Metastatic Renal Cell Carcinoma(mRCC) maintenace target therapy (TT) after complete response Sérgio Barroso Department of Oncology Hospital Do Espírito Santo, Évora

Maintenance target therapy (TT) after complete response Metastatic renal cell carcinoma carries a poor prognosis, with a median survival duration in the range of 1-year and a 2-year survival rate of only 10%–20% Approximately one-third of patients present with metastatic disease at the time of their initial diagnosis and a further 25% will develop metastases at a later stage. Rini BI, Campbell SC, Escudier B et al. Renal cell carcinoma. Lancet 2009; 373: 1119–1132.

Maintenance target therapy (TT) after complete response In the last years, antiangiogenic targeted therapies have become available and changed the treatment paradigm for patients with mRCC Understanding of the underlying molecular biology of RCC has established as relevant therapeutic targets the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR). M. Johannsen et al. , Annoncol, Sep 21, 2010

Maintenance target therapy (TT) after complete response Recently some target therapies has been approved for first- and second-line treatment of mRCC Sunitinib and Sorafenib Bevacizumab plus interferon Temsirolimus and Everolimus With these agents, CRs are very rare events, but partial responses can be achieved in 10%–39% of patients. 1.Motzer RJ, Hutson TE, Tomczak P et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009; 27(22): 3584–3590. 2.Escudier B, Pluzanska A, Koralewski A et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007; 370: 2103–2111. 3. Hudes G, Carducci M, Tomczak P et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007; 356: 2271–2281. 4. Escudier B, Eisen T, Stadler WM et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356: 125–134. 5. Motzer RJ, Escudier B, Oudard S et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomized, placebo-controlled phase-III study. Lancet 2008; 372: 449–456. 6. Ljundberg B, Hanbury DC, Kuczyk M et al. Renal cell carcinoma guideline. Eur Urol 2007; 51: 1502–1510. 7. Motzer RJ, Figlin RA, Olencki T et al. NCCN Practice Guidelines in Oncology—v.1. 2010 www.nccn.org

Maintenance target therapy (TT) after complete response Resistance Drug resistance remains an ongoing obstacle to successful treatment of many diseases, including mRCC Limits the success of therapy and reduces survival rates Benefits of target agents are well established; however, there are limitations There are few complete responses Initial partial responses are followed by progression In other cases there is no objective benefit Motzer RJ, et al. J Clin Oncol 2009; Rini B, et al. J Clin Oncol 2010; Escudier B, et al. J Clin Oncol 2010; Escudier B, et al. N Engl J Med 2007; Hudes G, N Engl J Med 2007

Patterns of resistance to targeted therapy Change in tumour measurements (%) Change in tumour measurements (%) Change in tumour measurements (%) Primary refractory (2–3 months of treatment) Early progressors (6–12 months of treatment) Late progressors Intrinsic resistance Evasive resistance Rini BI, and Flaherty K, Urol Oncol 2008

Tumour evolution Anti-VEGF therapy Anti-PDGF therapy Tumour Time VEGF FGF Non-angiogenic factors Time VEGF = vascular endothelial growth factor; PDGF = platelet-derived growth factor; FGF = fibroblast growth factor

Following stopping drug Anti-VEGF therapy Anti-PDGF therapy VEGF PDGF FGF Non-angiogenic factors Tumour Antiangiogenic sensitive CR Time

Evidence against maintenance: do not harm Anti-VEGF therapy Anti-PDGF therapy Antiangiogenic sensitive ???? Tumour CR Time

Maintenance target therapy (TT) after complete response In the era of cytokine-based therapy, consolidation of a PR or prolonged stabilization by surgical resection of residual disease was a beneficial option for a small proportion of patients with mRCC Brinkmann OA, Semik M, Gosherger G et al. The role of residual tumor resection in patients with metastatic renal cell carcinoma and partial remission following immunochemotherapy. Eur Urol Suppl 2007; 6: 641–645.

Maintenance target therapy (TT) after complete response With the new antiangiogenic agents, CRs are still rare, but PRs do occur much more frequently compared with cytokines. These patients might benefit from additional surgical resection of residual metastases, thereby possibly achieving a longer disease control Rini B, Shaw V, Rosenberg JE et al. Patients with metastatic renal cell carcinoma with long-term disease-free survival after treatment with sunitinib and resection of residual metastases. Clin Genitourin Cancer 2006; 5(3): 232–234.

