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HS Hochster

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  1. HS Hochster Safety and efficacy of oxaliplatin–fluoropyrimidine regimens with or without bevacizumab as first-line treatment of metastatic colorectal cancer (mCRC):Final analysis of the TREE study H. S. Hochster, L. L. Hart, R. K. Ramanathan, J. D. Hainsworth, S. Griffing, R. D. Mass, Y. Nagarwala, G. Jirau-Lucca, A. Shpilsky, B. H. Childs

  2. Background • Oxaliplatin–fluoropyrimidine regimens:standard combination chemotherapy for stage III and IV CRC • TREE-1 trial: comparison of three different oxaliplatin–fluoropyrimidine regimens (mFOLFOX, bFOL, CapeOx) for toxicity • Bevacizumab: promising results in mCRC when added to first-line chemotherapy (bIFL or 5-FU–LV)1,2 • TREE-2 trial: TREE-1 trial modified to include bevacizumab 1. Hurwitz H, et al. N Engl J Med 2004; 2. Kabbinavar F, et al. J Clin Oncol 2003

  3. Study design TREE-2 TREE-1 mFOLFOX mFOLFOX + bevacizumab (n=50) (n=75) n=223 n=150 bFOL +bevacizumab bFOL R R (n=50) (n=74) CapeOx(reduced dose)+ bevacizumab CapeOx (n=50) (n=74) Nov 2002 – Oct 2003 Nov 2003 – Apr 2004

  4. Treatment regimens: TREE-1 mFOLFOX6: 14-day cycle Day 1 Day 2 5-FU (400 mg/m2, IV bolus) LV (350 mg IV, 2 h) OX (85 mg/m2 IV, 2 h) 5-FU (2400 mg/m2 IV, 46 h) bFOL: 28-day cycle Day 1 Day 8 Day 15 LV (20 mg/m2, IV bolus) 5-FU (500 mg/m2, IV bolus) OX (85 mg/m2 IV, 2 h) OX (85 mg/m2 IV, 2 h) CapeOx: 21-day cycle Day 1 Days 1–15 CAPE (1000 mg/m2orally bida) OX (130 mg/m2 IV, 2 h) a28 doses in total

  5. Treatment regimens: TREE-2 mFOLFOX6 + bev: 14-day cycle Day 1 Day 2 5-FU (400 mg/m2, IV bolus) LV (350 mg IV, 2 h) BEV (5 mg/kg IV, 30–90 min) OX (85 mg/m2 IV, 2 h) 5-FU (2400 mg/m2 IV, 46 h) bFOL + bev: 28-day cycle Day 1 Day 8 Day 15 LV (20 mg/m2, IV bolus) 5-FU (500 mg/m2, IV bolus) BEV (5 mg/kg IV, 30–90 min) OX (85 mg/m2IV, 2 h) BEV (5 mg/kg IV, 30–90 min) OX (85 mg/m2 IV, 2 h) CapeOx + bev: 21-day cycle Day 1 Days 1–15 CAPE (850 mg/m2orally bida) BEV (7.5 mg/kg IV, 30–90 min) OX (130 mg/m2 IV, 2 h) a28 doses in total; 650 mg/m2 bid for patients with creatinine clearance 30–50 mL/min

  6. Inclusion criteria • Histologically documented adenocarcinoma of the colon or rectum • Inoperable metastatic disease • No prior chemotherapy for metastatic/recurrent disease • Age ≥18 years; ECOG performance status 0–1 • At least 1 unidimensional measurable lesion

  7. Exclusion criteria • Prior treatment with oxaliplatin or bevacizumab • Myocardial infarction within 6 months, current clinical evidence of congestive heart failure, or non-stable coronary artery disease • Blood pressure >160/110 mmHg on medication; symptomatic peripheral vascular diseasea • Peripheral neuropathy aTREE-2 cohort only

  8. Objectives • Primary: • Incidence of grade 3/4 toxicity during initial 12 weeksof therapy • Secondary: • Response rate (RECIST) • TTP (censored for second-line treatment) • TTF (treatment discontinuation, progression, or death) • Survival

  9. Demographic and baseline characteristicsa aWith the exception of tumor response, all data are presented for the as-treated population, defined as all patients who received at least one dose of treatment

  10. Grade 3/4 adverse events during first 12 weeks aDetermined by the investigator to be related (possibly or probably) to study drug

  11. Grade 3/4 adverse events occurring in ≥5% of patients aThe high incidence of dehydration and diarrhea in the CapeOx arm in TREE-1 was effectively reducedby capecitabine dose reduction in TREE-2. TE, Thromboembolic events

  12. Adverse events of special interest

  13. Best confirmed tumor response (per-protocol population)a aAll patients who received at least 1 treatment with oxaliplatinfluoropyrimidine ± bevacizumab and who have sufficient data to allow assessment of response

