Advances in the Management of Colorectal Cancer

Transcription

1 Advances in the Management of Colorectal Cancer Dr Ashraf Wadee Medical Oncologist Charlotte Maxeke Johannesburg Academic Hospital and Wits Donald Gordon Medical

2 Colorectal Cancer: Background 3 rd most common cancer in males & females with ~equal gender distribution. Second leading cause of cancer death worldwide after lung cancer. 1 in 3 people with CRC will die from their disease. ~105,000 cases of colon cancer and ~42,000 cases of rectal cancer yearly with ~60,000 deaths each year in USA 4 th most common cancer in South Africa in both men & women with ~2,500 new cases/year Highly curable if detected early.

3 2016 Estimated US Cancer: New GI Cases Prostate 21% Men Women 29% Breast Lung & bronchus 14% Colorectal 8% Urinary bladder 7% Melanoma 6% NHL 5% Kidney 5% Leukemia 4% H&N 4% Liver/Cholangio 3% All Other Sites 23% 13% Lung & bronchus 8% Colorectal 7% Uterine corpus 6% Thyroid 4% NHL 3% Melanoma 3% Leukemia 3% Pancreas 3% Kidney 21% All Other Sites ACS Surveillance Research 2015

4 2016 Estimated US Cancer: GI Cancer Deaths Lung & bronchus 27% Prostate 8% Colorectal 8% Pancreas 7% Liver/Cholangio 6% Leukemia 4% Esophagus 4% Urinary bladder 4% NHL 4% Brain/CNS 3% All other sites 25% Men Women 26% Lung & bronchus 14% Breast 8% Colorectal 7% Pancreas 5% Ovary 4% Uterine corpus 4% Leukemia 3% Liver/Cholangio 3% NHL 2% Brain/CNS 24% All other sites ACS Surveillance Research 2015

5 Chemotherapy for mcrc Treatment of colorectal cancer is one of the more rapidly advancing areas of cancer research 5FU based chemotherapy has been the mainstay of colorectal cancer therapy since 1950s Addition of folinic acid in 1980s improved responses from ~10% to ~20% The addition of a number of new drugs since mid 1990s has dramatically changed the outlook of advanced colorectal cancer.

6 5FU 6

7 5 FU 7

8 Modern therapies Oxaliplatin Irinotecan Oral capecitabine Monoclonal antibodies: bevacizumab cetuximab panitumumab ramucirumab VEGF trap - aflibercept Multikinase inhibitor regorafenib Oral trifluridine/tiparicil

9 Angiogenesis inhibition

10 Angiogenesis is Required for Sustained Tumor Growth Tumor Cells Ligand Receptor Interaction Angiogenic Factors: VEGF Proliferation Invasion and Migration

11

12 Bevacizumab Recombinant humanized monoclonal antibody against VEGF. Binds directly to VEGF, inhibiting its activity and preventing angiogenesis Prevents the interaction of VEGF with VEGFR-1 (flt-1), VEGFR-2 (KDR) and VEGFR-3 (flt-4) on the surface of endothelial cells. Reduces micro-vascular growth and inhibits progression of local and metastatic disease.

13 Bevacizumab MOA 13

14 IFL +/- bevacizumab Randomized study in mcrc compared irinotecan-based therapy (IFL) + placebo versus IFL + bevacizumab (Hurwitz et al; N Engl J Med 2004). Median PFS: 10.6 months vs. 6.2 months Median OS: 20.3 vs months, p<0.05 Response rate: 44.8% vs. 34.8% IFL is however a suboptimal regimen and is more toxic than infusional 5FU-based chemotherapy!

15 Phase III ML18147 (TML): Continuing Bevacizumab Beyond Progression Stratified by first-line CT (oxaliplatin or irinotecan based), first-line PFS ( 9 vs > 9 mos), time from last BEV dose ( 42 vs > 42 days), ECOG PS at baseline (0/1 vs 2) Progressive mcrc after BEV + standard first-line CT (either oxaliplatin or irinotecan based) (n = 820) Standard second-line CT (oxaliplatin or irinotecan based) until PD (n = 411) Bevacizumab 2.5 mg/kg/wk + standard second-line CT (oxaliplatin or irinotecan-based) until PD (n = 409) Primary endpoint: OS Secondary endpoints: PFS, ORR, safety Bennouna J, et al. Lancet Oncol. 2013;14:29-37.

