G. Ceresoli - Prostate and renal cancer - State of the art and update on systemic therapy of renal cancer
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G. Ceresoli - Prostate and renal cancer - State of the art and update on systemic therapy of renal cancer
- 1. RENAL CANCER: state of the art Giovanni Luca Ceresoli Thoracic and GU Oncology Unit Humanitas Gavazzeni Clinic – Bergamo, Italy 27/10/2011 - 29/10/2011, Amman, Jordan 3rd EASO Masterclass in Clinical Oncology
- 2. Survival by the MSKCC Risk Factor Model (n=463) Motzer, JCO 2002 Time From Start of IFN - (years) Proportion Surviving 0 2 16 14 13 11 9 5 4 3 6 15 12 10 8 7 6 MSKCC Criteria : Favorable : 0 risk factors present Intermediate : 1 or 2 risk factors Poor : 3 or more risk factors 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
- 3. Molecular Pathways in RCC
- 4. Progress in the Treatment of RCC IFN- α and high-dose IL-2 1980s 1995 1999 2004 2005/2006 2007 2009/2011 High-dose IL-2 IFN- α shows improved survival vs. hormonal therapy Sorafenib Sunitinib Temsirolimus, Bevacizumab + IFN Everolimus “ orphan” disease “ overcrowded”disease 8 RCTs; 7 drugs Pazopanib, Axitinib
- 5. mRCC: available drugs ANTI-VEGF LIGANDS TKIs mTOR INHIBITORS Bevacizumab Sorafenib Sunitinib Pazopanib (Axitinib) Temsirolimus Everolimus
- 6. Licensed Targeted Agents for mRCC * treatment-naive pts; ** pretreated pts 10.9 vs 7.3 P=0.0069 5.5 vs 3.1 P<0.0001 8.6 vs 4.8 NS 626 Temsirolimus vs IFN- a 18.3 vs 17.4 P=0.069 8.4 vs 4.9 P<0.0001 26 vs 13 P<0.0001 732 Bevacizumab + IFN- a vs IFN- a (CALGB) 14.8 vs 14.4 P=0.177 4.9 vs 1.9 P<0.001 1 vs 0 – 410 Everolimus vs Placebo Agent n ORR (%) Median PFS (months) Median OS (months) Sunitinib vs IFN- a 750 31 vs 6 P<0.000001 11 vs 5 P<0.001 26.4 vs 21.8 P=0.0510 Bevacizumab + IFN- a vs IFN- a (AVOREN) 649 31 vs 13 P=0.0001 10.4 vs 5.5 P<0.0001 23.3 vs 21.3 P=0.1291 Sorafenib vs Placebo 903 10 vs 2 P<0.001 5.5 vs 2.8 P<0.000001 17.8 vs 14.3 P=0.0287 Pazopanib vs Placebo 435 30 vs 3 P<0.001 11.1 vs 2.8* 7.4 vs 4.2** P<0.0001 22.9 vs 20.5 P=0.224
- 7. Ljungberg B et al. Eur Urol 2010; 58:398-406 Treatment Risk or prior treatment Recommended agent First line Low- or intermediate-risk Sunitinib Bevacizumab plus IFN-a Pazopanib High-risk Temsirolimus Second line Prior cytokine therapy Sorafenib Pazopanib Prior VEGFR therapy Everolimus Prior mTOR inhibitor therapy Clinical trials
- 8. FIRST-LINE TREATMENT (Low or intermediate risk) RR: 30-31%, mPFS 10.4-11 mos, mOS 22.9-26.4 mos * AVOREN study; ** Results in treatment-naive pts only good: 39% intermediate: 55% poor: 3% good: 29% intermediate: 56% poor: 8% good: 38% intermediate: 56% poor: 6% Prognostic groups Agent n ORR (%) Median PFS (months) Median OS (months) Sunitinib vs IFN- a 750 31 vs 6 P<0.000001 11 vs 5 P<0.001 26.4 vs 21.8 P=0.0510 Bevacizumab + IFN- a vs IFN- a* 649 31 vs 13 P=0.0001 10.4 vs 5.5 P<0.0001 23.3 vs 21.3 P=0.1291 Pazopanib vs Placebo 233 (435) 30 vs 3 P<0.001 11.1 vs 2.8** P<0.0001 22.9 vs 20.5 P=0.224
