 2013 +/- Bevacizumab + FOLFOX or FOLFIRI q 2 wks Send tumor tissue block to SWOG PCO Randomize Patients w/ Wild type K-ras tumor Untreated advanced or mCRC N =1142 Screen for eligibility Cetuximab + FOLFOX or FOLFIRI q 2 wks Re-open: 6/09 Closed to accrual: 2/12 Patients enrolled: N = 2334 (total) 1177 (final endpt)

  33. Search for anti-VEGF biomarkers • Bevacizumab • Plasma; blood mRNA & DNA; tumor IHC, mRNA, DNA • pVEGF-A putative biomarker (JCO, 2012) • Aflibercept • Plasma for pK and pD; VEGF • Regorafenib • Anticipate extensive biomarker analysis • Yes/no nature of outcome may yield biomarker • Brivanib • Plasma 83-analyte (data analysis) PRESENTED BY:

  34. COST of CARE PRESENTED BY: The Elephant in the Room

  35. Cost of Cancer Care: Issues and Implications Meropol and Schulman, JCO, 2007

  36. Impact on Cost of Care: back of the envelope • Bevacizumab • $2864 per 400 mg vial* • Average weekly dose = 175 mg • Regorafenib • Sorafenib $8377 / month • Aflibercept $$$ unknown $$ per UCSF pharmacy PRESENTED BY:

  37. Colorectal cancer in 2012: my reality check • These are modest advances • A minority of patients appear to benefit • And the costs are unsustainable THE CHALLENGE • Actually deliver on promise of personalized medicine • To do so, we need better tools to predict outcomes • And it must be affordable PRESENTED BY:

  38. CRC 2012: making it affordableMultiple Choice (may select more than one) • Implement an agency like NICE PRESENTED BY:

  39. NICE: National Institute for Health and Clinical Excellence • Critical analysis of cost:benefit • Determines what will be covered by National Health Insurance in UK • Approval does not mean coverage • Non-approval does not mean non-coverage http://guidance.nice.org.uk/CG131 PRESENTED BY:

  40. CRC 2012: how to live within our meansMultiple Choice (may select more than one) • Implement an agency like NICE • Let the market take care of things (as with generic drugs) • Await a bold cost-slashing move by Pharma (e.g. Cipla) • Give the FDA (or other panel) authority over drug pricing • Moratorium on studies powered to find clinically insignificant impact (to be defined) • Make the discovery of predictive biomarkers as high a priority as finding new drugs or indications PRESENTED BY:

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