Angiogenesis Targeted Therapies in Renal Cell Carcinoma

Transcription

1 Angiogenesis Targeted Therapies in Renal Cell Carcinoma John S. Lam, MD Department of Urology David Geffen School of Medicine University of California-Los Angeles

2 Patient Case CC: Abdominal pain VS: T 99.6, BP 146/90, HR 102 Assessment: Excessive fatigue in recent weeks

3 History History of present illness (HPI): 62-year-old female presents with abdominal pain associated with night sweats, early satiety, and 10 pound weight loss over the past 3 months Eastern Cooperative Oncology Group (ECOG) score = 0 Patient is taking no medications Patient has no known drug allergies Social history: married, denies use of tobacco and recreational drugs, social ETOH Family history includes a father with a history of prostate cancer ROS: otherwise normal

4 Physical Examination Physical Examination Alert and Oriented x 3 Well-built, well-nourished HEENT: WNL Neck: supple, no lymphadenopathy CV: S1, S2 present, no murmurs Pulmonary: bilateral clear to auscultation GI: soft, non-tender, non-distended, palpable right upper quadrant abdominal mass GU: WNL Extremities: warm without clubbing, cyanosis, edema Neuro: grossly intact

5 Laboratory Evaluation Laboratory evaluation WBC of 8,400/cu mm, hematocrit of 29.2 g/dl, and platelet count of 154,000/cu mm Electrolytes were within normal limits. Blood urea nitrogen was 22 mg/dl, and creatinine was 0.9 mg/dl Liver enzymes, alkaline phosphatase, albumin, and total bilirubin were within normal limits Urinalysis: 2+ blood, 20 RBC, 2 WBC

6 Imaging and Diagnosis Imaging Abdominal CT: A 9.5-cm-by-7.5-cm lobulated, enhancing soft tissue mass with extension into the renal vein The mass displaced the right kidney medially Enlarged retroperitoneal lymph nodes Chest CT: pulmonary metastases Bone Scan: negative MRI brain: negative Biopsy: clear cell RCC

7 Patient Case

8 Patient Case

9 Patient Case Lung nodule

10 Patient Case Pathology Clear cell RCC Fuhrman grade 3 Size: 10 cm Renal vein involvement Margin negative 25% tumor necrosis Collecting system involvement CA IX: 95% positive Lymph nodes negative pt3b N0 M1

11 Multitargeted Approaches in mrcc: Sunitinib (SU11248) Small-molecule receptor tyrosine kinase inhibitor Inhibits all VEGFRs, PDGFR-A, PDGFR-B, c-kit, and FLT-3 Oral administration Both antitumor and antiangiogenic activity FDA approved January 26, 2006 for treatment of advanced RCC Receptors VEGFR-1 VEGFR-2 PDGFR c-kit FGFR-1 EGFR IC 50 nm F H 3 C N H O N H O N H CH 3 N CH 3 CH 3 FGFR-1=fibroblast growth factor receptor; FLT-3=FMS-like kinase 3.

12 Sunitinib (SU11248) for Renal Cell Carcinoma: Rationale for Receptor Targeted Therapy Mutant VHL Stabilizes HIF-1 Clear Cell Carcinoma Binds to hypoxia regulated region on VEGF and PDGF genes PDGF & VEGF VEGF PDGF SU11248 Substrate Substrate P X R2 R2 P K K P P P VEGFR X Endothelial (Tumor) Cell Membrane Endothelial cell proliferation Pericyte proliferation Tumor proliferation X R1 R1 P K K P P P P P PDGFR X X SU11248 Substrate Substrate P Tumor Vasculature Development and Proliferation

13 Phase II Evaluation of Sunitinib in mrcc Two independent, single-arm, multicenter, phase II trials (trial 014: N=63; trial 1006: N=106) Patients with advanced disease and failure of prior cytokine therapy Sunitinib Continue sunitinib treatment unless progression or intolerability Dosing schedule 4 weeks on, 2 week off (4/2) Sunitinib 50 mg/day* Sunitinib *Dose reduction permitted (to 37.5 mg/day and then to 25 mg/day)

14 Sunitinib in mrcc: Hand-Foot Syndrome Hand-foot syndrome All grades Grade 3 12% 3%

15 Patient Case Lung nodule

16 Efficacy of Sunitinib in Phase II Trial as 2 nd -line Therapy After Cytokine Progression (N=105)* Overall response CR PR Stable disease 3 months Median PFS Investigator assessment 44% 1% 43% 22% 8.1 months Independent central review 34% 0% 34% 29% 8.3 months CR=complete response; PR=partial response; PFS=progression-free survival Motzer RJ, et al. JAMA 2006;295:

17 40 20 Sunitinib (SU11248) for RCC: Trial 1 Maximum % Reduction of Target Lesions by Patient Partial responders by RECIST SD/PD patients % change from baseline

18 Duration of Response Trials 1 and 2 Proportion of Patients Progression Free Median TTP trial 1: 8.7 months Median PFS trial 2: 8.1 months Pooled analysis: 8.2 months (95% CI: 7.8, 10.4) Sunitinib Therapy (months) Motzer RJ, et al. JAMA 2006;295:

19 Objective Response to Sunitinib in Patients with mrcc Response, n (%) Study 014 (N=63) Study 1006* (N=105) Pooled analysis (N=168) Overall response CR PR 25 (40) 0 25 (40) 46 (44) 1 (1) 45 (43) 71 (42) 1 (1) 70 (42) SD 3 months 17 (27) 23 (22) 40 (24) PD, SD <3 months or not evaluable 21 (33) 36 (34) 57 (34) * Study ongoing Motzer RJ, et al. JAMA 2006;295:

