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Bevacizumab in combination with capecitabine for the first-line treatment of elderly patients with metastatic colorectal cancer ( mCRC ): Results of a randomized international phase III trial (AVEX).

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  1. Bevacizumab in combination with capecitabine for the first-line treatment of elderly patients with metastatic colorectal cancer (mCRC): Results of a randomized international phase III trial (AVEX) David Cunningham,1Istvan Lang,2 Eugenio Marcuello,3 Vito Lorusso,4Janja Ocvirk,5 Dong Bok Shin,6 Derek Jonker,7 Stuart Osborne,8Niko Andre,9 Daniel Waterkamp,8 Mark P. Saunders10 1Royal Marsden Hospital, London and Surrey, United Kingdom; 2National Institute of Oncology, Budapest, Hungary; 3Hospital de Sant Pau de Barcelona, Barcelona, Spain; 4National Cancer Institute "Giovanni Paolo II" Bari, Italy; 5Department of Medical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia; 6Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Korea; 7Department of Medical Oncology, The Ottawa Hospital, Ottawa, Ontario, Canada; 8F. Hoffmann-La Roche Ltd, Basel, Switzerland; 9Roche Pharma AG, Grenzach-Wyhlen, Germany; 10Christie Hospital, Withington, Manchester, United Kingdom

  2. Disclosures • David Cunningham • Research funding from F. Hoffmann-La Roche Ltd., Merck KGaA, Novartis, Celgene, Amgen, and AstraZeneca

  3. Background and rationale • Although the median age of patients diagnosed with mCRC is 69 years, older patients are in general undertreated and the optimal treatment approach still needs to be evaluated1,2 • Bevacizumab (BEV) is a standard of care in mCRC3-5 and prior analyses have suggested that elderly patients benefit from the addition of BEV to chemotherapy6-8 • AVEX is the first phase III trial to prospectively evaluate the use of a biologic in an elderly patient population with mCRC 1Howlader N, et al. http://seer.cancer.gov/csr/1975_2009_pops09; 2Golfinopoulos V, et al. Cancer Treat Rev. 2006;32:1–8; 3Hurwitz H, et al. N Engl J Med. 2004;350:2335–42; 4Giantonio BJ, et al. J ClinOncol. 2007;25:1539–44; 5Bennouna J, et al. Lancet Oncol. 2013;14:29–37; 6Cassidy J, et al. J Cancer Res ClinOncol. 2010;136:737–43; 7Kozloff MF, et al. Oncology. 2010;78:329–39; 8Price TJ, et al. Ann Oncol. 2012;23:1531–6.

  4. Study design Capecitabine 1000 mg/m2 b.i.d. days 1–14, q21d + Bevacizumab 7.5 mg/kg day 1, q21d Stratification factors: • ECOG PS (0–1 vs 2) • Geographic region Previously untreated mCRC, age 70 yearsN=280 Randomize 1:1 Capecitabine 1000 mg/m2 b.i.d. days 1–14, q21d • Key inclusion criteria • ECOG PS 0–2 • Prior adjuvant chemotherapy allowed if completed >6 month before inclusion • Not optimal candidates for a combination chemotherapy with irinotecan or oxaliplatin • Key exclusion criteria • Prior chemotherapy for mCRC or prior adjuvant anti-VEGF treatment • Clinically significant cardiovascular disease • Current or recent use of aspirin (>325 mg/day) or other NSAID • Use of full-dose anticoagulants or thrombolytic agents

  5. Statistical considerations • Primary endpoint: PFS • Secondary endpoints: ORR, time to response, duration of response, OS, safety • Designed to detect a 31% reduction in the risk of progression (HR 0.69) • 232 events required to achieve 80% power for a 2-sided test at the 5% level • PFS/OS curves estimated using Kaplan-Meier method, differences assessed using unstratified log-rank tests • Stratified Cox regression model used to estimate HR HR = hazard ratio; PFS = progression-free survival; ORR = overall response rate; OS = overall survival

  6. Select baseline patient characteristics ITT population. Cape = capecitabine; ECOG PS = Eastern Cooperative Group performance status.

