Positioning Antiangiogenesis Drugs and Other Agents in Renal Cell Cancer Treatment Ahmad Awada, MD, PhD Medical Oncology Clinic Institut Jules Bordet Université Libre de Bruxelles (U.L.B.) Brussels, Belgium
RCC : Pathology Clear cell (75-85%) Proximal tubule origin Deletion in chromosome 3p Papillary (15%) 85% of these are Dx as stage I tumors Prox tubule origin, but 3p is normal Trisomy 12, 16, 20 can be seen Chromophobic (5%) Oncocytic (uncommon) usually not aggressive Collecting duct origin 11q13 rearrangements in some cases Collecting duct (Bellini s duct) tumors. Rare Unclassifiable (<3%)
International Kidney Cancer Working Group : Prognostic Factors for Survival 1 Prognostic Factors Risk Groups : Survival Group Med. OS Good Risk 27.8 mos Interm Risk 11.4 mos Poor Risk 4.1 mos 3748 untreated RCC patients from 11 centers in US and Europe 1 IKCWG, ASCO, 2007
Treatment mrcc before the era of antiangiogenic agents Nephrectomy in selected patients Interferon alfa (IFN) IL-2 Allogenic stem cell transplantation Radiation therapy (palliative) Surgical excision of metastatic disease (selected M1 patients) Clinical trials Oliver et al, Br J Urol 1989 Steis et al, Cancer 1987 Rosenberg et al, N Engl J Med 1987
IFN + Nephrectomy in mrcc and Survival 11.1 mos vs 8.1 mos p =0.05 17 mos vs 7 mos Flanigan et al. NEJM (2001) Mickisch et al. Lancet (2001)
Immunomodulatory therapies Goal : to boost tumour antigenicity or host surveillance IFN-α 14% responses IL-2 median duration of response: 6m high dose : 21% responses low dose : 13% responses no impact in DFS and OS Fisher et al, Cancer J Sci Am 2000 Clark et al, J Clin Oncol 2003
Von Hippel-Lindau (VHL) syndrome is characterized by the development of clear cell RCC Autosomal dominant disorder with inherited susceptibility to retinal angiomas, cystic lesions of pancreas/kidney/epididymis, CNS hemangioblastomas, adrenal pheochromocytomas and clear cell RCC Lifetime risk of RCC is > 70%, often occurring as bilateral and multifocal tumors. RCC causes death in 15-50% of VHL patients Couch V et al. Mayo Clin Proc. (75) 2000
Clear cell RCC is characterized by VHL gene inactivation * No significant VHL gene mutation (1%; 2/136) or methlyation (2%; 3/135) observed in non-clear cell RCC Rini et al, JCO (2005) Author VHL gene mutation Author VHL gene methylation Gnarra, 1994 57% (56/98) Herman, 1994 19% (5/26) Gallou, 1999 56% (73/130) Clifford, 1998 15% (7/45) Brauch, 2000 45% (68/151) Kondo, 2002 5.4% (11/202) Shuin, 1994 & Kondo, 2002 51% (104/202) Brauch, 2000 7% (10/151) Schraml, 2002 34% (38/113) Total 49% (339/694) Total 8% (33/424)
Molecular pathways and targeted therapies in renal-cell carcinoma NEJM 2007; 356:185-187
Medical Management of mrcc : Past and Recently developed therapeutic approaches
Bevacizumab (Avastin ) Anti-VEGF antibody (Bevacizumab) P P P P VEGFR-1 VEGF P P P P VEGFR-2 Endothelial cell Recombinant humanized monoclonal IgG 1 antibody Recognizes all isoforms of VEGF Estimated half-life approximately 20 days (range, 11-50 days) Presta et al. Cancer Res. (1997) Gordon et al. JCO (2001)
AVOREN Trial: B017705: study design Bevacizumab + IFN-α2a (n=327) PD RCC patients (n=649) 1:1 IFN-α2a + placebo (n=322) PD Bevacizumab/placebo 10mg/kg i.v. q 2w until progression IFN-α2a 9MIU s.c. three times/week (maximum of 52 weeks) (dose reduction allowed) P.I. Bernard Escudier
Progression-free survival (investigator assessed) Probability of being progression-free 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 5.4 10.2 HR=0.63, p<0.0001 Median progression-free survival: Bevacizumab + IFN = 10.2 months Placebo + IFN = 5.4 months 0 6 12 18 24 Time (months)
Bevacizumab - Don t Forget Caution in patients with bleeding or thrombosis risk Monitor blood pressure and treat hypertension Image CNS prior to initiation of therapy
VEGF-R directed small molecules in RCC XBAY 43-9006 SU11248 X
