New Perspectives in GI Malignancies
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Axel Grothey, M.D., Professor of Oncology; Consultant, Medical Oncology, Mayo Clinic ...

Axel Grothey, M.D., Professor of Oncology; Consultant, Medical Oncology, Mayo Clinic
New Perspectives in GI Malignancies

Presented at New Frontiers in the Management of Solid and Liquid Tumors hosted by the John Theurer Cancer Center at Hackensack University Medical Center. jtcancercenter.org/CME

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New Perspectives in GI Malignancies New Perspectives in GI Malignancies Presentation Transcript

  • New Perspectives in GI Malignancies Axel Grothey Professor of Oncology Mayo Clinic Rochester
  • Disclosures• Consulting activities (honoraria went to the Mayo Foundation) • Amgen • Bayer • Pfizer • Roche/Genentech • Sanofi-Aventis • BMSI WILL include discussion of investigational or off-label use of a product in my presentation.
  • New Perspectives• CRC • Duration of anti-VEGF therapy • Biomarker-driven treatment decisions • Novel agents• Gastric/GEJ cancer • Anti-HER2 therapy• Pancreas cancer • FOLFIRINOX
  • Treatment paradigms for mCRC• Some patients with stage IV disease can be cured by an interdisciplinary approach• In the palliative setting: FOLFOX = XELOX = FOLFIRI (XELIRI has problems with toxicity)• Most patients tolerate a chemotherapy doublet, but not all need it• The addition of biologics to chemotherapy has improved outcomes, but not as much as we hoped• We are on the verge of individualized therapy based on molecular predictive factors
  • Concept of “All-3-Drugs” - Update 2005 11 Phase III Trials, 5768 Patients 22 First-Line Therapy 21 Median OS (mo) 20 Infusional 5-FU/LV 19 + irinotecan 18 Infusional 5-FU/LV + oxaliplatin 17 Bolus 5-FU/LV 16 + irinotecan 15 Irinotecan + oxaliplatin 14 Bolus 5-FU/LV 13 P =.0001 12 LV5FU2 0 10 20 30 40 50 60 70 80 FOLFOXIRI Patients with 3 drugs (%) CAIRO 2007OS (mos) = 13.2 + (%3drugs x 0.1), R^2 = 0.85 Grothey & Sargent, JCO 2005
  • Biologic Agents in Colorectal Cancer = Monoclonal AntibodiesFabFc Murine Ab Chimeric Humanized Ab Human Ab “momab” Mouse-Human Ab “zumab” “mumab” “ximab” EGFR (17-1A) Cetuximab Panitumumab Bevacizumab VEGF
  • Nomenclature of Monoclonal Antibodies -mab monoclonal antibody -mo-mab mouse mab -xi-mab chimeric mab -zu-mab humanized mab -mu-mab human mab -tu-xx-mab tumor-directed xx mab -li-xx-mab immune-directed xx mab -ci-xx-mab cardiovascular-directed xx mab -vi-xx-mab virus-directed xx mabInf-li-xi-mab Beva-ci-zu-mab Ri-tu-xi-mab Pani-tu-mu-mab
  • Phase III Trial IFL +/- Bevacizumab in MCRC: Efficacy IFL+ Placebo IFL+ Bevacizumab (n=411) (n=402) P Value Median survival (mo) 15.6 20.3 0.00004 PFS (mo) 6.2 10.6 <0.00001 ORR (%) 35 45 0.0036 CR 2.2 3.7 PR 32.5 41.2 Duration of resp. (mo) 7.1 10.4 0.0014Hurwitz et al. N Engl J Med 2004
  • Phase III Trial of IFL +/- Bevacizumab in MCRC: PFS 1.0 Proportion progression-free HR=0.54, P<0.00001 Median PFS: 6.2 vs 10.6 mo 0.8 0.6 0.4 Treatment Group 0.2 IFL + placebo IFL + bevacizumab 0 0 10 20 30 Progression-free survival (mo)Hurwitz et al. N Engl J Med 2004
  • XELOX vs FOLFOX +/- Bevacizumab Roche NO16966 study design Recruitment Recruitment June 2003 – May 2004 Feb 2004 – Feb 2005 XELOX + XELOX XELOX + placebo bevacizumab N=317 N=350 N=350 FOLFOX4 + FOLFOX4 FOLFOX4 + placebo bevacizumab N=317 N=351 N=350 Initial 2-arm Protocol amended to 2x2 placebo- controled design after bevacizumab open-label study phase III data1 became available (N=634) (N=1401)1Hurwitz H, et al. Proc ASCO 2003;22 (Abstract 3646) Cassidy & Saltz, JCO 2008
  • PFS chemotherapy + bevacizumab superiority: primary endpoint 1.0 HR = 0.83 [97.5% CI 0.72–0.95] (ITT) 0.8 p = 0.0023PFS estimate 0.6 0.4 0.2 8.0 9.4 0 0 5 10 15 20 25 Months FOLFOX+placebo/XELOX+placebo N=701; 547 events FOLFOX+bevacizumab/XELOX+bevacizumab N=699; 513 events Saltz et al., JCO 2008
  • PFS chemotherapy + bevacizumabsuperiority: XELOX and FOLFOX subgroups 1.0 1.0 0.8 0.8PFS estimate 0.6 0.6 0.4 0.4 0.2 0.2 7.4 9.3 8.6 9.4 0 0 0 5 10 15 20 25 0 5 10 15 20 25 Months Months XELOX+placebo N=350; 270 events FOLFOX+placebo N=351; 277 events XELOX+bevacizumab N=350; 258 events FOLFOX+bevacizumab N=349; 255 events XELOX subgroup FOLFOX subgroup HR = 0.77 [97.5% CI 0.63–0.94] (ITT) HR = 0.89 [97.5% CI 0.73–1.08] (ITT) p = 0.0026 p = 0.1871 Saltz et al., JCO 2008
  • NO16966 PFS Subgroup Analyses: On-Treatment Population 1.0 XELOX Group FOLFOX Group 1.0 0.8 0.8Survival Survival 0.6 0.6 0.4 0.4 0.2 0.2 7.0 m 9.5 m 8.4 m 10.6 m 0 0 0 100 200 300 400 500 0 100 200 300 400 500 Study day Study day HR = 0.61 [97.5% CI 0.48–0.78] HR = 0.65 [97.5% CI 0.50–0.84] P ≤ .0001 P = .0002 FOLFOX4 + FOLFOX-4 + XELOX + placebo XELOX + Bev VS placebo VS Bev Saltz et al., ASCO GI 2007