Maintenance target therapy (TT) after complete response Because TT of mRCC in general remains palliative some issues are increasingly important long-term continuous treatment toxicity impairment of quality of life the high cost of these therapies Johannsen M, Flo¨ rcken A, Bex A et al. Can tyrosine kinase inhibitors be discontinued in patients with metastatic renal cell carcinoma and a complete response to treatment? A multicenter retrospective analysis. Eur Urol 2009; 55(6): 1430–1438.

Maintenance target therapy (TT) after complete response It is unknown if discontinuation TT and readministration in case of recurrence is feasible in patients with mRCC in which complete response is achieved: by targeted therapy alone or no evidence of disease with additional resection of residual metastases. M. Johannsen et al. , Annoncol, Sep 21, 2010

Maintenance target therapy (TT) after complete response Thus, two important questions whether these agents can be safely discontinued in highly selected patients with mRCC who achieve a CR Whether these agents can be resumed in case of recurrence of measurable disease with similar efficacy Johannsen M, Flo¨ rcken A, Bex A et al. Can tyrosine kinase inhibitors be discontinued in patients with metastatic renal cell carcinoma and a complete response to treatment? A multicenter retrospective analysis. Eur Urol 2009; 55(6): 1430–1438.

Maintenance target therapy (TT) after complete response

Maintenance target therapy (TT) after complete response Retrospective Study with 36 patients in whom TT was discontinued after CR to TT alone or NED after additional metastasectomy Outcome criteria evaluated were: time off TT, Recurrence of metastases response to re-exposure to TT. Univariate and multivariate analyses were carried out to identify variables potentially predictive of outcome. M. Johannsen et al. , Annoncol, Sep 21, 2010

Maintenance target therapy (TT) after complete response Treatment was discontinued in 36 patients with CR or NED under TT with: Sunitinib - 22 Sorafenib – 11 Bevacizumab/interferon - 2 Temsirolimus - 1 Recurrence was observed in 24 patients (66.7%). Re-exposure to TT was effective in 86.9% of these cases. Twelve patients (33.3%) remained recurrence free at a median follow-up of 12 months (range 3–31). Median time off TT was 7 months (range 1–31). Factors that correlate with outcome could not be identified. M. Johannsen et al. , Annoncol, Sep 21, 2010

Maintenance target therapy (TT) after complete response Conclusions: In the majority of patients with mRCC and CR or NED, discontinuation of TT was followed by recurrence but re-exposure to TT was effective. M. Johannsen et al. , Annoncol, Sep 21, 2010

Maintenance target therapy (TT) after complete response Complete remission with TKI in renal cell carcinomas: Experience in 65 patients of the French Kidney Cancer Group. multicentric retrospective analysis of a series of mRCC pts who developed CR under TKIs, either alone (sunitinib or sorafenib), or in combination with local treatment (surgery, radiotherapy or RFA) Albiges L, et al. ASCO 2010

Maintenance target therapy (TT) after complete response CR patients n=65 CR with TKI alone CR with TKI + local treatment Total CRs 39 26 TKI continuation after CR 12 3 TKI discontinuation after CR 27 23 Ongoing CR after discontinuation 63%1 65%2 =37% PD =35% PD 1. Median FU: 291 days 2. Median FU: 322 days Albiges L, et al. ASCO 2010

Maintenance target therapy (TT) after complete response Complete remission with TKI in renal cell carcinomas: Experience in 65 patients of the French Kidney Cancer Group. Conclusions: CR can occur after TKIs alone or combined with local treatment. CR was observed in every metastatic site, in every prognostic group, even in poor risk. When a CR is obtained, the interruption of TKI is possible, with more than 60% pts remaining in CR. Albiges L, et al. ASCO 2010

Maintenance target therapy (TT) after complete response Take Home messages In a large number of patients with CR or PR withdrawal of anti-VEGF-treatment leads to rapid progression In some patients, ongoing response might be possible without treatment; however, we do not know who these patients are Unless more data are available, treatment discontinuation might be restricted to selected patients (with pathological CR, surgical CR) This chronic disease appears to require appropriate treatment duration (ongoing treatment)

Maintenance target therapy (TT) after complete response 3 fundamental factors Dosing Treatment duration Optimum efficacy Side-effect management

Maintenance target therapy (TT) after complete response Some questions … Can’t we start treatment in first line with a less active agent that may require less sophisticated therapy management? Can the most active drug be reserved for later stages of disease? Is it clinically relevant to achieve the best outcome in first line? Sequential or Combination Therapy ?