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Cavemen and Rocket Scientists: A Perspective on Pancreatic Cancer Researchers

Cavemen and Rocket Scientists: A Perspective on Pancreatic Cancer Researchers. Robert A. Wolff, M.D. University of Texas, M.D. Anderson Cancer Center ASCO Poster Discussion Non-Colorectal GI Cancer Session Sunday, May 31 st , 2009. DISCLOSURE. I receive research funding from:.

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Cavemen and Rocket Scientists: A Perspective on Pancreatic Cancer Researchers

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  1. Cavemen and Rocket Scientists: A Perspective on Pancreatic Cancer Researchers Robert A. Wolff, M.D. University of Texas, M.D. Anderson Cancer Center ASCO Poster Discussion Non-Colorectal GI Cancer Session Sunday, May 31st, 2009

  2. DISCLOSURE I receive research funding from: Eli Lilly, and Company

  3. Agenda • Briefly discuss positive key elements of these posters which support the notion of rocket science • Provide constructive criticism of our collective Neandertal traits • Attempt to conclude (without being shot!)

  4. Table of Contents-1 • “Smart cytotoxics” • Nanoparticle albumin-bound (nab) paclitaxel (Von Hoff # 4525) • Cationic liposomal paclitaxel (Loehr # 4526) • A “clean” study regarding the role of radiation in adjuvant therapy in resected pancreatic ca • EORTC/FDCC/GERCOR: (Van Laethem # 4527) • Single institution attempts to improve drug development and therapy in pancreatic cancer • Hidalgo # 4528 and Laheru # 4529

  5. Table of Contents-2 • “Cooperative” group attempts to leverage collected data from completed trials • ECOG: DNA Repair Pathway SNPs (Yoon # 4530) • CALGB: GWAS and a prognostic SNP (Innocenti # 4531) • AViTA: Biomarker predicting rash to EGF-R inhibition and rash in response to erlotinib as prognostic in patients with metastatic pancreatic cancer (Verslype # 4532)

  6. “Smart” Cytotoxics: • nab-paclitaxel yields high response in SPARC + tumor cells! • SPARC+ by P antibody: 80% of patients responded, PFS 14 M • SPARC- by P antibody: 36% patients still respond to gem + nab paclitaxel (higher than gem alone) • Impressive PFS/OS in a pure metastatic population (especially those with > 50% drop in CA 19-9) • Phase III trial planned Gem +/- nab-paclitaxel • Suggests SPARC P-antibody as a predictive biomarker • Cationic liposomal paclitaxel and microenvironment. • Randomized Phase II trial in locally advanced/metastatic pancreatic cancer patients • Median Overall Survival = 8.4-9.4 Months for Gem + Liposomal Paclitaxel (dose dependent) • Median Overall Survival = 7.2 Months for Gem alone • Appears to be first “successful” attempt to target tumor angiogenesis in pancreatic cancer.

  7. Gemcitabine Dosing • Gemcitabine is a minimally effective when dosed at 1000 mg/m2 over 30 minutes. • In phase I, gemcitabine active at 180-525 mg/m2 over 30 minutes given weekly. No increase in intracellular levels of gem-triphosphate were observed using higher doses.1 • 2 randomized trials demonstrate fixed dose rate gemcitabine at or near MTD is better, but more toxic than standard dose gemcitabine.2,3 • Individualized maximal repeatable doses of gem range of from 300-700 mg/m2 weekly, closer to FDR gem. • In combination with radiation, 400 mg/m2 x 7 weeks, led to a median survival of 22 months in 86 patients with resectable PC, 25% NOT RESECTED!5 1. Abbruzzese JL et al JCO, 1991 2. Tempero JCO, 2003 4. Takahashi Y et al Pancreas, 2005 5. Evans DB, et al JCO, 2008 3. Poplin E, et al ASCO, 2006

  8. OR ? • Developing sophisticated cytotoxics with more specific targets in tumor cells or microenvironment. (Laser guidance). • Combining them with a club. • We must be more intelligent about the delivery of ALL our therapeutics to maximize efficacy and minimize toxicity. • Do you give IFL or FOLFIRI to your patients?

  9. Median Overall Survival 24 months Adjuvant Therapy: EORTC/FDCC/GERCOR • Clean study comparing 4 cycles of gemcitabine alone vs gemcitabine for 2 cycles followed by gemcitabine/XRT.

  10. OR ? Adjuvant Rx SURGERY GITSG CONKO 001 EORTC EORTC/FDCC ESPAC-1 ESPAC-3 RTOG 9704 Criteria for Resectability-No Standardized Surgery-No Strict Margin Assessments-No • Adjuvant therapy requires patients to have surgery first (a blunt weapon in pancreatic cancer). No efforts to standardize this.

  11. OR ? • Adjuvant therapy requires patients to have surgery first (a blunt weapon in pancreatic cancer). No efforts to standardize this. Adjuvant Rx SURGERY • .0 22.8 • 17.1 24.0 • 20.1 23.6 • 20.5 Criteria for Resectability-No Standardized Surgery-No Strict Margin Assessments-No

  12. OR ? • Adjuvant therapy requires patients to have surgery first (a blunt weapon in pancreatic cancer). No efforts to standardize this. Adjuvant Rx SURGERY Criteria for Resectability-No Standardized Surgery-No Strict Margin Assessments-No Survival Data Applies only to the Numerator

  13. The Numerator The Eligible 274 Metastatic at Restaging 12 Adjuvant Therapy 58% Median Survival 25.2 M The Fit 286 T4 + Metastatic + R1 + Islet Cell 558 R0 Resections 472 Inadequate Recovery 180 Died 6 Upfront Surgery 1030 The Denominator at the Mayo Clinic 1975-2005 Corsini M et al. JCO 2008

  14. The Numerator The Eligible 468 Metastatic at Restaging 17 Adjuvant Therapy 53% Median Survival 21.2 M The Fit 485 T4 or Metastatic 16 R0 or R1 Resections 873 Did not receive adjuvant rx 345 Death 43 Upfront Surgery 889 The Denominator at the Johns Hopkins 1993-2005 Herman J et al. JCO 2008

  15. The Numerator The Eligible Metastatic at Restaging? Adjuvant Therapy 90 patients Median Survival 24 months The Fit T4 or Metastatic at Surgery? R0 Resections Did not receive adjuvant rx? Died? Upfront Surgery The Denominator at EORTC Sites?