16 Continuing Bevacizumab Beyond Progression (TML): OS, PFS Overall Survival Progression-Free Survival OS (%) Unstratified* HR: 0.81 (95% CI: ; log-rank P =.0062) Stratified HR: 0.83 (95% CI: ; log-rank P =.0211) PFS (%) Unstratified* HR: 0.68 (95% CI: ; log-rank P <.0001) Stratified HR: 0.67 (95% CI: ; log-rank P <.0001) mos 11.2 mos Mos mo CT (n = 410) BEV + CT (n = 409) 5.7 mo Mos *Primary analysis method. Stratified by first-line CT (oxaliplatin based, irinotecan based), first-line PFS ( 9 mos, > 9 mos), time from last dose of BEV ( 42 days, > 42 days), ECOG PS at baseline (0, 1). Bennouna J, et al. Lancet Oncol. 2013;14:29-37.

17 Continuing Bevacizumab Beyond Progression (TML): Adverse Events Chemotherapy (n = 409) BEV + Chemo (n = 401) Patients, % All Grades Grade 3 5 All Grades Grade 3 5 AEs of special interest to BEV Hypertension Proteinuria 1 5 <1 Bleeding/hemorrhage 9 < Abscesses and fistulae 1 <1 GI perforation <1 <1 3 2 Congestive heart failure <1 <1 <1 VTE ATE 1 <1 <1 <1 Wound-healing complications <1 <1 1 <1 RPLS Arnold D, et al. ASCO Abstract CRA3503.

18 Aflibercept Novel multiple VEGF trap that binds VEGF-A & also targets VEGF-B & placental growth factor (PlGF)

19 Aflibercept MOA 19

20 Aflibercept improves survival in a phase III randomized trial in metastatic colorectal cancer Eric van Cutsem, Josep Tabernero, Radek Lakomy, Hans Prenen, Jana Prausova, Teresa Macarulla, Paul Ruff, Guy van Hazel, Vladimir Moiseyenko, David Ferry, Joe McKendrick, Jonathan Polikoff, Alexis Tellier, Remi Castan & Carmen Allegra. J Clin Oncol 2012; 30:

21 Phase III VELOUR Study: FOLFIRI ± ziv- Aflibercept as Second-line Therapy in mcrc Stratified by previous bevacizumab (yes vs no), ECOG PS (0 vs 1 vs 2) Patients with mcrc progressing on first-line oxaliplatin-based chemotherapy* (planned N = 1226) FOLFIRI + ziv-aflibercept 4 mg/kg q2w (n = 612) FOLFIRI + Placebo q2w (n = 614) *30% had previous bevacizumab. Primary endpoint: OS Secondary endpoints: PFS, ORR, safety, immunogenicity No correlatives Van Cutsem E, et al. J Clin Oncol. 2012;30: ClinicalTrials.gov. NCT

22 FOLFIRI ± ziv-aflibercept as Second-line Therapy in mcrc (VELOUR): OS, PFS Overall Survival Progression-Free Survival 100 Stratified HR: (95.34% CI: ; log-rank P =.0032) 100 Stratified HR: (95% CI: ; log-rank P <.0001) OS (%) Aflibercept/FOLFIRI Median: mos PFS (%) Aflibercept/FOLFIRI Median: 6.90 mos 20 Placebo/FOLFIRI Median: mos Mos 20 0 Placebo/FOLFIRI Median: 4.67 mos Mos Van Cutsem E, et al. J Clin Oncol. 2012;30:

23 2 nd -Line FOLFIRI ± ziv-aflibercept in mcrc (VELOUR): OS by Prior Bevacizumab Previous Bevacizumab No Previous Bevacizumab 100 HR: (95.34% CI: ) 100 HR: (95.34% CI: ) OS (%) Aflibercept/FOLFIRI Median: 12.5 mos OS (%) Aflibercept/FOLFIRI Median: 13.9 mos 20 Placebo/FOLFIRI Median: 11.7 mos Mos Pts at Risk, n Placebo 187 AFL Tabernero J, et al. Eur J Cancer. 2014;50: Placebo/FOLFIRI Median: 12.4 mos Mos Pts at Risk, n Placebo 427 AFL

24 2 nd -Line FOLFIRI ± ziv-aflibercept in mcrc (VELOUR): Safety by Prior Bevacizumab Overall Adverse Events, % FOLFIRI (n = 172) Prior Bevacizumab Tabernero J, et al. Eur J Cancer. 2014;50: Aflibercept/ FOLFIRI (n = 171) FOLFIRI (n = 433) No Bevacizumab Aflibercept/ FOLFIRI (n = 440) Serious AE Fatal AE due to PD Fatal AE not due to PD Grade 3/4 Adverse Event, % Grade Gr 3 Gr 4 Gr 3 Gr 4 Gr 3 Gr 4 Gr 3 Gr 4 Neutropenia Diarrhea Infections/Infestations Stomatitis Hypertension Fatigue