  • CAIRO2: Study design CapOx + BEV (COB, n=368)EGFR-detectable mCRC RPrimary endpoint CapOx + BEV +• Progression-free survival Cetuximab (COB-C, n=368)Secondary endpoints• RR• OS time Oxaliplatin d/c’d after 6 cycles• Toxicity i.e. after 18 weeks = 4.5 mos• Translational research Tol et al. NEJM 2009
  • CAIRO2 - KRAS genotyping (n=501) KRAS wild-type KRAS mutated p value n = 314 (61%) n = 196 (39%)Median PFS (months)COB 10.6 12.5 0.80COB-C 10.5 8.1 0.04p value 0.30 0.003Median OS (months)COB 22.4 24.9 0.82COB-C 21.8 17.2 0.06p value 0.64 0.03 Tol et al. NEJM 2009
  • BRiTE Registry - Patients with Bevacizumab Beyond Progression (BBP) Evaluable patientsBRiTE: (n=1953)Total N=19531445 pts with 1st PD932 deaths (1/21/07 cut-off) 1st ProgressionMedian follow-up 19.6 mo (n=1445) Physician decision - no randomization No Post-PD No BBP BBP Treatment (n=253) (n=531) (n=642) Grothey et al. JCO 2008
  • BRiTE: Patient Outcome Based on Treatment Post 1st PD No Post-PD No BBP BBP Treatment (n=253) (n=531) (n=642)# of deaths 168 306 260(%) (66%) (58%) (41%)Median OS 12.6 19.9 31.8(mo)1yr OS rate 52.5 77.3 87.7(%)OS after 1st 3.6 9.5 19.2PD (mo) Grothey et al. JCO 2008
  • AIO 0504 / Roche ML18147 Multinational European Trial Any-OX Any-IRI + BEV + BEV R R Any-IRI Any-OX Any-IRI Any-OX + BEV + BEVN = 820 Accrual completed May 31, 2010Primary EP: OS
  • mAbs Target Tumor Cell-Bound EGFR Ligand Extracellular EGF-R Ras PI3K PTEN Raf Intracellular Akt MEK MAPKCell survival DNA Cell Motility Proliferation Angiogenesis Metastasis
  • mAbs Target Tumor Cell-Bound EGFR Ligand Extracellular EGF-R Ras PI3K PTEN Raf Intracellular Akt MEK MAPKCell survival DNA Cell Motility Proliferation Angiogenesis Metastasis
  • RAS (RAt Sarcoma virus)• Three genes encode highly homologous proteins: H-RAS, N-RAS, and K-RAS• Point mutations in RAS genes occur in 30% of all cancers• K-RAS mutations present in 40% of CRC• Codons 12, 13, and 61 are most commonly involved• Mutations result in constitutive activation of RAS-RAF-MAPK signaling pathway leading to cell proliferation and enhanced cell survival
  • KRAS Status and Response to Cetuximab in Refractory mCRC Response confined to KRAS wt ORR, % Study Treatment N (% wt) mt wt Liévre et al, 2006 C-mab + CT 30 (57) 0 65 P-mab or Benvenuti et al, 2007 C-mab ± CT 48 (67) 6 31 De Roock et al, 2007 C-mab ± CT 113 (59) 0 40 Capuzzo et al, 2007 C-mab ± CT 81 (60) 6 26 Di Fiore et al, 2007 C-mab + CT 59 (73) 0 28 Khambata-Ford et al, 2007 C-mab 80 (62) 0 10 Liévre et al, 2008 C-mab ± CT 76 (64) 0 49ORR, overall response rate; p-mab, Panitumumab; c-mab, Cetuximab; CT, chemotherapy; mt, KRAS mt; wt, KRAS wt
  • KRAS as Biomarker for Panitumumab Response in Metastatic CRC • PFS log HR significantly different depending on K-ras status (P < .0001) • Percentage decrease in target lesion greater in patients with wild-type KRAS receiving panitumumab Patients With Wild-Type KRAS Patients With Mutant KRAS 1.0 Pmab + BSC Median Mean 1.0 BSC alone Events/N (%) Pmab + BSC 0.9 in Wks in Wks MeanProportion With PFS 0.9 BSC alone Median Proportion With PFS 0.8 12.3 19.0 Events/N (%) in Wks in Wks 115/124 (93) 0.8 0.7 114/119 (96) 7.3 9.3 9.9 0.7 76/84 (90) 7.4 0.6 95/100 (95) 7.3 10.2 HR: 0.45 (95% CI: 0.34-0.59) 0.6 0.5 Stratified log rank test: P < .0001 0.5 HR: 0.99 (95% CI: 0.73-1.36) 0.4 0.4 0.3 0.3 0.2 0.2 0.1 0.1 0 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 3436 38 4042 44 46 48 50 52 Weeks Weeks Amado et al. JCO 2008
  • NCIC CTG CO.17: Randomized Phase III Trial in mCRC Cetuximab vs BSC (no cross-over) KRAS mut KRAS wild-type All patients BSC Cetux BSC Cetux BSC Cetux n=83 n=81 n=113 n=117 n=285 n=287RR 0% 1.2% 0% 12.8% 0% 6.6%PFS 1.8 1.8 1.9 3.8 1.8 1.9(mos) <0.0001 <0.0001OS 4.6 4.5 4.8 9.5 4.6 6.1(mos) <0.0001 0.0046 Karapetis et al. NEJM 2008
  • CRYSTAL Study (1st Line) FOLFIRI + Cetuximab N = 599EGFR-expressing metastatic CRC R PFSStratified by: FOLFIRI N = 599• Regions• ECOG PS • Primary Endpoint: PFS (independent review) • Secondary Endpoints: RR, DCR, OS, Safety, QoL • Sample Size: 1217 patients randomized, ITT: 1198 pts Van Cutsem et al. NEJM 2009
  • 5-FU/LV/IRI (FOLFIRI) +/- Cetuximab: PFS Non-KRAS adjusted 1.0 0.9 0.8 Subgroup 0.7 effect HR = 0.851 P = 0.0479PFS estimate No benefit 0.6 8.0 vs 8.9 mos 0.5 0.4 0.3 0.2 FOLFIRI + Cetuximab 0.1 FOLFIRI 0.0 0 2 4 6 8 10 12 14 16 18 20 Months Van Cutsem et al. NEJM 2009