20 Progression-Free Survival by Response Trials 1 and 2 Responder SD 3 months SD <3 months, PD or NE Patients (n) Median PFS (months) % CI SD=stable disease, PD=progressive disease, NE = not evaluable, PFS=progression-free survival Motzer RJ, et al. JAMA 2006;295:

21 Treatment-related Adverse Events Incidence (%) Grade 2 Grade 3 Total Event Trial 1 Trial 2 Trial 1 Trial 2 Trial 1 Trial 2 Fatigue Diarrhea Dyspepsia Nausea Stomatitis Hypertension Vomiting Anorexia Hand-foot syndrome 0* 8 0* * Hand foot syndrome initially classified as dermatitis, rash or neurotoxicity before being recognized as a unique toxicity

22 Original Article Sunitinib versus Interferon Alfa in Metastatic Renal-Cell Carcinoma Robert J. Motzer, M.D., Thomas E. Hutson, D.O., Pharm.D., Piotr Tomczak, M.D., M. Dror Michaelson, M.D., Ph.D., Ronald M. Bukowski, M.D., Olivier Rixe, M.D., Ph.D., Stéphane Oudard, M.D., Ph.D., Sylvie Negrier, M.D., Ph.D., Cezary Szczylik, M.D., Ph.D., Sindy T. Kim, B.S., Isan Chen, M.D., Paul W. Bycott, Dr.P.H., Charles M. Baum, M.D., Ph.D., and Robert A. Figlin, M.D. N Engl J Med Volume 356(2): January 11, 2007

23 Phase III Trial of Sunitinib vs. Interferon-α in First-Line Treatment for mrcc Randomized, open-label, multicenter trial (100 sites: US, Canada, Europe, Australia, and Brazil) Endpoints: progression-free survival, overall survival, and response rate 1:1 Randomization N=750 Sunitinib: orally administered daily (schedule 4/2) IFN-α: administered TIW

24 Phase III Trial: Best Response by RECIST Investigator Assessment Response Pts with measurable disease at baseline (n) Objective response* Complete response Partial response Sunitinib (37%) IFN-α (9%) 0 33 Stable disease Progressive disease/ Not evaluable 176 (47%) 61 (16%) 213 (57%) 127 (34%) *Sunitinib vs. IFN-α: P <

25 Phase III Trial: Best Response by RECIST Independent Central Review Response Pts with measurable disease at baseline* (n) Objective response** Complete response Partial response Stable disease Progressive disease/ Not evaluable Sunitinib (31%) (48%) 72 (21%) IFN-α (6%) (49%) 147 (45%) *88 patients not yet assessed by central review **Sunitinib vs. IFN-α: P <

26 Phase III Trial: Progression-Free Survival Independent Central Review Progression Free Survival Probability Hazard Ratio = (95% CI: ) P < Sunitinib Median: 11 months (95% CI: 10 12) IFN-α Median: 5 months (95% CI: 4 6) Time (months) No. at Risk Sunitinib: No. at Risk IFN-α:

27 Baseline factor Sunitinib vs. IFN-α treatment effect, without adjusting for risk factors Phase III: Subgroup Analysis Progression-Free Survival* N 750 Prior nephrectomy 673 Sunitinib benefit IFN-α benefit Absence of prior nephrectomy 77 ECOG=0 456 ECOG=1 294 LDH 1.5xULN 716 LDH >1.5xULN 34 Time since diagnosis 1 year 344 Time since diagnosis <1 year 391 Hgb <LLN 219 Hgb LLN 515 Serum corrected Ca 10 mg/dl 688 Serum corrected Ca >10 mg/dl 46 *Independent Central Review Hazard ratio (95% CI)

28 Phase III Study: Progression-Free Survival by MSKCC Risk Status* Independent Central Review MSKCC Risk Factors: 0 (Favorable) MSKCC Risk Factors: 1-2 (Intermediate) Progression Free Survival Probability Hazard Ratio=0.371 (95% CI: ) Sunitinib (n=143) Median not reached IFN-α (n=121) Median: 8 months (95% CI: 7 NA) Progression Free Survival Probability Hazard Ratio=0.388 (95% CI: ) Sunitinib (n=209) Median: 11 months (95% CI: 11 11) IFN-α (n=212) Median: 4 months (95% CI: 3 4) Time (months) Time (months) *Motzer et al. JCO 2002;20: ; Excludes 17 pts from IFN-α with missing data

29 Phase III Study: Treatment-Related Adverse Events Event Fatigue Diarrhea Nausea Stomatitis Hypertension Hand-foot syndrome Ejection fraction decline Pyrexia Chills Myalgia Flu-like symptoms Sunitinib (%) All grade Grade 3/ * * 20 5* <1 1 0 IFN-α (%) All grade Grade 3/ /<1* <1 1 < <1 8 <1 * Greater frequency, P <0.05

30 Phase III Study: Outcome Summary Median Progression-free survival*, mos (95% CI) Independent review Investigator Objective response*, % (95% CI) Independent review Investigator Safety Patient-reported outcomes Sunitinib 11 (10-12) 11 (8-14) 31 (26-36) 37 (32-42) Acceptable Superior IFN-α 5 (4-6) 4 (4-5) 6 (4-9) 9 (6-12) * Sunitinib vs. IFN-α: P <

31 Targeted Therapy for RCC Conclusions Sunitinib shows activity in second-line therapy Randomized phase III pivotal trial of sunitinib show benefit over interferon in first-line therapy Future trials will include new combinations and comparisons of targeted agents Studies of tumor biology to identify markers of response are a priority