  7. Progression-free survival Cape + BEV (n=140) Cape (n=140) 1.0 HR=0.53 (95% CI: 0.41–0.69) P<0.001 0.8 PFS estimate 0.6 0.4 5.1 mo 9.1 mo 0.2 0.0 Time (months) Number at risk Cape + BEV 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 140 121 99 80 68 55 41 28 23 16 13 9 8 3 2 2 2 2 1 0 0 Cape 140 109 82 56 38 25 13 9 6 4 4 2 1 1 1 1 1 1 1 1 0 ITT population. 113 PFS events in the Cape + BEV arm; 127 PFS events in the Cape arm. CI = confidence interval; PFS = progression-free survival

  8. Subgroup analysis of PFS Cape + BEV better Cape alone better HR 0 0.6 1 2 ITT population.

  9. Overall survival Cape + BEV (n=140) Cape (n=140) HR=0.79 (95% CI: 0.57–1.09) P=0.182 1.0 0.8 OS estimate 0.6 0.4 16.8 mo 20.7 mo 0.2 0.0 Time (months) Number at risk Cape + BEV 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 2 0 140 126 120 106 95 89 81 67 60 51 44 40 34 24 16 15 12 10 8 6 5 4 Cape 1 0 140 120 108 94 85 73 62 57 49 37 33 23 19 13 11 10 9 7 6 5 5 3 ITT population. 75 OS events in each treatment arm.

  10. Subsequent therapies ITT population.

  11. Overall response rate ITT population. CR = complete response; PD = disease progression; PR = partial response; SD = stable disease.

  12. Study drug exposure Median treatment duration (months) Safety population.

  13. Overview of adverse events Safety population. AE = adverse event; SAE = severe adverse event.

  14. AEs of special interest to BEV Safety population. GI = gastrointestinal; RPLS = reverse posterior leukoencephalopathy syndrome.

  15. AEs related to chemotherapy occurring in ≥5% of patients in the Cape + BEV arm (selected) Safety population. Not listed: decreased appetite, abdominal pain, constipation, pyrexia, epistaxis, mucosal inflammation, lethargy, arthralgia, peripheral oedema, pain in extremity, pain, musculoskeletal pain, skin hyperpigmentation, dizziness, headache, upper abdominal pain, dyspepsia, pulmonary embolism, dry skin, paraesthesia, rhinorrhoea.

  16. Conclusion • AVEX is the first phase III trial to prospectively evaluate the use of a biologic in mCRC patients ≥70 years, a population that is in general undertreated • The addition of BEV to cape significantly improved PFS and ORR • PFS 9.1 vs 5.1 months (HR0.53;p<0.001) • ORR 19.3% vs 10.0% (p=0.042) • A numerically longer OS was observed in the BEV-containing arm, but this did not reach statistical significance • The safety profile was consistent with previously reported data of BEV in mCRC • Results from AVEX suggest that the combination of BEV and cape is an effective and well-tolerated regimen for patients ≥70 years with mCRC

  17. Acknowledgments • The authors would like to thank the patients and their families, the study investigators, study coordinators and nurses AVEX Study Investigators Austria Greil R Ludwig H Nitsche D Canada Berry S Brezden-Masley C Dowden S Jeyakumar A Jonker D Lohrisch C Welch S Hungary Dank M Lang I Pintér T Ruzsa A Italy Boni C Di Costanzo F Lorusso V Zeuli M Mexico Leon Rodríguez E Magallanes-Maciel M Poland Deptala A Koralewski P Slovenia Ocvirk J South Korea Park J-H Park Y-S Shin D-B Shin S-J Spain Alonso JD Anton Torres A Duenas Garcia R Marcuello E United Kingdom Cleator S Cunningham D Gollins S Hopkins K Potter V Saunders M Sizer B Steward W Waterston A

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