25 Ramucirumab MOA 25

26 Phase III RAISE Study: Second-Line Ramucirumab/FOLFIRI vs FOLFIRI Stratified by geographic region, KRAS mutation status, TTP after start of first-line therapy Patients with CRC and progression during or within 6 months of first-line bevacizumab, oxaliplatin, and a fluoropyrimidine (N = 1072) Ramucirumab 8 mg/kg + FOLFIRI q2w per cycle (n = 536) Placebo + FOLFIRI q2w per cycle (n = 536) Treat until PD or unacceptable toxicity Ramucirumab: anti-vegfr2 antibody Primary endpoint: OS Tabernero J, et al. Lancet Oncol. 2015;16:

27 Second-Line Ramucirumab/FOLFIRI vs FOLFIRI (RAISE): Overall Survival Overall Survival Median OS, mo (95% CI) HR (95% CI) P Value (log-rank) Ramucirumab + Placebo + FOLFIRI FOLFIRI ( ) ( ) ( ) (stratified).0219 (stratified) 0.2 Ramucirumab + FOLFIRI Placebo + FOLFIRI Mos Pts at Risk, n Ram + FOLFIRI Placebo + FOLFIRI Tabernero J, et al. Lancet Oncol. 2015;16:

28 Recap VEGF Targets 28

29 EGFR-1 Inhibition

30 EGFR-1 signalling Baselga J. Eur J Cancer 2001;37 Suppl 4:S16-S22.

31 Cetuximab Chimeric monoclonal antibody which binds to Epidermal Growth Factor Receptor (EGFR-1). Blocks binding of EGF to EGFR-1 thereby inhibiting intracellular tyrosine phosphorylation Prevents signaling to nucleus via ras-raf-mek-erk- MAPK pathway Inactive in ras mutant tumours

32 Cetuximab MOA 32

33 Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer Eric Van Cutsem, Claus-Henning Kohne, Erika Hitre, Jerzy Zaluski, Chung-Rong Chang Chien, Anatoly Makhson, Geert D Haens, Tamás Pintér, Robert Lim, Győrgy Bodoky, Jae Kyung Roh, Gunnar Folprecht, Paul Ruff, Christopher Stroh, Sabine Tejpar, Michael Schlichting, Johannes Nippgen and Philippe Rougier New England Journal of Medicine 2009; 360 (April 2):

34 Phase III CRYSTAL study Cetuximab + FOLFIRI EGFR-expressing mcrc Stratification factors: Region ECOG performance status Populations: Randomized patients (n=1217) Safety population (n=1202) ITT population (n=1198) R Cetuximab (IV 400 mg/m 2 on day 1, then 250 mg/m 2 weekly) + irinotecan (180 mg/m 2 ) + 5-FU (400 mg/m 2 bolus mg/m 2 as 46-h continuous infusion) + LV (every 2 weeks) FOLFIRI Irinotecan (180 mg/m 2 ) + 5-FU (400 mg/m 2 bolus mg/m 2 as 46-h continuous infusion) + LV (every 2 weeks) van Cutsem E et al. N Engl J Med 2009

35 Relating K-ras status to efficacy Primary endpoint: PFS in K-ras wild-type Progression-free survival estimate K-ras wild-type (n=348) HR=0.68; p=0.017 mpfs Cetuximab + FOLFIRI: 9.9 months mpfs FOLFIRI: 8.7 months 1-year PFS rate 25% vs 43% Months Cetuximab + FOLFIRI FOLFIRI van Cutsem E et al. NEJM 2009

36 Relating KRAS status to efficacy Overall survival: KRAS wild-type Overall survival estimate HR=0.84 (95% CI: ); p=0.22 mos Cetuximab + FOLFIRI (n=172): 24.9 months mos FOLFIRI (n=176): 21.0 months Months 2-year OS rate 51% vs 44% Cetuximab + FOLFIRI FOLFIRI van Cutsem E et al. NEJM 2009

37 Relating K-ras status to efficacy Primary endpoint: PFS in K-ras mutant Progression-free survival estimate K-ras mutant (n=192) HR=1.07; p=0.75 mpfs Cetuximab + FOLFIRI: 7.6 months mpfs FOLFIRI: 8.1 months Months Cetuximab + FOLFIRI FOLFIRI van Cutsem E et al. NEJM 2009