- 10. SECOND-LINE TREATMENT EAU Guidelines 2010 * Everolimus was as effective after 1 TKI, as it was after both; ** in CK pretreated pts 14.8 vs 14.4 P=0.177 4.9 vs 1.9 P<0.001 2 vs 0 – 410 Everolimus vs Placebo Agent n ORR (%) Median PFS (mos) Median OS (mos) Sorafenib vs Placebo 903 10 vs 2 P<0.001 5.5 vs 2.8 P<0.000001 17.8 vs 14.3 P=0.0287 Pazopanib vs Placebo 202 (435) 30 vs 3 P<0.001 7.4 vs 4.2** P<0.0001 22.9 vs 20.5 P=0.224 Treatment Risk or prior treatment Recommended agent Second line Prior cytokine therapy Sorafenib Pazopanib Prior VEGFR therapy Everolimus Prior mTOR inhibitor therapy Clinical trials
- 12. AXIS: Progression-Free Survival Time (months) Progression-Free Survival (probability) 0 2 4 6 8 0.0 0.5 0.9 1.0 10 12 14 16 18 20 Axitinib Sorafenib 6.7 4.7 6.3-8.6 4.6-5.6 P <0.0001 (log-rank) Stratified HR 0.665 (95% CI 0.544-0.812) mPFS, mo 95% CI 0.8 0.7 0.6 0.4 0.3 0.2 0.1 Rini et al. ASCO 2011
- 13. AXIS trial: Adverse Events Rini et al. ASCO 2011 Sorafenib (%) Axitinib (%) 32 32 51 12 8 17 22 32 29 53 All Grade 4 13 27 15 19 24 32 39 40 55 All Grade 0 0 Alopecia 4 <1 Rash 16 5 HFS <1 1 Stomatitis 0 <1 Hypothyroidism 1 3 Vomiting 1 3 Nausea 5 11 Fatigue 11 16 Hypertension 7 11 Diarrhea Grade 3/4 Grade 3/4 Event
- 14. Phase II results: RR27%, mPFS 11.8 mos; in clear cell mRCC who had undergone nephrectomy: RR 32%, mPFS 14.8 mos (Bhargava et al., ASCO 2010). Good toxicity profile.
- 15. Molecular targets of anti-angiogenic agents VEGFR-1 VEGFR-2 VEGFR-3 PDGFR-ß PDGFR-α c-Kit Flt-3 Anti-angiogenesis Bevacizumab Different activities against multiple kinase targets may result in differing efficacy and toxicity profiles VEGF-A VEGF-B VEGF-C VEGF-D VEGF-E Pazopanib 1 Sorafenib 2 Raf Sunitinib 3
- 16. Pazopanib 32 Sorafenib 25 Sunitinib 54 1. Kumar et al . Br J Cancer 2009; doi: 10.1038/sj.bjc.6605366. Figure adapted from Karaman et al. Nat Biotechnol 2008;26:127–32. Kinases inhibited with IC 50 <1 μ M Targeted therapies ??? Red circles: targeted kinases; larger cycles indicate higher affinity binding.
- 17. At 8.0 nM, pazopanib inhibits VEGFR-2 and c-Kit At 51.0 nM, sunitinib inhibits VEGFR-2 , VEGFR-3, PDGFR-α, PDGFR-β, c-Kit and Flt-3 1. Kumar et al . Br J Cancer 2009; doi: 10.1038/sj.bjc.6605366; 2. Karaman et al. Nat Biotechnol 2008;26:127–32. Different affinity for different drugs and kinases Flt-3 and c-Kit are expressed on haematopoietic stem cells and precursor cells. They are critical regulators in the proliferation and differentiation of haematopoietic progenitor cells.