  • CRYSTAL - KRAS wild-type mCRC (N=348): PFS 1.0 FOLFIRI + Cetuximab: 9.9 mosProgression-free survival estimate 0.9 FOLFIRI: 8.7 mos 0.8 HR=0.68, p=0.017 0.7 0.6 1-yr PFS rate 0.5 25% vs 43% 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 Months Cetuximab + FOLFIRI FOLFIRI Van Cutsem et al. NEJM 2009
  • CRYSTAL: Efficacy Update After Additional KRAS TestingKRAS wild-type FOLFIRI FOLFIRI + P value cetuximabn 350 316RR (%) 39.7 57.3 < 0.0001mPFS (mos) 8.4 HR 0.7 9.9 0.0012mOS (mos) 20 HR 0.8 23.5 0.0093KRAS mutated FOLFIRI FOLFIRI + P value cetuximabn 183 214RR (%) 36.1 31.3 0.34mPFS (mos) 7.7 7.4 0.26mOS (mos) 16.7 16.2 0.75 Van Cutsem et al. JCO 2011
  • COIN (cetuximab): First-line Study MRC-sponsored study supported Continuous* XELOX by Merck (109 UK/Irish Hospitals) Arm A or FOLFOX First-line mCRC Continuous XELOX (n= 2445) R or FOLFOX + Arm B cetuximab Intermittent** Arm C • Primary endpoints: XELOX or FOLFOX • OS in patients with K-ras wild-type tumours • Secondary endpoints include: 65% XELOX; 35% FOLFOX • OS in K-ras mutant; “all” wild-type (patient/physician choice) (K-ras, N-ras, B-raf); “any” mutant, ITT • PFS • Response rate • Quality of life • Health economic evaluation*Treatment until disease progression or unacceptable toxicity **Stop and Go treatment (12 wks then restart at progression) Maughan, et al. ECCO-ESMO 2009
  • COIN study: KRAS WT PFS Survival probability Arm A (XELOX/FOLFOX) 1.00 Arm B (XELOX/FOLFOX + cetuximab) Arm A Arm B Diff. 0.75 Median PFS, 8.6 8.6 +0.07 months 0.50 HR point estimate = 0.959 95% CI 0.84–1.09 p=0.60 0.25 0 0 6 12 18 24 30 36 42 Time (months)No. at riskArm A 367 245 92 41 18 11 6 1Arm B 361 249 103 42 22 9 6 0 Maughan, et al. ECCO-ESMO 2009
  • PFS by KRAS Mutation Status Final Analysis WT KRAS MT KRAS 100% 100%Proportion Event-Free Proportion Event-Free 90% 90% 80% 80% 70% 70% 60% 60% 50% 50% 40% 40% 30% 30% 20% 20% 10% 10% 0% 0% 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 Months Months Median Median Events (95% CI) Events (95% CI) n (%) months n (%) months Panitumumab + 270 / 325 10.0 (9.3 – 11.4) Panitumumab 204 / 221 7.4 (6.9 – 8.1) FOLFOX4 (83) + FOLFOX4 (92) FOLFOX4 280 / 331 8.6 (7.5 – 9.5) FOLFOX4 196 / 219 9.2 (8.1 – 9.9) (85) (89) HR = 0.80 (95% CI: 0.67 – 0.95) HR = 1.27 (95% CI: 1.04 – 1.55) Log-rank p-value = 0.01 Log-rank p-value = 0.02 Douillard et al., ASCO 2011
  • Response Rates Differences Chemo +/- EGFR mAbs Based on KRAS Status 25% Response Rate Difference KRAS wt 20 KRAS mut 15 10 5 0 -5 -10 CRYSTAL PRIME OPUS CAIRO2 COIN NORDIC 181 2nd line -15 -20 Clinical Trials
  • HR of PFS/DFS for EGFR mAbs Phase III trials in KRAS wt CRC Salvage Cetuximab (single agent) Panitumumab Second Line 181 CRYSTAL PRIME First-Line COIN Nordic Adjuvant N01471.2 1 0.8 0.6 0.4 0.2 0 Hazard ratio
  • mAbs Target Tumor Cell-Bound EGFR Ligand Extracellular EGF-R Ras PI3K PTEN Raf Intracellular Akt MEK MAPKCell survival DNA Cell Motility Proliferation Angiogenesis Metastasis
  • Role of PI3K Pathway • 40% of CRC tumors have RTKs mutations in PI3K pathway1 PIK3CA PIP2 P P P PIP3 P P P P PIP3 P • PI3K pathway dysregulation P P IRS2 P p85 PTEN PDK1 AKT2 P predicts Cetuximab resistance in PAK4 ? CRC cell lines2Mutations of PI3K pathway genes in CRC P AKT2/ PAK4Tumours PKK1 AKT2 PAK4 amp IRS2 amp INSRR ERBB4 PTEN PIK3CACSX3 T354M wt wt wt wt wt wt wt wt • Of 36 tumors with PI3KCACX10 T354M wt wt wt wt wt wt wt wt mutations, 27 also had alterationMX20CX7 D527E wt wt S302G wt wt wt wt wt wt wt wt wt wt wt wt wt wt in KRAS1HX66 wt R371H wt wt wt wt wt wt wtCO86 wt wt A279T wt wt wt wt 800del/ 968del wt • Patients treated with Cetuximab3HX63 wt wt E329K wt wt wt wt wt wtCO78 wt wt wt 15 fold wt wt wt wt wt • 4/31 PI3KCA mutationsCO82CO84 wt wt wt wt wt wt 8 fold wt wt 12 fold wt wt wt wt wt wt wt wt (4/16 non-responders)CO69HX160 wt wt wt wt wt wt wt wt 7 fold 6 fold wt wt wt wt wt wt wt wt • 4/31 ↓ PTEN gene copy numberMX5 wt wt wt wt wt T1014M wt wt wtCO87 wt wt wt wt wt wt I1030M wt wt • 3/30 PTEN mutationsMX9 wt wt wt wt wt wt wt 904-919del wt (3/15 non-responders)CX28 wt wt wt wt wt wt wt Y88C wtHX170 wt wt wt wt wt wt wt L325H/LOH wtHX199 wt wt wt wt wt wt wt R741/F341V R88Q • PI3KCA mut: early or late event?HX219 wt wt wt wt wt wt wt A86P/LOH wtHX242 wt wt wt wt wt wt wt R47S wt36 cases wt wt wt wt wt wt wt wt MUT 1. Parsons, et al. Nature 2005. 2. Jhawer, et al.90 cases wt wt wt wt wt wt wt wt wt Cancer Res 2008; 3. Perrone, et al. Ann Oncol 2009
  • PIK3CA Point Mutations CRC Exon 9 Hotspots Exon 20 Bader et al., Nat Rev Cancer 2005
  • PFS and PIK3CA Mutational Status in mCRCPatients Treated With Panitumumab/Cetuximab PIK3CA mut Exon 9: 4 pts Exon 20: 11 pts 110 pts Cetuximab 13% > 85% received at least 1 prior Panitumumab 20% Rx Cetuximab/Irinotecan 67% Sartore-Bianchi A et al, Cancer Res 2009
