Rationale for VEGFR-targeted Therapy in RCC

Transcription

1 Rationale for VEGFR-targeted Therapy in RCC EIKCS, Budapest, May 2013 Tim Eisen

2 Tim Eisen - Disclosures Company Research Support Advisory Board Trial Management Group Honoraria Astra Zeneca Astellas + + Aveo Bayer GSK Immatics + Pfizer Roche + +

3 Proportion of patients with recurrence (%) Adjuvant therapy: a key unmet need We need effective therapies in the adjuvant setting RCC recurs in ~20 60% of patients post-nephrectomy, 1,2 Incidence and time to recurrence depend on risk score 2,3 Median time to recurrence 5 9 months in patients with ptxn+ tumours months in patients with pt1 tumours *Kassouf et al reported data from multiple studies; within each tumour type, each bar represents a different study pt1 pt2 pt3 ptxn+ Tumour type pre-nephrectomy* Lam JS et al. Curr Urol Rep 2005;6:7 18; 2. Eisen T et al. Eur Urol Suppl 2007;6:492 8; 3. Kassouf W et al. Can Urol Assoc J 2009;3:73 6.

4 Metastases-free survival after resection Leibovich BC et al. Cancer 2003;97:

5 Angiogenesis is one of many steps leading to metastasis Fidler & Ellis, Nature Medicine (2000)

6 Ferrara & Kerbel, Nature 2005 Angiogenesis Key Pathways Tumour growth requires angiogenesis Interacting network of signals Positive & negative regulators Signals from various cell types Signals to various cell types Endothelial cells proliferate, migrate & form new vessels Pericytes stabilise vasculature

7 Poorly understood VEGFR inhibitor effects Direct effect on tumour Immunomodulation Inflammation Tumour immunity Off target effects of small molecules

8 Lessons from colorectal cancer Results have been reported for two Phase III trials of adjuvant bevacizumab in colorectal cancer: NSABP C-08 1 mfolfox6 mfolfox6 + bevacizumab Bevacizumab administered 1 year AVANT 2 FOLFOX4 FOLFOX4 + bevacizumab XELOX + bevacizumab Bevacizumab administered 48 wks Neither study met its primary endpoint However are there still lessons that we can learn? 1. Allegra CJ et al. J Clin Oncol 2011, De Gramont A et al. Lancet Oncol 2012;.

9 AVANT study design FOLFOX4 (24 weeks) Resected colon cancer (high-risk stage II and stage III) (n=3450) FOLFOX4 (24 weeks) Bevacizumab 5 mg/kg q2w with chemotherapy and 7.5 mg/kg q3w monotherapy (48 weeks) XELOX4 (24 weeks) Bevacizumab 7.5 mg/kg q3w (48 weeks) Primary endpoint: DFS Secondary endpoints: OS, safety De Gramont A et al. Lancet Oncology 2012.

10 De Gramont A et al. Lancet Oncol Disease-free survival in AVANT Disease-free survival at 1 year Disease-free survival at 3 years FOLFOX4 + bevacizumab XELOX + bevacizumab Favours bevacizumab addition Favours chemo only Favours bevacizumab addition Favours chemo only

11 Post-operative bevacizumab in ovarian/peritoneal/fallopian tube cancer RANDOMIZE 1:1:1 Primary endpoint: Progression-free survival Secondary endpoints: Overall survival, safety, QoL Inclusion criteria: Patients with epithelial ovarian, primary peritoneal or fallopian tube cancer Disease stage after debulking surgery: Stage III optimal or suboptimal; Stage IV Less than 1 12 weeks since debulking surgery No prior chemotherapy N = 1873 Cytotoxic therapy (6 cycles) Maintenance Carboplatin AUC 6 + paclitaxel 175 mg/m 2 + Placebo + Bevacizumab (15 mg/kg) + Bevacizumab (15 mg/kg) therapy (16 cycles) Placebo Placebo Bevacizumab (15 mg/kg) QoL, quality of life. Burger RA et al. J Clin Oncol 2010;28:abstract LBA1.

12 Key findings in ovarian/peritoneal/fallopian tube cancer Three-arm Phase III study of 1st-line systemic therapy after debulking surgery in advanced epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer Regimen 1: Standard chemotherapy + placebo, then maintenance placebo Regimen 2: Standard chemotherapy + Bev, then maintenance placebo Regimen 3. Standard chemotherapy + Bev, then maintenance Bev Significantly lower risk of 1st progression/death in patients with maintenance bevacizumab (regimen 3 vs regimen 1; p < ) Trend toward lower risk of 1st progression/death with regimen 2 vs regimen 1 Hazard ratio Favours add-on bevacizumab Favours standard therapy Bev, bevacizumab Burger RA et al. J Clin Oncol 2010;28.

13 ...but there are limitations to cross-study and cross-tumour comparisons Biology can vary considerably between tumour types Outcome with one particular agent may not indicate outcome with a different agent CRC and ovarian cancer studies added bevacizumab to existing adjuvant regimen In RCC, there is no approved adjuvant regimen; studies are evaluating antiangiogenic agents as monotherapy Adjuvant data in RCC are urgently needed and eagerly awaited!

14 Many questions to consider Do we need to inhibit VEGFR as potently in micrometastases as strongly as in macrometastases? Is long-term low dose VEGFR inhibition the way to go? Novel immunotherapeutic options Other modalities

15 MAMS vs traditional Traditional Approach Multi-arm, Multi-stage Phase II T1 T2 T3 T4 C T1 T2 T3 T4 Phase II C T1 Phase III C T3 C T4 Phase III