- 18. Grade 3/4 (%) Adverse Events NR* *NR= Not reported in prescribing information or source reference NR* 1 2 3
- 19. Lab Abnormalities Pazopanib (N=586) Sunitinib (N=375) Sorafenib (N=451) All Grades Grade 3/4 All Grades Grade 3/4 All Grades Grade 3/4 ALT increased, % 52 10 46 3 NA NA AST increased, % 54 7 52 2 NA NA Tot.bilirubin increased, % 35 2 19 1 NA NA Anemia, % 24 2 71 3 44 2 Neutropenia, % 31 2 72 12 18 5 Thrombocytopenia, % 30 2 65 8 12 1
- 22. Advanced RCC: factors influencing treatment DISEASE-RELATED FACTORS Prognostic scores (MSKCC, Heng, French) Tumor burden Number and sites of metastases PATIENT-RELATED FACTORS Age Performance status Comorbidity HISTOLOGIC SUBTYPE Clear cell carcinoma Non-clear cell carcinoma TREATMENT STATUS Treatment na ïve Treatment refractory: cytokines, TKIs, mTOR inhibitors BIOLOGICAL FACTORS Tumor-related Patient-related (genetic/pharmacogenomic factors)
- 23. RCC: non-clear cell histology RCC is a collection of different types of tumors, each with a specific genetic, histological and clinical pattern. Clear cell (75-85%) Papillary (Type I + II) (12-14%) Chromophobic (4-6%) Oncocytic (2-4%) Collecting duct (1%) VHL C-met FH Proximal nephron Distal nephron No standard treatment, consider TKIs
- 24. Survival by the MSKCC Risk Factor Model (n=463) Motzer, JCO 2002 Time From Start of IFN - (years) Proportion Surviving 0 2 16 14 13 11 9 5 4 3 6 15 12 10 8 7 6 MSKCC Criteria : Favorable : 0 risk factors present Intermediate : 1 or 2 risk factors Poor : 3 or more risk factors 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
- 25. Prognostic Factors (1 st line): Heng Model Adverse prognostic factors Overall survival probability according to risk group Heng, JCO 2009 Overall survival probability N = 645 pts >ULN Platelets >ULN Neutrophils >ULN Calcium <LLN Hemoglobin < 1 year Time from dx < 80 KPS 9.4 months Poor 3 to 6 28.5 months Intermediate 1-2 37 months Favorable 0
- 26. Heng et al., ASCO 2010 Prognostic Factors (2 nd line): Heng Model
- 27. Clinical practice PS 0 PS 1 PS > 1 Good risk Intermediate risk Poor risk “ 90% of poor risk patients are PS 2-3” (B. Escudier, Warszawa 2011)
- 28. When Should we Treat? A Three Stage Treatment Scheme Rini BJ Proc ASCO 2008, Kirchner H Expert Rev Anticancer Ther, 2010
- 34. TKI–TKI–mTOR or TKI–mTOR–TKI? We do know that Everolimus is as effective after 1 TKI, as it is after both TKI/VEGF inhibitor 2 mTOR inhibitor TKI/VEGF inhibitor 1 mTOR inhibitor ? TKI/VEGF inhibitor
- 35. Porta C, et al. EJMCO 2010 Sequential treatment PRIMARY REFRACTORY PATIENTS (20%)
- 40. VEGF baseline levels are PROGNOSTIC, NOT PREDICTIVE Bukowski, ASCO 2007 Lara, ASCO 2010
- 41. Correlation of sVEGFR-2 with PFS and tumor response Hutson et al . J Clin Oncol 2008;26(15S):Abstract 5046 and oral presentation. PAZOPANIB
- 42. Multiple markers: PAZOPANIB Multiplatform analysis of plasma Cytokines and Angiogenic Factors (CAFs) Tran et al., ASCO 2010
- 43. Association of IL8 Polymorphism with OS ( P = 0.003) PAZOPANIB Xu et al., JCO 2011 Pts with the wild type AA genotype had twice as long mOS than pts who had the variant TT genotype.
- 44. Association of FGFR2 Polymorphism with OS ( P = 0.01) PAZOPANIB Xu et al., JCO 2011 Patients with the wild type CC genotype had significantly prolonged median OS compared with patients with the variant TT genotype.