  • Fig. 1 PIK3CA mut Exon 9: 17 pts Exon 20: 4 pts Cetuximab 16 Cetuximab/Irinotecan 184 Total Patients 200 Prenen H et al, Clin Cancer Res 2009
  • PTEN Expression and Cetuximab Efficacy PTEN + median PFS = 4.7 months PTEN – median PFS = 3.3 months 1.0 PTEN + PTEN – (n=33) (n=22) Log-rank test: p=0.005 0.8 HR=0.49; 95% CI: 0.20–0.75 PFS estimateResponders(CR+PR+SD) 12 (36%) 1 (5%) 0.6Non-responders 21 (64%) 21 (95%) 0.4 PTEN+ n=55 0.2 PTEN- 0.0 0 2.5 5.0 7.5 10.0 12.5 15.0 Months • Fisher’s Exact Test p=0.008 • Concordance primary tumor sample/metastasis: 27/45 (60%)CR = complete response; PR= partial response Loupakis et al, ASCO 2008SD = stable disease Loupakis et al, J Clin Oncol 2009
  • PTEN and KRAS Status: Effect on Efficacy PTEN + KRAS wild-type median = 5.5 months All other median PFS PTEN + KRAS = 3.8 months wild-type All other 1.0 (n=17) (n=28) Log-rank test: p=0.001 0.8 HR=0.42; 95% CI: 0.17–0.65 PFS estimateResponders(CR+PR+SD) 8 (47%) 1 (4%) 0.6Non responders 9 (53%) 27 (96%) PTEN+ 0.4n=45 PTEN- 0.2 0.0 0 2.5 5.0 7.5 10.0 12.5 15.0• Fisher’s Exact Test p=0.008 Months Loupakis et al, ASCO 2008
  • Challenges with PTEN• Expression in primary tumors does not reflect expression in metastases • PTEN is not mutated in mCRC, its expression can be regulated by methylation, miRNAs, and/or other regulatory mechanisms• Difficulty in standardizing IHC in different labs Supplemental Figure 1: Representative examples of PTEN positive (A, B) and negative (C, D) cases. The cases reported in A and C panels were evaluated at Ospedale Niguarda Ca’ Granda (Milan, Italy) whereas those in B and D at the Institute of Pathology in Locarno (Switzerland). Sartore-Bianchi et al, Cancer Res 2009
  • BRAF Mutations in CRC • BRAF is primary effector EGF of KRAS signaling Tumor Cell • BRAF mutations: • Occur most frequently in exon 15 (V600E) Ras • Found in 4%-14% of P P patients with CRC Raf • Mutually exclusive P P with KRAS mutations MEK Tumor cell proliferation Erk and survivalYarden. Nat Rev Mol Cell Biol. 2001;2:127; Di Nicolantonio. J Clin Oncol.2008;26:5705; Artale. J Clin Oncol. 2008;26:4217.
  • Wild-type BRAF is required for response to EGFR inhibitors in mCRC Patients with KRAS wild-type status 100 BRAF wild-type 100 BRAF wild-type BRAF mutant BRAF mutant 80 p=0.0010 80 p<0.0001PFS (%) OS (%) 60 60 40 40 20 20 0 0 0 100 200 300 400 500 600 700 800 900 0 200 400 600 800 1,000 1,200 1,400 Time since start Time since start of treatment (days) of treatment (days) Di Nicolantonio et al., J Clin Oncol 2008
  • CRYSTAL trial update: outcome inKRAS wild-type/ BRAF mutated mCRC KRAS wt/BRAF wt KRAS wt/BRAF mt (n=566) (n=59) FOLFIRI FOLFIRI + FOLFIRI FOLFIRI + Cetuximab Cetuximab (n= 289) (n= 277) (n=33) (n=26)mOS (mo) 21.6 25.1 10.3 14.1HR [95% CI] 0.83 [0.687–1.004] 0.91 [0.507–1.624]p-valuea 0.0549 0.7440mPFS (mo) 8.8 10.9 5.6 8.0HR [95% CI] 0.68 [0.533–0.864] 0.93 [0.425–2.056]p-valuea 0.0016 0.8656RR (%) 42.6 61.0 15.2 19.2[95% CI] [36.8–48.5] [55.0–66.8] [5.1–31.9] [6.6–39.4]p-valueb <0.0001 0.9136aStratified log-rank test; bCochran-Mantel-Haenszel test Van Cutsem et al, JCO 2011
  • CRYSTAL trial update: outcome inKRAS wild-type/ BRAF mutated mCRC Van Cutsem et al, JCO 2011
  • Response to EGFR mAb-based Therapy in KRAS wt CRC Satore-Bianchi et al., PLoS 2009
  • Bevacizumab vs EGFR Antibodies in Advanced CRC - SimplifiedAgent Strength WeaknessBevacizumab • Delay in tumor • Limited single progression agent activity • Gain in time • Weak effect on RR • Toxicity profile (per RECIST)EGFR • Single agent activity • Gain in time toantibodies • Consistent increase progression in RR moderate • Activity independent • Toxicity profile of line of therapy • Predictive marker
  • Take-Home Messages: OptimizedMedical Therapy of Advanced CRC1. Identify the goal of therapy • RR only matters for • conversion therapy of liver metastases or • if patient is symptomatic from his tumor burden • For most patients gain of time and maintaining QOL is more important • Strength of BEV2. Treat to progression – and perhaps beyond? • Be mindful about toxicities, stop oxaliplatin before neurotoxicity develops • Some select patients can have CFI
  • Take-Home Messages: OptimizedMedical Therapy of Advanced CRC3. Expose patients to all potentially active agents • These agents are the oncologist’s tools to keep patients alive • Use fluoropyrimidine-based combinations as default backbone, reserve sequential single agent therapy for select patients4. Reutilize chemotherapeutic agents (in different combinations?) in the course of the therapy • Continuum of care vs distinct lines of therapy5. We need new drugs!