Therapeutic inhibition of VEGF in RCC: receptor blockade (SU11248) F N H H 3 C O N H O CH 3 N H N CH 3 CH 3 Oxindole TK inhibitor Orally bioavailable small molecule Selective multitarget inhibition of: PDGF-R VEGF-R Kit Flt-3 Plasma half-life 40 hours Mendel et al. Clin Cancer Res (2003)
Sunitinib : Tumor responses in different sites of metastasis Motzer et al, JCO 2006 A,B,C: responses in patient with multiple metastatic sites from a large primary RCC after treatment; D,E: responses in patient 2 with multiple hepatic, lung, and pleural metastases; F,G: responses in patient 3 with large retroperitoneal lymphadenopathy and hepatic metastases
Sinutinib vs IFN (First-line) : Baseline demographic and clinical characteristics Motzer et al. NEJM 2007; 356:115-24
Sinutinib vs IFN : Best tumor response
Sinutinib vs IFN : Kaplan-Meier estimates of progression-free survival (independent central review)
Sinutinib vs IFN : Progression-free survival in subgroups, according to baseline factors (independent central review)
Sorafenib vs Placebo : Demographic and baseline characteristics (intention-to-treat population) SECOND LINE STUDY AFTER CYTOKINES Escudier et al. NEJM 2007; 356:125-34
Sorafenib vs Placebo : best response rates
Sorafenib vs Placebo : Kaplan-Meier analysis of overall survival and progression-free survival
Sorafenib vs Placebo : Hazard ratios for progression-free survival among subgroups of patients
Sorafenib (BAY 43-9006) : Hand-foot skin reaction Escudier B et al. Oral presentation, ECCO 13, Nov 3, 2005
Sorafenib and Sunitinib : skin toxicity (1) Acral erythema (hand and foot syndrome) : painfull symmetric erythematous and oedematous areas on the palms and soles, commonly preceded or accompained by paesthesias generally arises after 2-4 weeks of treatment, Is dose dependent Sunitinib skin toxicity consisted of (A) painful periungual erythema, (B) bullous lesions on the fingers, (C) plantar areas with erythema that consisted of hyperacanthosis, intraepidermal cleavage, and (D) microscopic examination.
Sorafenib and Sunitinib : skin toxicity (2) maculopapular rash in back and extremities Thrombocytopenic Purpura Rash
Subungual splinter hemorrhages VEGFR may be involved in the renewal of spiral capillaries that sustain frequent microinjuries at the extremities of the fingers. Blocking these receptors might prevent the physiologic repair of traumatized nail bed capillaries and result in subungual splinter hemorrhages Subungual splinter hemorrhages could reflect the anti-vegfr properties, and nail beds might offer an interesting clinical monitoring window to the antiangiogenic effects (with Sorafenib)
Modification of hair and skin pigmentation Sunitinib-induced hair depigmentation. In patients with (A) no gray hair before treatment; (B) facial hair; (C) eyelashes; (D) hair will progressively grow discolored under exposure to sunitinib; and (E) hair discoloration was reversible during the washout period
Multi-targeted Kinases - Hypertension Proposed mechanism : Reduced number of arterioles and capillaries Alteration of the microvascular network Decrease in vascular wall compliance and distensibility Reduced nitric oxide bioactivity In clinical practice: Onset ± 3 weeks after the beginning of therapy and persists for at least 18 weeks To be treated actively with oral antihypertensive agents
Sunitinib (Sutent) - Hypothyroidism Prospective study of 42 pts treated for a median of 37 weeks with Sunitinib. (Desai et al.; Ann Intern Med, 2006) The risk of hypothyroidism increased with the duration of Sunitinib treatment Abnormal TSH concentrations in 26 pts (62 %) 15 pts (36 %) persistent, primary hypothyroidism (6 pts had TSH alterations before entry in the study) 4 pts (10%) isolated TSH supression 7 pts (17 %) transient mild TSH elevations 2 pts with no visualzed thyroid tissue in ultrasonography (Destructive thyroiditis through follicular cell apoptosis?) Anti-tumor activity in advanced thyroid cancers?