  14. CapeOx+ bev (n=72) mFOLFOX+ bev (n=71) bFOL+ bev (n=70) 1.0 1.0 0.8 5.5 5.5 5.8 6.5 4.9 4.4 0.8 4.7–6.5 4.0–6.6 4.9–6.7 0.6 Probability mFOLFOX + bevacizumab bFOL + bevacizumab CapeOx + bevacizumab mFOLFOX bFOL CapeOx 0.6 0.4 Probability 0.2 0.4 0 0 5 10 15 20 25 0 5 10 15 20 25 Time to treatment failure (months) Time to treatment failure (months) 0.2 mFOLFOX (n=49) bFOL (n=50) CapeOx (n=48) 0 Median (months) Median (months) 95% CI 5.4–8.3 3.5–6.1 3.0–5.8 95% CI Time to treatment failure TREE-1 TREE-2

  15. mFOLFOX+ bev (n=71) mFOLFOX (n=49) bFOL+ bev (n=70) bFOL (n=50) CapeOx (n=48) CapeOx+ bev (n=72) 1.0 1.0 Median (months) Median (months) 8.7 9.9 6.9 8.3 10.3 5.9 95% CI 95% CI 7.9–11.7 6.5–9.8 6.6–9.9 4.2–8.0 5.1–7.4 8.6–12.5 0.8 0.8 0.6 0.6 mFOLFOX + bevacizumab bFOL + bevacizumab CapeOx + bevacizumab mFOLFOX bFOL CapeOx Probability Probability 0.4 0.4 0.2 0.2 0 0 0 5 10 15 20 25 0 5 10 15 20 25 Time to tumor progression (months) Time to tumor progression (months) Time to tumor progressiona TREE-1 TREE-2 aWith censoring for second-line treatment

  16. 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0 0 5 10 15 20 25 30 35 40 Survival time (months) Survival: TREE-1 CapeOx (n=48) mFOLFOX (n=49) bFOL (n=50) Median (months) 19.2 17.9 17.2 95% CI 14.2–24.2 11.5–24.6 12.5–22.3 CapeOx mFOLFOX bFOL

  17. 1.0 0.9 0.8 0.7 0.6 Probability 0.5 0.4 0.3 0.2 0.1 0 0 5 10 15 20 25 30 35 40 Survival time (months) Survival: TREE-2 mFOLFOX+ bev (n=71) bFOL+ bev (n=70) CapeOx+ bev (n=72) Median (months) 26.0 20.7 27.0 95% CI 18.0–NE 18.8–25.3 21.8–NE CapeOx + bevacizumab mFOLFOX + bevacizumab bFOL + bevacizumab NE, not evaluable

  18. Survival: chemotherapy regimens combined

  19. Survival: oxaliplatin-based regimens combineda TREE-1 (n=147) TREE-2 (n=213) 1.0 0.9 Median survival (months) 18.2 24.4 0.8 95% CI 14.5–21.6 21.4–26.8 0.7 0.6 Probability 0.5 0.4 TREE-1 TREE-2 0.3 0.2 0.1 0 0 5 10 15 20 25 30 35 40 Survival time (months) aSequential cohorts without (TREE-1) and with bevacizumab (TREE-2)

  20. Efficacy summary aPer-protocol population. bCensored for second-line therapy. cAll three treatment arms combined

  21. Conclusions (1) • Oxaliplatin, in combination with bolus, infusional, or oral fluoropyrimidine regimens, is active and well tolerated in previously untreated mCRC • No major differences in activity were observed between the three fluoropyrimidine regimen, but bFOL may be the least efficacious (response and TTP in both cohorts) • With dose reductiona of capecitabine, CapeOx with bevacizumab was tolerated much better (compared with CapeOX in TREE-1) • equivalent activity to FOLFOX with bevacizumab aFrom 1000 mg/m2 (TREE-1) to 850 mg/m2 orally bid (TREE-2),

  22. Conclusions (2) • Bevacizumab, when added to oxaliplatin–fluoropyrimidine regimens results in increased efficacy with the expected toxicity profile • Addition of bevacizumab did not change TTF but improved TTP • Overall survival was improved with the addition of bevacizumab (sequential historical cohorts) • Median survival time was: 18.2 months in TREE-1a (95% CI:14.5–21.6 months) 24.4 months in TREE-2a (95% CI: 21.4–26.8 months) aAll three treatment arms combined

  23. Investigators Lowell Hart, Florida Cancer Specialists R. Ramanathan, Univ Pittsburgh John Hainsworth, Sarah Cannon Cancer Center Louis Fehrenbacher, Kaiser Permanente Yusif Abubakr, Florida Oncology Lee Schwartzberg, West Cancer Clinic Peter Eisenberg, California Cancer Care James Atkins, Southeastern Medical Oncology Maunuel Modiano, Arizona Clinical Research Center Marshall Levine, Greater Baltimore Medical Center Joaquina Veranda, Kansas City VA Hospital Gladys Rodriguez, South Texas Oncology Michael Wertheim, Treasure Coast George Geils, Charleston Hematology Oncology Margaret Deutsch, Raleigh Hematology Oncology Renato LaRocca, Kentuckiana Cancer Institute David Mintzer, Pennsylvania Hematology Oncology Other investigators sanofi aventis Gilbert Jirau-Lucca, MS Arkady Shpilsky, PhD Yasir Nagarwala Lauri Wells, MD Barry Childs, MD Genentech Robert Mass, MD Eric Hedrick, MD David Emanuel, MD OTHERS Nursing personnel Data Personnel Research Staff PATIENTS Acknowledgment