  • VEGF Biology PlGF VEGF-C, VEGF-B VEGF-A VEGF-DCell membrane Functions VEGF-R1 VEGF-R2 VEGF-R3 (Flt-1) (KDR/Flk-1) (Flt-4) Migration Proliferation Lymphangio- Invasion Survival genesis Survival Permeability
  • Large molecule VEGF inhibitors PlGF VEGF-A VEGF-C, VEGF-B Bevacizumab VEGF-D RamucirumabAflibercept(VEGF Trap) Functions VEGF-R1 VEGF-R2 VEGF-R3 (Flt-1) (KDR/Flk-1) (Flt-4) Migration Proliferation Lymphangio- Invasion Survival genesis Survival Permeability
  • 52 EFC10262: VELOUR Phase III Trial 2nd Line FOLFIRI +/- VEGF-TRAP (Aflibercept) Aflibercept 4 mg/kg 600 pts IV + FOLFIRI q 2 weeks mCRC after failure of an oxaliplatin R 1:1 based regimen Placebo + FOLFIRI Stratification factors: 600 pts q 2 weeks Prior bevacizumab (Y/N) ECOG PS (0 vs 1 vs 2)PIs: Allegra, Van Cutsem 30% of patients had prior BEV
  • Overall Survival - ITT Population Van Cutsem, et al. WCGC 2011Cut-off date = February 7, 2011; Median follow-up = 22.28 months
  • Comparison VELOUR vs E3200 VELOUR E3200Prior Tx Oxaliplatin-based Irinotecan-based (IFL)Prior 30% noneBEVArms FOLFIRI FOLFIRI HR FOLFOX FOLFOX HR + PL + AFL p-value + PL + BEV p-valuemOS 12.06 13.5 0.817 10.8 12.9 0.75(mos) 0.0032 0.0011mPFS 4.67 6.9 0.758 4.7 7.3 0.61(mos) 0.00007 <0.000 1RR (%) 11.1 19.8 0.0001 8.6 22.7 <0.000 1 Van Cutsem, et al. WCGC 2011; Giantonio, et al. JCO 2007
  • Progression Free Survival – Stratification Factors ITT Population ECOG PS: p=0.196 Prior BEV: p=0.695 Tabernero et al., ECCO/ESMO 2011
  • 56 I4T-MC-JVBBPhase III Trial 2nd Line FOLFIRI +/- Ramucirumab 525 pts Ramucirumab IV + FOLFIRI q 2 weeks mCRC after failure FP/oxaliplatin R 1:1 + BEV regimen 525 pts Placebo + FOLFIRIStratification factors: q 2 weeks• Region• KRAS status• First-line TTP (<>6 mos) PIs: Tabernero, Grothey Primary EP: OS
  • The Complex Process of Tumor Angiogenesis
  • Cytokine increase on BEV therapy Kopetz et al., JCO 2010
  • Regorafenib – A Multi-Kinase Inhibitor Cellular Phosphorylation Assays IC50 nM VEGFR-2 Phosphorylation, 293 Cells 8 TIE2-Receptor Phosphorylation, CHO Cells 31 PDGFR-β Phosphorylation, Aortic SM Cells 90 mVEGFR3 Phosphorylation, 293 Cells 150Mutant RET Phosphorylation, Thyroid TT Cells 10Mutant c-KIT Phosphorylation, GIST 882 Cells 20 FGF-10 FGFR MCF-7 Cells 150-300 MAPK ERK-P HCC, HepG2 Cells 500 Cell Proliferation Assays IC50 nM VEGF/HuVEC (2% FCS) BrdU 4 bFGF/ HuVEC (2% FCS) BrdU 120 PDGFBB/Aortic SM (0.1% BSA) BrdU 121 Thyroid TT RET C643W (10% FCS) 33 GIST 882 KIT K642E (10% FCS) 45 Breast, MDA MB 231 (10% FCS) 570 Melanoma, A375 (10% FCS) 900 HCC HepG2 (10% FCS) 560
  • Regorafenib Salvage Therapy Registration Trial Regorafenib 160 mg od 3wks on/1 wk off + BSC Primary CRC 2:1 randomization endpoint:3rd/4th line OS Placebo + BSC • Primary endpoint OS: increase OS from 4.5 to 6.0 months; HR = 0.75 • Significance level/power: 0.025 (one-sided)/90% • Accrual period (months): 26 ( accrual rate 30 pat./month) • Study duration (months): 31.5 • Total number of events: 582 Accrual completed • Total number of patients: 690 Feb 2011, within 10 mos
  • Cape +/- Perifosine Rand Phase II Perifosine 50 mg PO QD Patients with 2nd or3rd line mCRC Capecitabine 825 mg/m2 BID d 1 - 14 No prior Rx with CAP in metastatic setting R Cycle = 21 Days Prior Rx with 5-FU or Placebo PO QD 5-FU based regimen Capecitabine 825 mg/m2 BID d 1 - 14  Primary Objective: – To compare time to progression (TTP) of P-CAP vs. CAP as 2nd or 3rd line Rx  Secondary Objective: – To compare overall response rate (CR + PR) and overall survival – To evaluate the safety of P-CAP vs. CAP Richards et al., ASCO 2010
  • Median Overall Survival (OS) ALL EVALUABLE 5-FU REFRACTORY PATIENTS PATIENTS Median OS: P-CAP: Median OS: P-CAP: 17.7 mos [95% CI (8.5, 24.6)] 15.1 mos [95% CI (7.3, 22.3)] Median OS: CAP: Median OS: CAP: 10.9 mos [95% CI (5, 16.9)] 6.6 mos [95% CI (4.7, 11.7)] p-value = 0.0161 p-value = 0.0112Hazard ratio: 0.410 Hazard ratio: 0.313 (0.193, 0.868) (0.122, 0.802)Phase III trial (1:1 Cape/Peri vs Cape) started Richards et al., ASCO 2010
  • X-PECT Phase III Trial Treatment / Schema Perifosine 50 mg PO QD  Patients with refractory mCRC Capecitabine 1000 mg/m2 BID d 1 - 14  No prior Rx with CAP in metastatic R Cycle = 21 Days setting Placebo PO QD Capecitabine 1000 mg/m2 BID d 1 - 14 Randomized 1:1, Double-blind Primary Endpoint: N = ~430 patients  Overall Survival RECIST v 1.1 Secondary Endpoints: CTCAE v 4.0  PFS, ORR, Safety
