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What’s New in Gastrointestinal Cancers? Pancreatic cancer: The past, present and future

What’s New in Gastrointestinal Cancers? Pancreatic cancer: The past, present and future. Andrew H. Ko, MD Division of Hematology/ Oncology GI Malignancies Program, UCSF. Estimated new cancer cases and deaths, United States, 2014 (Siegel, CA Cancer J Clin 2014;64:9-29).

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What’s New in Gastrointestinal Cancers? Pancreatic cancer: The past, present and future

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  1. What’s New in Gastrointestinal Cancers?Pancreatic cancer: The past, present and future Andrew H. Ko, MD Division of Hematology/ Oncology GI Malignancies Program,UCSF

  2. Estimated new cancer cases and deaths, United States, 2014 (Siegel, CA Cancer J Clin2014;64:9-29)

  3. Point #1: Current therapies for pancreatic cancer produce survival times of often greater than one year, even for patients with metastatic disease.

  4. Treatment of Metastatic Disease:Moving Beyond GemcitabineMonotherapy • Gemcitabine originally approved in 1997 for first-line therapy of advanced PDAC • Median survival (vs. bolus 5-FU): 5.65 vs. 4.41 months (p=0.0025) • 1-year survival: 18% vs. 2% • Clinical benefit response: 23.8% vs. 4.8% ** • RR 5.4% vs. 0% Survival with treatment with gemcitabine and 5-FU gemcitabine 5-FU ** Composite of performance status, weight change, and analgesic requirement. Burris et al, J ClinOncol 1997.

  5. Previous phase III trials in advanced pancreatic cancer

  6. FOLFIRINOX emerges as a new gold standard:Results of the PRODIGE 4/ACCORD 11 Trial Stratified by ECOG PS (0 vs. 1),center, tumor location (head vs. other) 6 months of chemo planned for each arm Conroy et al, NEJM 2011.

  7. Demographics: Representative of Real-World Population? Conroy et al, NEJM 2011.

  8. Efficacy Results Conroy et al, NEJM 2011.

  9. Survival Curves Showing Benefit of FOLFIRINOX vs. Gemcitabine Conroy et al, NEJM 2011.

  10. Safety and Toxicity Results *No 1o prophylaxis with G-CSF, but 42.5% on FOLFIRINOX used at some point. Conroy et al, NEJM 2011.

  11. Prolongation of QoL in patients treated with FOLFIRINOX compared to gemcitabine, despite greater toxicity – longer time to deterioration in: Global health score Physical, cognitive, and social functioning Symptoms such as fatigue, N/V, pain, and anorexia QoL Assessment on FOLFIRINOX Study • Time until definitive deterioration >20 points, EORTC-C30 global health STATUS/QoL questionnaire Gourgou-Bourgadeet al, J ClinOncol 2013.

  12. A second new first-line option for metastatic pancreatic cancer: Gemcitabine/nab-Paclitaxel ALBUMIN-BOUND PACLITAXEL www.drugdiscovery.com

  13. Phase III trial (MPACT) in Advanced Pancreatic Cancer Stratification by KPS, region, liver metastases Von Hoff et al, NEJM 2013.

  14. Study Results: Efficacy Von Hoff et al, NEJM 2013.

  15. Gemcitabine/nab-Paclitaxel Confers Improvement in Overall Survival Von Hoff et al, NEJM 2013.

  16. Study Results: Safety Von Hoff et al, NEJM 2013.

  17. Comparison: FOLFIRINOX vs. Gemcitabine/nab-Paclitaxel phase III trials Will (or should) a head-to-head comparison between these two regimens ever be performed? 2. Can we now start thinking about sequencing regimens in pancreatic cancer? 3. Are these regimens appropriate to use in earlier-stage (e.g. adjuvant) settings?

  18. Point #2: Although we have an expanding array of therapeutic options for advanced pancreatic cancer, currently there is NO established standard of care for patients who have progressed on first-line treatment – but some intriguing possibilities are coming down the pike.

  19. Current approach in treatment sequencing for advanced pancreatic cancer 3rd line 2nd line 1st line

  20. 1. Pelzer, J ClinOncol 2008 (abstract); 2. Berk, Hepatogastroent 2012; 3. Xiong, Cancer 2008; 4. Neuzillet, World J Gastroent 2012; 5.Takahara, Cancer ChemotherPharmacol 2013; 6. Boeck, Oncology 2007; 7. Ko, Br J Cancer 2013; 8. Tang, J ClinOncol 2009 (abstract); 9. Kulke, J ClinOncol 2007; 10. O’Reilly, Oncologist 2010; 11. Ko, J ClinOncol 2013 (abstract).

