APPLICAZIONI CLINICHE DEL BEVACIZUMAB

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1 INNOVAZIONI TERAPEUTICHE IN ONCOLOGIA MEDICA Prof. Giovanni Mantovani Cagliari, giugno 2005 APPLICAZIONI CLINICHE DEL BEVACIZUMAB Prof. Giuseppe Colucci Dipartimento di Oncologia Medica IRCCS Oncologico - BARI

2 BEVACIZUMAB (AVASTIN) A recombinant humanized anti-vegf MAb - human IgG1 framework with antigenbinding regions from a murine Mab (mubab VEGF A.4.6.1) - 93% human & 7% mouse Binds all forms of VEGF and prevents receptor binding Effectively depletes circulating VEGF Terminal half-life, days

3 PHASE II TRIAL OF AVASTIN PLUS 5-FU / LEUCOVORIN IN METASTATIC COLORECTAL CANCER 5-FU/LV (n=36) PD Previously untreated 5-FU/LV + Avastin MCRC 5mg/kg q2w (n (n=35) = 104) PD Optional: Avastin 10 mg/kg q2w 5-FU/LV + Avastin 10 mg/kg q2w (n=33) PD Primary end point: TTP and RR 5-FU and LV administered at: 500 mg/mq IV every week x 6 (repeat q8w) Kabbinavar et al., J Clin Oncol, 2003

4 PHASE II TRIAL IN MCRC: EFFICACY SUMMARY 5FU/LV 5mg/kg q2w 10mg/kg q2w Pooled (n=36) (n=35) (n=33) (n=68) Median TTP (mo) P value, log-rank* Confirmed RR (%) P value, X 2 * Median Survival (mo) P value * Compared with control Kabbinavar et al.; JCO, 2003

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6 AVASTIN IN MCRC: CONCLUSIONS FROM PHASE II, CONSIDERATIONS FOR PHASE III Efficacy: - The addition of Avastin to 5-FU/LV - Increased response rate - Prolonged both time to progression and survival - Benefit seen at both dose levels (greater at 5 mg/kg q2w) Safety: - Generally well-tolerated / safe - Four potential Avastin related safety signals: - Hypertension - Proteinuria - Thrombosis - Bleeding

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9 PHASE III TRIAL IN MCRC: ENDPOINTS Primary endpoints - Duration of survival Additional endpoints - Response rate (PR + CR) - Progression free survival - Response duration - Quality of life - Safety

10 PHASE III TRIAL: BASELINE CHARACTERISTICS IFL + Placebo IFL + Avastin (n=412) (n=403) Age median (range) 59.2 yrs (21-83) 59.2 yrs (23-86) Race: white black other 80% 11% 9% 79% 12% 9% ECOG: % 44% 0.5% 59% 41% 0.2% Adjuvant therapy: chemotherapy 27% 24% radiation Primary disease: colon rectum Gender: male female 14% 81% 19% 60% 40% 14% 77% 23% 59% 41%

11 PHAE III TRIAL: EFFICACY SUMMARY IFL + Placebo IFL + Avastin (n=412) (n=403) P value Median survival (mo) PFS (mo) ORR (%) CR PR Duration of response (mo) <

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15 Post-progression therapy effect on survival in AVF2107 1st-line PFS OS (mos) No OX-PTT(122) 5,8 14,8 IFL/pbo (411) 6,2 15,6.001 Ox-PTT (109) 7,4 22,2 No Ox-PTT (125) 9,1 19,6 IFL/BV (402) 10,6 20,3.005 Ox-PTT (97) 9,4 25,1 E.E.Hedrick, H.Hurwitz, ASCO 2004 (3517)

16 EFFICACY END POINT RESULTS Efficacy End Point IFL/Placebo FU/LV/BV (n = 100) (n=110) Median survival months Hazard ratio P value Median progr.-free survival, months Hazard ratio P value Objective response rate, CR + PR % P value Duration of response, months Median 95% CI to to Hurwitz, JCO 2005

17 ADVERSE EVENTS DURING FIRST-LINE THERAPY: PATIENTS WITH ADVERSE EVENTS OF ANY GRADE WITH > 10% DIFFERENCE BETWEEN TREATMENT ARMS IN EVENT RATES Efficacy End Point Cardiovascular Hypertension Hypertension, grade 3 Hematologic/lymphatic Leukopenia Leukopenia, grade 3 or 4 Epistaxis Skin/appendages Alopecia Dry skin Exofoliative dermatitis Skin discoloration Special senses Taste perversion Lacrimation disorder IFL/Placebo FU/LV/BV (n = 100) (n=110) N. PTS % N.PTS % Hurwitz, JCO 2005

18 PLANNED PHASE III TRIAL OF AVASTIN WITH OXALIPLATIN-BASED THERAPY IN FIRST-LINE MCR: SWOG Avastin 7.5 mg/kg q 3w Previously untreated MCRC (n = 2200) Primary end point: Survival XELOX FOLFOX-6 + Placebo + Avastin 5 mg/kg q 3w + Placebo

19 ADJUVANT CR TRIAL: NSABP C-08 + Avastin PD FLOX - Avastin PD Stage II and stage III CRC (n = 5015) FOLFOX + Avastin - Avastin PD PD CAPOX + Avastin - Avastin PD PD Proposed trial will assess clinical benefit of adding Avastin to different adjuvant therapies for the treatment of stage II or stage III CRC

20 CONCLUSIONI L Avastin è sicuramente un farmaco attivo ed efficace nel CRC Bisogna usarlo con prudenza in pazienti selezionati Non è la risoluzione del problema Diversi studi hanno dimostrato che è attivo anche in altri tumori (polmone, mammella, ovaio )