New Options in Metastatic Colorectal Cancer. Jeffrey A. Bubis, DO, FACOI, FACP Fleming Island Baptist South Palatka

Transcription

1 New Options in Metastatic Colorectal Cancer Jeffrey A. Bubis, DO, FACOI, FACP Fleming Island Baptist South Palatka

2 4 th most frequently diagnosed CA in the US 2 nd leading cause of CA death in the US Incidence is decreasing 60.5/ people in / people in / people in 2010 NCCN Guidelines Colon Cancer, v Available at:

3 Mortality from CRC 35% reduction from 1990 to 2007 In 2010, down 46% from peal rates NCCN Guidelines Colon Cancer, v Available at:

4 Fluoroacetic acid previously known to inhibit the aconitase step of the citric acid cycle. In 1954, uracil was found to be more easily absorbed in liver tumors than in normal hepatocytes First report on its efficacy was in Nature in Heidelberger C., Chaudhuri N. K., Danneberg P. et al. (March 1957). "Fluorinated pyrimidines, a new class of tumour-inhibitory compounds". Nature 179 (4561):

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8 Survival 1950 s median survival 12 months 2010 s 25% 5 year OS with chemo-biologic therapy 2010 s 30-50% 5 year OS with multimodality therapy Kemeny NE, Treatment of Metastatic Colon Cancer: The Times They Are A-Changing. JCO June 1, 2013 vol. 31 no Looupakis F, et al. Initial Therapy with FOLFOXIRI and Bevacizumab for Metastatic Colorectal Cancer. N Engl J Med 2014; 371:

9 It s not just 5-FU anymore Patented in 1957 The sole active agent in mcrc until: Oxaliplatin, irinotecan 2004 Bevacizumab, Cetuximab 2006 Panitumumab 2012 Regorafenib, Afibercept

10 Some patients with isolated metastatic disease can be cured with multimodality therapy.

11 Lung No randomized trials 5 year survival 35% 10 year suvival 20-30% Kanzaki R, Higashiyama M, Oda K, et al. Outcome of surgical resection for recurrent pulmonary metastasis from colorectal carcinoma. Am J Surg 2011; 202:419. Rama N, Monteiro A, Bernardo JE, et al. Lung metastases from colorectal cancer: surgical resection and prognostic factors. Eur J Cardiothorac Surg 2009; 35:444. Tampellini M, Ottone A, Bellini E, et al. The role of lung metastasis resection in improving outcome of colorectal cancer patients: results from a large retrospective study. Oncologist 2012; 17:1430.

12 Prognostic factors Lung Normal pre-thoracotomy CEA Absence of regional lymph node spread Metachronous rather than synchronous presentation Longer duration of time from diagnosis to development of metastases

13 Patient selection Exclusion Liver Common hepatic artery Common hepatic duct Common bile duct Main portal vein Involvement of all three hepatic veins >70% liver involvement More than six segments Inadequate predicted post-resection functional hepatic reserve

14 Liver 5 year survival average 40%, up to 58% in some trials One third of 5 year survivors suffer a cancerrelated death Those that survive 10 years appear to be cured Tomlinson JS, Jarnagin WR, DeMatteo RP, et al. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol 2007; 25:4575.

15 No randomized trials Lung & Liver If complete resection can be accomplished, surgery should be considered In the only published report 2 year DFS = 42% Kim S, Kim H, Hong Y, et al. The outcome of pulmonary metastasectomy from colorectal cancer and the role of postoperative chemotherapy (abstract). Data presented at the 2009 ASCO Gastrointestinal cancers Symposium, San Francisco, CA, January 16th, 2009.

16 Stereotactic Radiotherapy

17 Some patients with diffuse metastatic disease can achieve long-term survival with biologic therapy.

18 Unresectable Disease 2002 Average OS was months year survival is 11-25% Why the improvement?

19 Well tolerated Better Efficacy Cytoxic Combinations 5-FU/Capecitabine Oxaliplatin Irinotecan FOLFOX FOLFIRI FOLFOXIRI

20 Targeted Biologic Therapies Bevacizumab Afibercept Regorafenib Cetuximab Panitumumab Kozlowski S et al. N Engl J Med 2011;365:

21 Judah Folkman

22 VEGF Stimulates endothelial mitogenesis Promotes endothelial survival Controls vascular permeability Increased expression of TPA, matric matalloproteinaces, and collagenaces needed for endothelial cell migration