- 45. Development of Resistance; Angiogenic Escape VEGF No angiogenesis Hypoxia Cancer cells VEGF inhibitors Early Phase: Response to Anti-VEGF Treatment Endothelial Cell VEGF PIGF Second wave of angiogenesis Cancer cells Endothelial Cell FGF, IL8 and other factors Late Phase: Escape to Anti-VEGF Treatment HIF HIF VEGF inhibitors Casanovas et al. Cancer Cell, 2005
- 50. Cytoreductive Nephrectomy: Phase III CARMENA Trial Untreated patients with mRCC and primary in place (N = 576) Nephrectomy followed by sunitinib Sunitinib alone Sponsor: French NCI Primary endpoint: DFS
- 51. Cytoreductive Nephrectomy: Phase III SURTIME Trial Untreated patients with mRCC and primary in place (N = 458) Nephrectomy Sunitinib Sponsor: EORTC Sunitinib Nephrectomy Primary endpoint: DFS
- 55. OR 5% OR 9% 68% 39% Response rate PFS mPFS 5.7 mos mPFS 5.6 mos Escudier B, et al. J Clin Oncol 2009 First-line Sorafenib vs IFN: Results
- 56. Placebo (n=451) Sorafenib (n=452) 20% 74% Maximum % reduction in tumor measurement Baseline Week 6 RR 10% SD 74% Escudier et al., NEJM 2007 Tumor burden: ORR vs tumor shrinkage rate
Editor's Notes
- Thank-you. Dear chairmen, dear colleagues… It is a pleasure for me to have this lecture on renal cancer. This is the last session of the Masterclass, and I would like to take this opportunity to thank again the scientific committee and the organizers, Daniela and Roberta and all you attendees for your interactive participation to this event.
- For several decades , the prognosis of patients with renal cell carcinoma (RCC) has remained poor. The only effective treatments were nephrectomy (for patients with resectable disease) and, in selected cases, cytokine therapy with alfa interferon and interleukin 2. Patients were stratified according to the prognostic model of MSKCC in 3 groups: favorable, intermediate and poor prognosis, Reference Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M, et al. Interferon-alfa as a comparitive treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol . 2002;20:289-286.
- In the last years, the advances in the understanding of molecular biology of renal cancer have allowed the identification of various pathways involved in the pathogenesis and the progression of this disease. In the presence of a mutated/ deleted VHL gene, HIF-1 is not destroyed via the proteasome/ ubiquitin pathway, and thus accumulates, leading to the transcription of hypoxia inducible genes. Also the activation of mTOR pathway leads to an increase expression of HIF-1 alfa. This results in the production of a series of growth factors, including VEGF and PDGF- , ultimately leading to increased angiogenesis.
- The improved understanding of the underlying biology has led to the development of several compounds that have rapidly come to CLINICAL FRUITION. What just a few years ago was a sort of “orphan disease” has become an OVERCROWDED and complex field of development of new drugs. In the last 5 years, at least 8 LARGE RANDOMIZED TRIALS with these new compounds have been published o in the most important medical journals, and now the sequence and the combination of the different treatments is under evaluation, as well as the development of new compounds.
- These are the actually available drugs : bevacizumab that is a monoclonal antibody, several multiple tyrosine kinase inhibitors (sorafenib, sunitinib, pazopanib and, more recently, axitinib), and the mTOR inhibitors temsirolimus and everolimus.
- These drugs have been studied in large phase III randomized trials. Sunitinib, the combination of bevacizumab and alfa-interferon and temsirolimus have been compared in the first line setting with the standard arm of interferon alone. Sorafenib was studied in second line after citokines failure, everolimus after TKIs failure. Both were compared with a placebo. The study with pazopanib is a sort of hybrid study: it was started as a second line treatment after citokines failure, and there amended to include also treatment-naive patients. All these studies showed a statistically significant improvement in disease-free survival , while overall survival analysis was mostly not significant due to extensive cross-over and post-study treatments.