  16. OR ? • We need to select patients for surgery andfor adjuvant therapy. • Insist up high-quality imaging. • Use radiographic criteria for resectability. • Standardize the operation (akin to TME). • Strict margin assessments and restaging after surgery.

  17. Important effort to truly personalize therapy. Failure to engraft has prognostic significance. Tumors grown in mice mimic sensitivity and resistance to gemcitabine in the patients. Very appealing model for evaluating cytotoxic therapy. Xenografts do not recapitulate the tumor microenvironment. Is it practical to perform tumor xenografts in patients with advanced disease? ? Johns Hopkins and Pancreatic Cancer Research:Mice as Guinea Pigs

  18. Use small numbers of patients to maximize information about specific therapies. PK data regarding the cytotoxic (alone/with FTS) and the molecular agent (alone/with cytotoxic). Pre- and post-biopsy assessments of effects of drug on the putative target (K-RAS). Is a decrease in K Ras levels cause by FTS of only 44% considered sufficient to alter biology? ? Johns Hopkins and Pancreatic Cancer Research:People as Guinea Pigs Where are we going with FTS?

  19. Exploiting ECOG 1201:SNPs in DNA Repair Pathways predicting Pathologic Complete Responses Evaluated samples from patients with adenocarcinoma of esophagus or GE junction enrolled on a prospective clinical trial: 60 of 97 enrolled patients had adequate tissue for analysis.

  20. Builds on previous retrospective analysis of DNA repair gene SNPs in patients with squamous cell or adenocarcinoma of E/GEJ1 Prognostic, but not predictive. How do we use this in the future? Exclude these patients? ? Exploiting ECOG 1201:SNPs in DNA Repair Pathways predicting Pathologic Complete Responses Tissue analysis from a prospective randomized trial in patients with adenocarcinoma. XRCC1 Arg399Gln AA/AG vs GG had a 5-fold increased risk of failing to achieve a path CR. 1. Wu X, et al JCO, 2006

  21. Leveraging CALGB 80803: Gem/Placebo vs Gem/Bevacizumab:Genome-wide Association Study (GWAS) CALGB 80803 study of gemcitabine + placebo versus gemcitabine + bevacizumab (no difference in PFS or OS) Robust GWAS of samples from 338 patients testing >500,000 SNPs Discovered a “bad” SNP IL17F H161R: 3.9% frequency and associated with poor prognosis IL17F H161R associated with up-regulation in angiogenesis pathways and aggressive biology Why no benefit with gem/bevacizumab in “good” SNPs of IL17F? ?

  22. Leveraging CALGB 80803: Gem/Placebo vs Gem/Bevacizumab:Genome-wide Association Study (GWAS) CALGB 80803 study of gemcitabine + placebo versus gemcitabine + bevacizumab (no difference in PFS or OS) CALGB 80803 study of gemcitabine + placebo versus gemcitabine + bevacizumab (no difference in PFS or OS) This needs to be validated, but it appears to be prognostic, not predictive of response. We are smarter now, but are we wiser? Is “Publish or perish” the modern equivalent of “fight or flight”? Robust GWAS of samples from 338 patients testing >500,000 SNPs Robust GWAS of samples from 338 patients testing >500,000 SNPs Discovered a “bad” SNP IL17F H161R: 3.9% frequency and associated with poor prognosis Discovered a “bad” SNP IL17F H161R: 3.9% frequency and associated with poor prognosis IL17F H161R associated with up-regulation in angiogenesis pathways and aggressive biology IL17F H161R associated with up-regulation in angiogenesis pathways and aggressive biology Why no benefit with gem/bevacizumab in “good” SNPs of IL17F? ?

  23. R A N D O M I Z A T I O N GE-B (n=306) PD Previously untreated metastatic pancreatic cancer 1:1 GE-P(n=301) PD G: 1,000mg/m2 on days 1, 8, 15, 22, 29, 36, 43 for first 8 weeks, days 1, 8, 15 in subsequent 4-week cycles; E 100mg/day; B 5mg/kg q2w AViTA Trial: Rash as a Marker of Efficacy to Erlotinib?

  24. AViTA Trial: Rash is a Marker of Good Prognosis! Median Overall Survival

  25. Confirms results from PA.3 (Gem +/- Erlotinib). This is an important observation Multivariate analysis shows a positive correlation between low CRP levels, no active smoking, and increased chance of a rash If lack of rash is bad, we can get patients to stop erlotinib, or alternatively push up the dose of erlotinib in an effort to generate a rash? ? No evidence that development of rash is predictive of erlotinib efficacy. Retrospectively prognostic, not predictive! AViTA Trial: Rash is a Marker of Good Prognosis!

  26. In Conclusion The brain trust in cancer research is getting larger and more sophisticated. Our researchers are doing A LOT of smart things! Not everything we do is smart and this impedes our progress. We owe it to our patients to do better!

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