  • Gastric cancer: a global disease • 4th most common malignant disease ~ 930,000 • 2nd most common cause of cancer-related death worldwide ~700,000 • Falling incidence of distal gastric cancer • Increasing incidence of proximal gastric cancer • Wide geographical variationIncidence (males) >20/100000 ≥10 - ≤20/100000 <10/100000 www.cancer.gov Kamangar F et al. J Clin Oncol 2006;24:2137–50
  • Esophageal and Gastric Carcinoma US Incidence in 2009• 37,600 new cases • Gastric: 21,130 (56%) • Esophagus: 16,470 (44%)• Increase in Esophageal , GEJ, cardia adeno • Obesity, GERD, Barrett’s, tobacco, EtOH • Are adenocarcinomas of the distal esophagus, GE junction, and upper stomach the same?• Decline in Gastric Cancer, SCC incidence• 4.5% of U.S. cancer deaths • Esophageal: 88% fatality rate • Gastric: 50% fatality rate• Male > Female Jemal 2009
  • Metastatic gastroesophageal cancer• Longstanding search for a true standard regimen• Multiple combinations are feasible in the first line setting• No data as to whether combinations are better than sequential therapy• Active agents • Fluoropyrimidines, platinums, taxanes, irinotecan, (anthracyclines), trastuzumab in HER2+
  • Phase III Data of Chemotherapy Regimens in Advanced Gastric CaRegimen RR (%) TTP/PFS OS (mos) Ref (mos)CF 35 8.3 Bleiberg,Cisplatin 100 mg/m2 D1 EJC 19975-FU 1000 mg/m2 CIV D1-5ECF 42 7.0 9.4 Ross,Epirubicin 50 mg/m2 D1 JCO 2002Cisplatin 60 mg/m2 D15-FU 200 mg/m2/d CIV D1-21DCF 37 5.6 9.2 Van Cutsem,Docetaxel 75 mg/m2 D1 JCO 2006Cisplatin 75 mg/m2 D15-FU 750 mg/m2 CIV D1-5EOX 48 7.0 11.2 Cunningham,Epirubicin 50 mg/m2 D1 NEJM 2008Oxaliplatin 130 mg/m2 D1Capecitabine 625 mg/m2 BID
  • Targeted Therapies• Conventional, cytotoxic chemotherapy has limited benefit• Targeted agents: attempt to block specific tumor growth pathways • Monoclonal antibodies • Tyrosine kinase inhibitors • Soluble receptors to growth factors • Inhibition of pathways involved in protein synthesis and degradation
  • Molecular Targets: Esophagogastric Cancer• KRAS mutation: < 5-10%• BRAF mutation: < 5%• EGFR over expression: 50-80% • TKI’s inactive • Cetuximab monotherapy inactive• EGFR mutation: < 5%• CMET: < 10%• HER2 over expression: 10-25% Galizia W J Surg 31: 1458; 2007 Mammano Anticancer Res 26: 3547; 2006 Lee Oncogene 22: 6942; 2003 Yano Oncol Rep 15: 65; 2006
  • Trastuzumab plus Chemotherapy in Advanced HER2+ Gastric Cancer: ToGARationale: A subpopulation of gastric cancers overexpress HER2 5-FU or Capecitabine (investigator discretion) + Cisplatin + TrastuzumabScreen 3807 (n=294) HER2+ GCGC patients for HER2 (n = 810, R 22%) 5-FU or Capecitabineexpression (n = 584) (investigator discretion) + Cisplatin Stratification by (n=290) •Gastric vs GEJ •Advanced vs metastatic •5-FU vs capecitabine 5-FU 800 mg/m2/d infusional d1-5 q3w X 6 Capecitabine 1000 mg/m2 bid d1-14 q3w X 6 Cisplatin 80 mg/m2 q3w X 6 Trastuzumab 6 mg/kg q3w to PD (8 mg/kg loading) Primary endpoint: OS Bang et al., Lancet 2010 Bang et al. J Clin Oncol 2009; 27(suppl): 215s (abstract 4556)
  • Patient demographics and baseline characteristics Characteristic F+C F+C + trastuzumab n=290 n=294 Sex, % Male / Female 75 / 25 77 / 23 Age, median (range) years 59.0 (21-82) 61.0 (23-83) Weight, median (range) kg 60.3 (28-105) 61.5 (35-110) Region, n (%) Asia 166 (56) 158 (53) C/S America 26 (9) 27 (9) Europe 95 (32) 99 (33) Other 9 (3) 14 (5) Type of GC (central assessment) Intestinal 74.2a 76.8b Diffuse 8.7a 8.9b Mixed 17.1a 14.3b Prior gastrectomy 21.4 24.1Highest recruitment was from Korea, Japan, China and RussiaF, fluoropyrimidine; C, cisplatin an=287; bn=293 Bang et al., Lancet 2010
  • HER2 Positivity IHC Bang et al. ASCO 2009
  • HER2 Positivity Worldwide (ROW) Bang et al. ASCO 2009
  • HER2 Positivity Histological Type Bang et al., Lancet 2010
  • HER2 Positivity GEJ vs Gastric Ca Bang et al. ASCO 2009
  • ToGA: Primary end point: OS Event 1.0 Median Events OS HR 95% CI p value 0.9 0.8 FC + T 167 13.8 0.74 0.60, 0.91 0.0046 0.7 FC 182 11.1 0.6 0.5 0.4 0.3 0.2 0.1 11.1 13.8 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. 294 277 246 209 173 147 113 90 71 56 43 30 21 13 12 6 4 1 0 at 290 266 223 185 143 117 90 64 47 32 24 16 14 7 6 5 0 0 0 riskT, trastuzumab Bang et al., Lancet 2010