- These studies have generated several guidelines that have been frequently updated due to the availability of new drugs. These for example are the guidelines of the European Association of Urologists. Guidelines have been stratified according to the MSKCC risk categories.
- Sunitinib, the combination of bevacizumab and alfa-IFN and pazopanib are the possible options for first-line treatment in patients with low or intermediate risk. As you can see from this slide, the results of these 3 studies are quite similar, with an overall response rate of about 30%, and a median PFS of 11 months. Of note, median OS is over 2 years.
- In patients with poor risk, guidelines suggest the use of temsirolimus, an IV mTOR inhibitor. However, criteria for inclusion in the temsirolimus study were modified as compared to MSKCC criteria; one third of the patients were in reality intermediate risk patients.
- In second line treatment after failure of cytokines sorafenib and pazopanib are the two possible options. Due to the unfrequent use of CK at present in mRCC, this group is becoming a theoretical group only. Most patients are treated in first line with TKIs or bevacizumab plus IFN. In patients failing after one or two TKIs, guidelines suggests the use of everolimus. There is no standard option for patients failing a prior mTOR inhibitor therapy.
- There are other drugs coming in a short time to the clinical practice. One is AXITINIB, another oral multi-target TKI. The results of a phase III study in patients pretreated with a first line (sunitinib, bevacizumab + alfaIFN, temsirolimus or cytokines have been recently reported at last ASCO Meeting in June this year. Axitinib was compared in a randomized phase III study with sorafenib in second-line treatment. Primary endpoint was PFS.
- Progression-free survival was significantly longer in axitinib arm, with a median value of 6.7 months vs 4.7 months for sorafenib.
- Toxicity profile was similar for the two drugs, except for an higher incidence of hypertension and hypothyroidism in the axitinib arm, and a more frequent occurrence of hand-foot syndrome and the other skin toxicities for sorafenib.
- Another interesting drug who is being evaluated in a phase III trial is tivozanib, an oral TKI with promising results in phase II trial. Tivozanib seems to have a particularly good toxicity profile, with less off-target toxicities except for a manageable hypertension. In phase III this drug is being compared with sorafenib in patients naive or pretreated with citokines.
- But are all these TKIs identical? The answer is no, because they have different activities against multiple kinase targets, and this may results in different efficacy and toxicity profiles. 1
- In vitro studies have demonstrated that small molecule–kinase inhibitors have different activity at different concentrations on different kinases. In this graphic representations called dendrograms, the targeted kinases for every single drug are marked with red circles, where larger circles indicate higher-affinity binding. Pazopanib and sorafenib inhibits fewer additional receptors than sunitinib. 1
- This could explain the different toxicity profile of the different TKIs. For example pazopanib has much lower affinity to Flt-3 and c-kit than sunitinib. These kinases are expressed on haematopoietic stem cells and precursor cell. This is the molecular explanation of the higher incidence of hematological toxicity (mainly neutropenia and thrombocytopenia) with sunitinib. Flt-3 and c-Kit are expressed on haematopoietic stem cells and precursor cells. They are critical regulators in the proliferation and differentiation of haematopoietic progenitor cells Kumar et al . Br J Cancer 2009; doi: 10.1038/sj.bjc.6605366. 1
- Also the other differencies in toxicity profiles of 1
- Rialzo delle transaminasi e della bilirubina è transitorio rientra con la sospensine del farmaco o con riduzione di dose a seconda del tipo di tossicità che si manifesta. Insorge all’inizio della terapia e si stabilizza fino a non presentare più l’evento per tutto il decorso del trattamento che nel frattempo è a 600 mg (vd. Paz. Della sternberg) 1
- A major advance in RCC was to realize that this disease is not one entity but rather a collection of different types of tumors, each derived from the various parts of the nephron and each possessing distinct genetic, histological and clinical features. In my presentation I will focus mainly on CLEAR CELL carcinoma, that represents about 80% of all the cases of renal cancer.
- Reference Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M, et al. Interferon-alfa as a comparitive treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol . 2002;20:289-286.