23 Anti-VEGF

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26 Bevacizumab Humanized monoclonal antibody targeting VEGF With standard first-line therapy Median OS 23.7 vs 18.2 months With standard second-line therapy Median OS 11.2 vs 9.8 months Hochster HS, Hart LL, Ramanathan RK, et al. Safety and efficacy of oxaliplatin and fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer: results of the TREE Study. J Clin Oncol 2008 Bennouna J, Sastre J, Arnold D, et al. Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): a randomised phase 3 trial. Lancet Oncol 2013

27 Significant Toxicities HTN (5-18%) Proteinuria (2%) Bevacizumab Nephrotic syndrome (<1%) Bleeding/Thrombosis (2-3%) GI tract perforation ( %) Posterior Reversible Leukoencephalopathy Syndrome <0.5% Avastin Package Insert:

28 Afibercept Recombinant fusion protein that prevents VEGF-A, VEGF-B, and PIGF from bding to their receptors. VEGF-A affinity is greater than that of bevacizumab

29 Afibercept Approved for use in second line therapy after failure of a an oxaliplatin-containing regimen. Median OS 13.5 vs 12.1 months Toxicity similar to bevacizumab Tabernero J, Van Cutsem E, Lakomý R, et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer 2014; 50:320.

30 Regorafenib Orally active inhibitor of angiogensis (including VEGF-1, 2, 3) and oncogenic receptor tyrosine kinases Median OS 8.8 vs 6.3 months FDA-approved for patients who have failed oxaliplatin and irinotecan, anti-vegf and anti- EGFR Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013 Kim T, Xu R, Yau T, et al. CONCUR: A randopmized, placebo-controlled phase 3 study of regorafenib monotherapy iin Asian patients withe previously treated metastatic colorectal cancer (abstract 500O). Data presented at the 2014 ESMO Congress, September 27, 2014, Madrid Spain. (abstract available online at (Accessed on December 04, 2014).

31 Cetuximab

32 Cetuximab A mouse/human chimeric monocloncal antibody MOA ADCC Inhibition of cell growth Induction of apoptosis

33 Cetuximab Benefit is restricted to patients with wild-type RAS mutation OS vs months Improvements in TTP and PFS Sobrero AF, Maurel J, Fehrenbacher L, et al. EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 2008 Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004 Van Cutsem E, Köhne CH, Hitre E, et al. Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 2009

34 Panitumumab Fully human monoclonal antibody specific to the extracellular domain of EGFR Similar efficacy to cetuximab but approved as monotherapy

35 Toxicities Panitumumab Severe IRR in the middle SE US Rash Magnesium wasting VTE

36 Regorafenib Oral inhibitory of VEGF 1-3 Approved in the third line OS 6.4 vs 5 months Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebocontrolled, phase 3 trial. Lancet 2013

37 TAS-102 On the horizon Increased survival (7.1 vs 5.3 months) in patients treated with all current agents Well tolerated Not yet approved Yoshino T, Mizunuma N, Yamazaki K, et al. TAS-102 monotherapy for pretreated metastatic colorectal cancer: a double-blind, randomised, placebo-controlled phase 2 trial. Lancet Oncol 2012 Van Cutsem E, Ohtsu A, Falcone A, et al. Phase III RECOURSE trial of TAS-102 vs placebo, with best supportive care, in patients with metastatic colorectal cancer (mcrc) refractory to standard therapies (abstract LBA13). Data presented at the 2014 ESMO Congress, September 27, 2014, Madrid, Spain. Abstract available online at (Accessed on December 04, 2014). Yoshino T, Mayer R, Falcone A, et al. Results of a multicentger, randomised, double-blind, phase III study of TAS-102 vs. placebo, with best supportive care, in patients with metastatic colorectal cancer (mcrc) refractory to standard therapies (RECOURSE). (abstract O-022). Data presented at the 16th ESMO World Congress on Gastrointestinal Cancer, June 28, 2014, Barcelona, Spain. Abstract available online at Improved-Survival-with-TAS-102-in-Metastatic-Colorectal-Cancer-Refractory-to- Standard-Therapies (Accessed on December 04, 2014).

38 How do you put it together Continuum of care model Continuous vs intermittent therapy

39 Thank you