  21. Novel Drugs in Development for Advanced/Metastatic Pancreatic Cancer • Next-generation cytotoxic agents • Example: MM-398 (nanoliposomalirinotecan) • Novel signaling pathway inhibitors • Example: Ruxolitinib(JAK-STAT inhibitor) • Immunotherapeutic approaches • Example: CRS-207 (attenuated Listeria vaccine)

  22. Novel Cytotoxic Agents: MM-398Taking the old, and making it better • Novel nanoliposomal encapsulation of irinotecanwith improved pharmacokinetics and tumour bio-distribution A Drummond et al, Cancer Res 2006

  23. Phase III NAPOLI-1 Trial (NCT01494506) • Stratified by: • Baseline albumin • KPS • Ethnicity Primary endpoint: overall survival

  24. Phase III NAPOLI-1 trial results Von Hoff, ESMO World Congress on GI Cancer, 2014 (abstract)

  25. Where will MM-398 fit into the treatment paradigm for advanced PDAC? • Currently under review for FDA approval – would be the first agent indicated for use in the salvage setting for metastatic pancreatic cancer • Is newer really better? • How much better is MM-398/5-FU/LV compared to, say, FOLFIRI? • How will a drug in this setting be priced? What is the cost value relative to clinical benefit?

  26. Seeking novel targets in pancreatic cancer Figure adapted from Ryan DP, N Engl J Med 2010

  27. Enter ruxolitinib, an inhibitor of JAK-STAT signaling • Janus kinases (JAKs): mediate cytokine signaling by activating STAT transcription factors • Persistent activation of Stat3 is oncogenic and prevalent in many solid tumors1 • In mouse models of pancreatic cancer, JAK-STAT signaling is required for cancer progression2 and contributes to cancer-related cachexia3 • Pancreatic cancer: clinical hallmarks of weight loss, cachexia, anorexia all reflect systemic inflammation • Ruxolitinib reduced levels of inflammatory cytokines and improved symptoms and overall survival in myelofibrosis4-5 Inflammatory Cytokines JAK1 JAK2, JAK3,TYK2 P P STAT 1) Hedvat, Cancer Cell 2009. 2) LesinaCancer Cell. 2011; 3)Gilabert, J Cell Physiol2014; 4) Verstovsek S, N Engl J Med 2012; 5) Harrison C, et al. N Engl J Med 2012.

  28. RECAP study design Ruxolitinib (15 mg BID, days 1–21) Capecitabine (1000 mg/m2 BID, days 1–14) RANDOMIZED n=64 • Patient Eligibility • Histologically confirmed metastatic PDAC • Karnofsky PS ≥60 • Failed gemcitabine 1:1 Placebo(BID, days 1–21) Capecitabine(1000 mg/m2 BID, days 1–14) n=63 • Endpoints • Primary: OVERALL SURVIVAL • Secondary: Clinical benefit response, ORR (RECIST), PFS, QoL, safety • Prospectively defined subgroup analyses, including C-reactive protein, albumin, and performance status, were conducted to explore an inflammation hypothesis

  29. Entire study population (n=127) • Med OS 136.5 v 129.5 days • 6-mo surv 42% v 35% • HR 0.79 (p=0.25) CRP > 13 mg/L (n=60) • Med OS 83 v 55 days • 6-mo surv42% vs 11% • HR 0.47(p=0.01)

  30. Is C-reactive protein a reasonable predictive biomarker? • C-reactive protein Well-characterized and sensitive marker of systemic inflammation and tissue damage • First acute-phase protein to be described (originally identified in serum of patients with Strep pneumoniae – precipitates the somatic C-polysaccharide of bacteria) • Classic examples in predictive biomarkers in cancer therapy: HER2 trastuzumab; KRAS cetuximab; BRAF  vemurafenib • Advantage sof CRP: • Blood-based rather than tissue-based • Separate companion diagnostic test would not need to be developed! Dancey, Clin Cancer Res 2010.

  31. Objective response rate (ORR) and clinical benefit response (CBR) * Composite of pain, weight, and performance status

  32. Grade 3 or 4 Adverse Events 33

  33. Recapping RECAP • Smart trial design and drug development strategy! • Start with enrollment of broader, unselected patient population, but with pre-planned analysis of subgroup(s) of interest (those with higher levels of systemic inflammation as reflected by elevated CRP levels) • Phase III registrational trials (JANUS-1 and -2) now ongoing, limited to this select subgroup of patients • Survival benefit of ruxolitinib may relate to alleviating cachexia and inanition, as much as reducing tumor burden

  34. Immunotherapy Platforms in Pancreatic Cancer GVAX Pancreas Irradiated, whole-cell tumor vaccine CRS-207 (Aduro Biosciences) Live-attenuated Listeria monocytogenes • Potent activation of innate and antigen-specific immune response GVAX Dendritic Cell GM-CSF ΔinlB ΔactA Tumor antigens Antigen uptake & Activation Tumor Cell Destruction • Deletion of virulence genes (actA,inlB) • Insertion of mesothelin expression • cassette – validated immune target T Cell Leet al, Gastrointestinal Cancers Sympsosium 2014.