  • ToGA: Secondary end point: PFSEvent 1.0 Median Events PFS HR 95% CI p value 0.9 0.8 FC + T 226 6.7 0.71 0.59, 0.85 0.0002 0.7 FC 235 5.5 0.6 0.5 0.4 0.3 0.2 0.1 5.5 6.7 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Time (months) No. 294 258 201 141 95 60 41 28 21 13 9 8 6 6 6 4 2 0 at risk 290 238 182 99 62 33 17 7 5 3 3 2 2 1 1 0 0 0 Bang et al., Lancet 2010
  • ToGA: Efficacy: OS by HER2 statusSubgroup N Median OS Hazard 95% CI (months) ratioAll 584 11.1 vs 13.8 0.74 0.60, 0.91 Pre-planned analysis IHC0/FISH+ 61 7.2 vs 10.6 0.92 0.48, 1.76 IHC1+/FISH+ 70 10.2 vs 8.7 1.24 0.70, 2.20 IHC2+/FISH+ 159 10.8 vs 12.3 0.75 0.51, 1.11 IHC3+/FISH+ 256 12.3 vs 17.9 0.58 0.41, 0.81 IHC3+/FISH- 15 17.7 vs 17.5 0.83 0.20, 3.38 Exploratory analysis IHC0 or 1+/FISH+ 131 8.7 vs 10.0 1.07 0.70, 1.62 IHC2+/FISH+ or IHC3+ 446 11.8 vs 16.0 0.65 0.51, 0.83 0.2 0.4 0.6 1 2 3 4 5 Favors T Risk ratio Favors no T Bang et al., Lancet 2010
  • ToGA: OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)Event 1.0 Median Events OS HR 95% CI 0.9 0.8 FC + T 120 16.0 0.65 0.51, 0.83 0.7 FC 136 11.8 0.6 0.5 0.4 0.3 0.2 0.1 11.8 16.0 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months)No. 228 218 196 170 142 122 100 84 65 51 39 28 20 12 11 5 4 1 0 at 218 198 170 141 112 96 75 53 39 28 20 13 11 4 3 3 0 0 0risk Bang et al., Lancet 2010
  • Secondary end point: tumor response rate Intent to treat Patients p=0.0017 F+C + trastuzumab (%) p=0.0145 F+C 47.3% 41.8% 32.1% 34.5% p=0.0599 5.4% 2.4% CR PR ORR ORR= CR + PRCR, complete response; PR, partial response Bang et al., Lancet 2010
  • ToGA: Select Grade 3/4 Toxicities* Fluoropyrimidine + Fluoropyrimidine + Cisplatin + Cisplatin Trastuzumab (n = 290) (n = 294)Hematologic Neutropenia 27% 30% Anemia 12% 10%Nonhematologic Diarrhea 9% 4% Nausea 7% 7%Asymptomatic LVEF drops 6% 1% (< 50%) *2 deaths due to cardiac events in each arm Bang et al., Lancet 2010
  • Pertuzumab and trastuzumab bind to distinct epitopes on HER2 extracellular domain Pertuzumab-HER2 complex Trastuzumab-HER2 complex Pertuzumab Dimerization domain Trastuzumab • Activates antibody-dependent • Activates ADCC cellular cytotoxicity (ADCC) • Prevents HER2 domain cleavage • Has a major effect on role of • Inhibits HER2-mediated signalling pathways HER2 as a co-receptor with HER3 or EGFR • Inhibits multiple HER-mediated signaling pathwaysFigures adapted from Hubbard SR. Cancer Cell 2005;7:287–288
  • Trastuzumab plus Pertuzumab in Gastric Cancer Xenografts 4-1ST (HER2-positive) MKN-28 (HER2-negative)1,000 1,000 1,000 1,000Tumor volume (mm3) Tumor volume (mm3) a Control Pertuzumab 40 mg/kg Control Trastuzumab 20 mg/kg Pertuzumab 40 mg/kg Pertuzumab 40 mg/kg + Pertuzumab 40 mg/kg + trastuzumab 20 mg/kg Trastuzumab 20 mg/kg a, b, c 100 100 100 100 1 1 8 8 15 15 22 22 1 1 8 8 15 15 22 22 Days after treatment started Days after treatment started Yamashita et al., AACR 2010
  • Phase III Trials with HER2 Targeted Agents CapeOx + Placebo N=535 LOGiC Primary EP: OS (was PFS) CapeOx + Lapatinib Data expected mid 2012 http://clinicaltrials.gov/ct2/show/NCT00680901
  • RTOG 1010 – Proposed Neoadjuvant Phase III Trial in Esophagus/GEJ ACAPrimary EP: DFS (15  27 mos, HR 0.56) N=160 Pts with HER+ PI: H. Safran, Providence, RI
  • Advanced Esophago-Gastric Cancer: Summary• Chemotherapy backbone • Two drug regimens preferred (FOLFIRI, FOLFOX, XELOX, Cape-Cis) • Marginal benefit for 3 drug regimens (Docetaxel + CF) • ECF/EOX: is E needed in metastatic disease?• Molecular Targeted Therapies • VEGF, EGFR/HER pathways targeted • Phase II and III development with chemo, chemoRT • Molecular markers to select therapy: • HER2+  Trastuzumab should be used
  • Median OS in Advanced Gastric/GEJ Cancer BSC (1) 12 months FAMTX (2) C+S1 (3) CF (4) IF (5) EOF (6) DCF (4) ECF (6) ECX (6) XP (7) EOX (6) Trastuzumab + XP/FP (8) HER2 IHC 2+/FISH+ or IHC 3+ 0 5 10 15 Median OS in patients with advanced gastric cancer (months)1. Murad, AM et al. Cancer 1993; 72:37−41. 2. Vanhoefer U, et al. JCO 2000; 18:2648−2657.3. Ajani JA, et al. JCO 2009; 27(S15):Abstract 4511. 4. Van Cutsem E, et al. JCO 2006; 24:4991−4997.5. Dank M, et al. Ann Oncol 2008; 19:1450−1457. 6. Cunningham D, et al. NEJM 2008; 358:36−46.7. Kang YK, et al. Ann Oncol 2009; 20:666−673. 8. Bang, et al. Lancet 2010.