38 Anti-EGFR monoclonal antibody rash

39 Panitumumab Fully human anti-egfr-1 monoclonal antibody

40 Panitumumab MOA 40

41 Randomized, phase 3 study (PRIME) of panitumumab with FOLFOX-4 versus FOLFOX-4 alone as first-line treatment in patients with. previously untreated metastatic colorectal cancer Jean-Yves Douillard, Salvatore Siena, Jim Cassidy, Josep Tabernero, Ronald Burkes, Mario Barugel, Yves Humblet, György Bodoky, David Cunningham, Jacek Jassem, Fernando Rivera, Ilona Kocákova, Paul Ruff, Maria Błasińska-Morawiec, Martin Šmakal, Jean-Luc Canon, Mark Rother, Kelly Oliner, Michael Wolf, Jennifer Gansert Journal of Clinical Oncology 2010; 28(31): Douillard et al. J Clin Oncol 2010; 28(31):

42 PFS (WT KRAS Exon 2): Panitumumab + FOLFOX4 versus FOLFOX4 alone Douillard et al. J Clin Oncol 2010; 28(31):

43 OS (WT KRAS Exon 2): Panitumumab + FOLFOX4 versus FOLFOX4 alone Douillard et al. J Clin Oncol 2010; 28(31):

44 PFS (MT KRAS): Panitumumab + FOLFOX4 versus FOLFOX4 alone Douillard et al. J Clin Oncol 2010; 28(31):

45 OS (MT KRAS): Panitumumab + FOLFOX4 versus FOLFOX4 alone Douillard et al. J Clin Oncol 2010; 28(31):

46 Small molecule multi-targeted kinase inhibition

47 Regorafenib: Oral Multikinase Inhibitor Targeting Multiple Tumor Pathways F Cl F F N H O N H F O N O N H Regorafenib Biochemical Activity Regorafenib IC 50 Mean ±SD nmol/l (n) VEGFR1 13 ± 0.4 (2) Murine VEGFR2 4.2 ± 1.6 (10) Murine VEGFR3 46 ± 10 (4) TIE2 311 ± 46 (4) PDGFR-β 22 ± 3 (2) FGFR1 202 ± 18 (6) KIT 7 ± 2 (4) RET 1.5 ± 0.7 (2) Inhibition of proliferation Inhibition of tumor microenvironment signaling Inhibition of neoangiogenesis RAF ± 0.6 (4) B-RAF 28 ± 10 (6) KIT PDGFR RET PDGFR-β FGFR VEGFR1-3 TIE2 B-RAF V600E 19 ± 6 (6) Wilhelm SM, et al. Int J Cancer. 2011;129: Mross K, et al. Clin Cancer Res. 2012;18: Strumberg D, et al. Expert Opin Invest Drugs. 2012;21:

48 Regorafenib Small molecule multi-targeted kinase inhibitor inhibits VEGFR1,2 & 3, KIT, PDGFR-α & β, RET, FGFR1 & 2, TIE2, DDR2, TrkA, Eph2A, RAF, SAPK2, PTK5 & ABL Anti-angiogenic, anti-tumour & anti-stromal effects Common AEs include weakness, anorexia, HFS syndrome, mucositis, weight loss, infections, hypertension & dysphonia SAEs include severe liver damage, bleeding, blistering of skin, severe hypertension, myocardial infarction & bowel perforation

49 Phase III CORRECT: Regorafenib After Failure of Standard Therapy in mcrc Patients with progression after all available standard therapy (N = 760) 2:1 Arm A: Regorafenib 160 mg po qd + BSC 3 wks on, 1 wk off (n = 505) Arm B: Placebo + BSC 3 wks on, 1 wk off (n = 255) Primary endpoint: overall survival Prior systemic, anticancer therapies (palliative) 1-2 prior lines: 26% 3 prior lines: 26% 4 prior lines: 48% Grothey A, et al. Lancet. 2013;381:

50 Regorafenib After Failure of Standard Therapy in mcrc (CORRECT): OS, PFS Overall Survival HR: 0.77 (95% CI: ; P =.0052) Progression-Free Survival HR: 0.49 (95% CI: ; P <.0001 ) OS (%) Placebo (n = 255) Regorafenib (n = 505) Mos From Randomization PFS (%) Placebo (n = 255) Regorafenib (n = 505) Mos From Randomization Regorafenib Placebo Median OS, mo IQR Regorafenib Placebo Median PFS, mo IQR Primary endpoint met prespecified stopping criteria at second interim analysis (1-sided P at approximately 74% of events required for final analysis) Grothey A, et al. Lancet. 2013;381:

51 Regorafenib in Previously Treated Asian mcrc Patients (CONCUR): OS OS (%) Median OS (Primary Endpoint) Regorafenib: 8.8 months (95% CI: ) Placebo: 6.3 months (95% CI: ) HR: 0.55 (95% CI: ) P = Regorafenib Placebo Pts at Risk, n Regorafenib Placebo Mos After Randomization Li J, et al. Lancet Oncol. 2015;16:

52 Regorafenib After Failure of Standard Therapy in mcrc (CORRECT): Safety Adverse Event, % Regorafenib (n = 500) Placebo (n = 253) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Hand foot skin reaction < 1 0 Fatigue 47 9 < < 1 Hypertension Diarrhea 34 7 < Rash/desquamation Anorexia Oral mucositis Thrombocytopenia 13 3 < 1 2 < 1 0 Fever Nausea 14 < Dose modification due to adverse event in 67% of patients receiving regorafenib vs 23% of patients receiving placebo. Grothey A, et al. Lancet. 2013;381:

53 Summary of targeting VEGF 53

54 New Chemotherapy Regimens 54

55 TAS-102: Novel Investigational Combination Chemotherapy TAS-102 consists of: A cytotoxin (trifluridine), which inhibits cell growth A thymidine phosphorylase inhibitor (tipiracil hydrochloride), which protects trifluridine from breakdown In a phase II trial, [1] TAS-102 demonstrated promising efficacy and a manageable safety profile in patients with mcrc who were refractory or intolerant to standard chemotherapies In September 2015 the US FDA approved TAS-102 for pts with mcrc and wild-type RAS who have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-vegf biologic, and an anti-egfr monoclonal antibody Approval based on phase III RECOURSE trial [2] 1. Yoshino T, et al. Lancet Oncol. 2012;13: Mayer RJ, et al. N Engl J Med. 2015;372:

56 TAS-102: Mechanism of Action Capecitabine 5-FU (5-fluorouracil) TAS-102 (trifluorothymidine) Active Metabolites FUTP (fluorouridine triphosphate) FdUMP (fluorodeoxyuridine monophosphate) FdUTP (fluorodeoxyuridine triphosphate) RNA damage via direct incorporation Disrupts DNA synthesis and repair via TS (thymidylate synthase) inhibition DNA damage via direct incorporation TF-TMP (trifluorothymidine monophosphate) TF-TTP (trifluorothymidine triphosphate) 1. Longley DB, et al. Nat Rev Cancer. 2003;3: Capecitabine Prescribing Information Matsuoka K, et al. Mol Cancer Ther. 2015;14:

57 Phase III RECOURSE Study: TAS-102 in mcrc w/ 2 Prior Lines of Std. Chemo Stratified by KRAS status (wild type vs mutant), time between first diagnosis of metastases and randomization (< vs 18 mo), region (Japan vs US/Europe/Australia) Patients with mcrc and 2 prior lines of std. chemotherapy, ECOG PS 0-1 (N = 800) TAS mg/m 2 BID, D1-5 and 8-12 q4w + Best Supportive Care (n = 534) Placebo + Best Supportive Care (n = 266) Treat until PD, unacceptable toxicity, or death Primary endpoint: OS Secondary endpoints: PFS, ORR, DCR, safety Mayer RJ, et al. N Engl J Med. 2015;372:

58 TAS-102 in mcrc w/ 2 Prior Lines of Std. Chemo (RECOURSE): Overall Survival Survival distribution function TAS-102 Placebo Months from randomization Mayer RJ, et al. N Engl J Med. 2015;372: TAS-102 (n = 534) Placebo (n = 266) Events # (%) 364 (68) 210 (79) HR (95% CI) 0.68 ( ) Stratified log-rank test P<.0001 Median OS, months % alive at: Median follow-up: 11.8 months 6 months months 27 18

59 TAS-102 in mcrc w/ 2 Prior Lines of Std. Chemo (RECOURSE): Grade 3 AEs AE, % TAS-102 Placebo Neutropenia 38 0 Leukopenia 21 0 Anemia 18 3 Febrile neutropenia 4 0 Mayer RJ, et al. N Engl J Med. 2015;372:

60 Checkpoint inhibition PD-L1 and PD-L2 (programmed death receptor ligands) on tumour cells bind to programmed death receptor (PD-1) on T- cells inhibiting cellular immunity Anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab inhibit PD-1 / PD-L1/2 interaction disinhibiting T-cell blockade FDA and EMA approved in metastatic melanoma and non-small cell lung cancer Pembrolizumab is under investigation in MSI-High (multisatellite instability) positive mcrc tumours (~10% CRC)

61 How meaningful is all this?? 61

62 Thank You 62