  35. Phase 2 Study of GVAX/CRS-207 vs. GVAX Alone in Metastatic Pancreatic Cancer CY/GVAX Primary objective: overall survival CRS-207 Arm A, n=60 24 months follow-up Subjects with metastatic pancreatic cancer; failed or refused chemotherapy R R * Additional courses if clinically stable 20-wk treatment Course*: 6 doses, q3w 2:1randomization Arm B, n=30 24 months follow-up Le et al, Gastrointestinal Cancers Sympsosium 2014.

  36. Overall Survival – Full Analysis Set Median OS, Full analysis set: Arm A: 6.0 months Arm B: 3.4 months p=0.0057, HR 0.4477 Median OS, Per-protocol set (subjects receiving at least one dose of CRS-207): Arm A: 9.7 months Arm B: 4.6 months p=0.0167, HR 0.5290 Toxicities related to CRS-207: transient fevers, rigors, lymphopenia

  37. Phase II ECLIPSE Trial (NCT02004262)(Recruiting) Primary endpoint = overall survival

  38. Point #3: As is frequently the case in oncology, more does not always mean better in pancreatic cancer (case in point: radiation).

  39. Locally advanced pancreatic cancer: unresolved questions 1. Moertel, Cancer 1981; 2. Philip, J ClinOncol 2009; 3. J Natl Cancer Instit 1988; 4. Klaassen, J ClinOncol 1985; 3:373. 5. Chauffert, Ann Oncol 2008; 6. Loehrer, J ClinOncol 2011; 7. Huguet, J ClinOncol 2007; 8. Ko, Int J RadiatOncolBiol Phys 2007; 9. Crane, J ClinOncol 2011; 10. Mukherjee, Lancet Oncol 2013.

  40. LAP-07 was the largest trial conducted for patients with locally advanced pancreatic cancer MEDIAN OS 16.4 mos MEDIAN PFS 8.4 mos After 4 months: MEDIAN OS 15.2 mos MEDIAN PFS 9.9 mos Hammel, J ClinOncol 2013, 31 (suppl):LBA 4003.

  41. Updated LAP-07 data reveal other differences in patient outcomes when radiation is given Implications here that better local control, as well as more time off therapy, may translate into better QoL-- but this assumption not confirmed by patient-reported outcomes (PRO)

  42. Implications/unresolved issues of LAP-07 • Do we conclude from this study that radiation should or should not be routinely given to patients with locally advanced pancreatic cancer? • Do more effective systemic therapies (FOLFIRINOX, gemcitabine/nab-paclitaxel) attenuate, or accentuate, any survival benefit that radiation might offer?

  43. As chemotherapy improves to better sterilize distant disease, locoregional control with RT may become more important… but only up to a point Beyond this point, chemorx can control both distant and locoregional disease  therefore, importance of RT would decline Marks and Prosnitz, Int J Rad Onc Bio Phys, 2000; 48:625-27.

  44. Finding the ‘sweet spot’ where both chemotherapy and radiation impact overall survival Locally advanced pancreatic cancer Could FOLFIRINOX, or gemcitabine/nab- paclitaxel, be here on the curve? Or here? Gemcitabine/erlotinib Punglia et al, N Engl J Med 2007;356:2399-405.

  45. Other recent examples in GI oncology demonstrating this principle that more does not always equal better • Use of EGFR inhibitors (cetuximab, panitumumab) in metastatic colorectal cancer • Expanded KRAS testing shows that we may still be overtreating some patients with this class of agents who are unlikely to benefit! • Adjuvant sorafenib in hepatocellular carcinoma • No benefit yet identified in patients following resection, ablation, or embolization • Ciardello, J ClinOncol 2014 (suppl); 32:5s, abstr 3506;. • Bokemeyer, J ClinOncol 2014 (suppl); 32:5s, abstr 3505. • Bruix, J ClinOncol2014 (suppl) 32:5s, abstr4006. • Lencioni, J Clin Oncol 2012 (suppl); 30:4, abstr LBA154).

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