Metastatic RCC : Temsirolimus mtor inhibitor Dose : 25 mg iv qw Phase III (poor risk pts) : Temsirolimus vs IFNα vs Temsirolimus + IFNα Temsirolimus > IFNα or combination in terms of OS and PFS (4 months difference) Dose reduction : Temsirolimus 25 % IFNα 40 % Toxicities : Asthenia, diarrhea, rash, Anemia/thrombocytopenia, hyperglycaemia and hyperlipaemia KCS Chicago 09-2006
Phase III Temsirolimus: OS and PFS by Tumor Histology* For patients with clear-cell tumors and with other tumor histologies, median OS and PFS were greater for TEMSR vs IFN Histology Type Overall Survival n (%) IFN (n=207) TEMSR 25 mg (n=209) TEMSR vs IFN Median mos n (%) Median mos Hazard Ratio a (95% CI) Clear-cell 170 (82.5) 8.2 169 (82) 10.6 0.85 (0.64, 1.08) Other 36 (17.5) 4.3 37 (18) 11.6 0.55 (0.33, 0.90) Progression-free Survival, Independent [Investigator Assessment] Clear-cell 170 (82.5) 3.8 [2.0] 169 (82) 5.5 [3.8] Other 36 (17.5) 1.8 [1.7] 37 (18) 7.0 [4.0] a Unstratified Cox proportional hazard model. *ITT population. Adapted from Dutcher J et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL. 0.84 (0.67, 1.05) [0.82 (0.66, 1.02)] 0.36 (0.22, 1.59) [0.40 (0.25, 0.65)]
Phase III Temsirolimus: OS and PFS by MSKCC Risk Group* TEMSR benefits patients with poor-prognostic features Too few patients in study with intermediate prognostic features for meaningful assessment of this subgroup MSKCC Prognostic Features a n (%) Overall Survival (P=0.0272) c IFN (n=207) TEMSR 25 mg (n=209) TEMSR vs IFN Median mos n (%) Median mos Hazard Ratio b 95% CI Intermediate 51 (24.6) 17.7 64 (30.6) 13.0 1.17 (0.74, 1.84) Poor 156 (75.4) 6.0 145 (69.4) 10.2 0.70 (0.55, 0.89) Progression-free Survival, Independent [Investigator] Assessment (P=0.0440 [P=0.4649]) c Intermediate 51 (24.6) 5.6 [3.6] 64 (30.6) 7.0 [3.8] Poor 156 (75.4) 2.3 [1.9] 145 (69.4) 5.1 [3.8] 1.13 (0.74, 1.70) [0.84 (0.57, 1.23)] 0.69(0.54, 0.87) [0.73 (0.58, 0.92)] a Intermediate=1 or 2 of 5 MSKCC poor-prognostic features; poor=3 or more MSKCC poor-prognostic features; b unstratified Cox proportional hazard model; c test of interaction between TEMSR and IFN based on unstratified Cox proportional hazard model. *ITT population. Adapted from Dutcher J et al. Presented at ASCO Annual Meeting; June 1-5, 2007; Chicago, IL.
RCC Treatment Alogrithm in 2007 Regimen Setting Therapy Treatment Naïve Patient Treatment Refractory Patient ( 2 nd Line) MSK Risk : Good or Intermediate MSK Risk : Poor Cytokine Refractory Refractory to VEGF/VEGFR or mtor Inhibitors Sunitinib Bevacizumab + IFNα Temsirolimus Sorafenib Investigational
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Bevacizumab in mrcc PLACEBO Q 2 WEEKS Treatmentrefractory, metastatic RCC R A N D O M I Z E (n=40) BEVACIZUMAB (3 MG/KG) Q 2 WEEKS (n=37) PD BEVACIZUMAB (10 MG/KG) Q 2 WEEKS (n=39) Yang JC et al. NEJM (2003)
Bevacizumab in mrcc Placebo Low-dose High-dose Bevacizumab Bevacizumab Response rate 0% 0% 10% TTP (months) 2.5 3.0* 4.8** OS (months) 13.0 15.1 15.5 *p=0.041 vs. placebo; **p < 0.001 vs.placebo Yang JC et al. NEJM (2003)
Time to Progression 100 % of Patients Free of Progression 80 60 40 20 p =0.041 Low-dose Placebo p < 0.001 High-dose Placebo 0 0 6 12 18 24 30 36 0 6 12 Months from On-Study Date 18 24 30 36 Yang JC et al. NEJM (2003)
Phase III trials of molecular-targeted therapies in clear cell RCC : Conclusions 1. Sunitinib > IFN (1st line ; Low + intermediate risk factors) 2. Temsirolimus > IFN (1st line ; Poor risk factors) 3. Bevacizumab + IFN>IFN (1st line) 4. Sorafenib > Placebo (2nd line after cytokines ; Low + intermediate risk factors) 5. Improvement in PFS (and most probably in OS) as well as in QOL