- RCC is the most common kidney cancer accounting for 80–85% of all renal cancers 1 and 2–3% of all adult cancers. 2 It is almost twice as common in men than women and most frequently occurs during the later years of life, though it may also occur in children. 3,4 These data also illustrate the higher prevalence of renal cancers in developed countries, particularly in patients from Northern Europe and North American countries. 3,4 1. Motzer RJ et al. N Engl J Med 1996;335:865–75. 2. Levine E et al. Adult malignant renal parenchymal neoplasms. In Clinical urography, 2nd edition. 2000, Saunders: Philiadelphia, USA. p. 1440–559. 3. GLOBOCAN 2002; Cancer Incidence, Mortality and Prevalence Worldwide 2002 estimates. 2006 http://www-dep.iarc.fr/. 4. Cancer Research UK, UK kidney cancer statistics. 2008 http://info.cancerresearchuk.org/cancerstats/types/kidney/?a=5441.
- RCC is the most common kidney cancer accounting for 80–85% of all renal cancers 1 and 2–3% of all adult cancers. 2 It is almost twice as common in men than women and most frequently occurs during the later years of life, though it may also occur in children. 3,4 These data also illustrate the higher prevalence of renal cancers in developed countries, particularly in patients from Northern Europe and North American countries. 3,4 1. Motzer RJ et al. N Engl J Med 1996;335:865–75. 2. Levine E et al. Adult malignant renal parenchymal neoplasms. In Clinical urography, 2nd edition. 2000, Saunders: Philiadelphia, USA. p. 1440–559. 3. GLOBOCAN 2002; Cancer Incidence, Mortality and Prevalence Worldwide 2002 estimates. 2006 http://www-dep.iarc.fr/. 4. Cancer Research UK, UK kidney cancer statistics. 2008 http://info.cancerresearchuk.org/cancerstats/types/kidney/?a=5441.
- AA: wild type genotype TT: variant genotype AT: heterozygote Patients with the wild type AA genotype had median overall survival of 30 months, which is twice as long as those who had the variant TT genotype.
- CC: wild type genotype TT: variant genotype CT: heterozygote Patients with the wild type CC genotype had significantly prolonged median OS compared with patients with the variant TT genotype.
- This cartoon shows an hypothesis of “angiogenic escape” to anti‑VEGF treatment, which may be responsible for resistance to treatment. Other growth factors, such as basic fibroblast growth factor, are involved. New drugs targeting these factors are under evaluation.
- mRCC, metastatic renal cell carcinoma. Two ongoing trials that will attempt to answer the question of the optimal role for cytoreductive nephrectomy in this setting. The first is the phase III CARMENA trial, which is essentially recapitulating the initial interferon trials of nephrectomy or not followed by sunitinib for metastatic kidney cancer patients who present with a primary tumor.
- mRCC, metastatic renal cell carcinoma. Two ongoing trials that will attempt to answer the question of the optimal role for cytoreductive nephrectomy in this setting. The first is the phase III CARMENA trial, which is essentially recapitulating the initial interferon trials of nephrectomy or not followed by sunitinib for metastatic kidney cancer patients who present with a primary tumor.
- BID, twice daily; DOR, duration of response; IV, intravenously; mRCC, metastatic renal cell carcinoma; MSKCC, Memorial Sloan-Kettering Cancer Center; ORR, objective response rate; PK, pharmacokinetics; PFS, progression-free survival; PO, orally; QW, once weekly.
- CI, confidence interval; CR, complete response; HR, hazard ratio; ORR, objective response rate; PD progressive disease; PFS, progression-free survival; PR, partial response; SD, stable disease.
- Even though tumor shrinkage rate was higher in the sorafenib arm, response rate and PFS did not differ significantly in comparison to the IFN arm. The reason for these absence of substantial effect of sorafenib versus IFN in the front-line setting is not entirely clear, but might result from weaker inhibition of VEGF than with sunitinib.
- Response rate with sorafenib was 10%, but an high rate of tumor shrinkage (disease stabilization) was observed. A typical tumor central necrosis causing a minor increase in tumor size was frequently observed.