  • The dismal prognosis of pancreatic cancer• Pancreatic cancer has the 5-year OS worst survival of any solid tumor• In 2007, it is estimated that there will be: • 37,170 new cases • 33,370 deaths• These dismal statistics reflect the early distant spread of PC and the inadequacy of current therapies
  • Gemcitabine vs 5-FU Efficacy Gem 5-FU pRR 5.4% 0% —CBR 24% 5% 0.0022Med survival (months) 5.7 4.4 0.0025Time to progressive disease (months) 2.1 0.9 0.001312-month survival 18% 2% 0.0025 Burris JCO 1997
  • Gemcitabine vs 5-FU Survival Gemcitabine 5-FU Log-Rank Test p = 0.0009 Burris JCO 1997
  • Pancreas Cancer: Prodige 4 - ACCORD 11 trial design for both arms: R A FOLFIRINOX CT scans: N obtainedMetastatic D every 2 monthspancreatic O cancer M 6 months of chemotherapy I Gemcitabine recommended Z E Stratification : • center • performance status: 0 versus 1 • location of the tumor: head versus other location of the primary Conroy et al. NEJM 2011
  • Experimental Arm: FOLFIRINOX Oxaliplatin 85 mg/m2 over 2 hours, Leucovorin 400 mg/m2 over 2 hours, Irinotecan 180 mg/m2 in 90 mn infusion, 5-FU 400 mg/m2 bolus, 5-FU 2400 mg/m2 on 46-h infusion. 1 cycle = 14 days Bolus 5-FU 400 mg/m2 2hOxaliplatin Leucovorin Continuous 5-FU85 mg/m2 400 mg/m2 2.400 mg/m2 Irinotecan 2h 180 mg/m2 46 h q2wks 1 h 30 Conroy et al. NEJM 2011
  • Patients characteristics Folfirinox GemcitabineCharacteristics p N=171 N=171Median age (yrs) 61 61 NS[range] [25-76] [34-75]Sex Male 106 (62%) 105 (61.4%) Female 65 (38%) 66 (38.6%) NSBaseline PS 0 64 (37.4%) 66 (38.6%) 1 106 (62.0%) 105 (61.4%) NS 2 1 (0.6%) 0 (0.0%)Location of primary Head 62 (36.3%) 60 (35.1%) Other 109 (63.7%) 111 (64.9%) NS Conroy et al. NEJM 2011
  • Safety: hematological AEs Folfirinox Gemcitabine pAE, % per patient N=167 N=169 All Grade 3/4 All Grade 3/4 Grade 3/4Neutropenia 79.9 45.7 54.8 18.7 0.0001Febrile Neutropenia 7.2 5.4 2.4 0.6 0.009Anemia 90.4 7.8 94.6 5.4 NSThrombocytopenia 75.2 9.1 54.8 2.4 0.00842.5 % of the pts received G-CSF in the F arm vs 5.3% in the G armOne toxic death occurred in each arm Conroy et al. NEJM 2011
  • Objective Response Rate Folfirinox Gemcitabine p N=171 N=171Complete response 0.6% 0%Partial response 31% 9.4% 0.0001CR/PR 95% CI [24.7-39.1] [5.9-15.4]Stable disease 38.6% 41.5%Disease control 70.2% 50.9% 0.0003CR+PR+SDProgression 15.2% 34.5%Not assessed 14.6% 14.6%Median duration 5.9 mo. 4 mo. nsof response Conroy et al. NEJM 2011
  • Progression-Free SurvivalMedian PFS Folfirinox: 6.4 mo. Median PFS Gemcitabine: 3.3 mo 1.00 HR=0.47 : 95%CI [0.37-0.59] 0.75 Probability 0.50 p<0.0001 0.25 0.00 0 3 6 9 12 15 18 21 24 27 30 33 36 Months Number at risk Gemcitabine 171 88 26 8 5 2 0 0 0 0 0 0 0 Folfirinox 171 121 85 42 17 7 4 1 1 0 0 0 0 Gemcitabine Folfirinox Conroy et al. NEJM 2011
  • Overall Survival Median follow up: 26.6 months [95% CI: 20.5 – 44.9] Folfirinox Gemcitabine p HR N=171 N=171Median survival 11.1 mo. 6.8 mo. <0.0001 0.57[CI 95%] [ 9 - 13.1] [ 5.5 - 7.6]1-yr. survival 48.4% 20.6%18-mo. survival 18.6% 6% Conroy et al. ASCO 2010
  • Overall Survival 1.00 HR=0.57 : 95%CI [0.45-0.73] 0.75 Probability 0.50 Stratified Log-rank test, p<0.0001 0.25 0.00 0 3 6 9 12 15 18 21 24 27 30 33 36 MonthsNumber at risk Gemcitabine 171 134 89 48 28 14 7 6 3 3 2 2 2 Folfirinox 171 146 116 81 62 34 20 13 9 5 3 2 2 Gemcitabine Folfirinox Conroy et al. ASCO 2010
  • Where are we in pancreas cancer?• FOLFIRINOX is new standard of care for good-PS patients • Trials in development to use FOLFIRINOX as adjuvant and neoadjuvant therapy • Can novel agents be added to FOLFIRINOX?• Gemcitabine (+/- erlotinib) still FDA regulatory standard • Novel agents in phase II/III trials with GEM • Abraxane, Hedgehog inhibitors, IGFR mAbs• Biomarker-driven treatment decisions explored • hENT, ERCC-1, SPARC, KRAS…
  • Conclusions – Key Issues• CRC • Individualized therapy • Duration of anti-VEGF therapy • Novel agents• Gastric/GEJ cancer • HER2 targeted agents • Anti-angiogenesis• Pancreas cancer • New standard of care • Difficult drug development for regulatory purposes