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Nuevos tratº cáncer renal 2014

Nuevos tratº cáncer renal 2014






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  • Tener en cuenta la mejor secuencia de administración, <br />
  • Escudier B, et al. Ann Oncol 2012;23(suppl 7):vii65–vii71; Corrigendum Ann Oncol 2013. <br />
  • Kaplan-Meier plot of progression-free survival (PFS) as determined by independent radiology review. (A) Overall intent-to-treat population; (B) no prior treatment. <br />
  • BID, twice daily; ECOG PS, Eastern Cooperative Oncology Group performance status; mRCC, metastatic renal cell carcinoma; MSKCC, Memorial Sloan Kettering Cancer Center; PFS, progression-free survival; QD, once daily; RECIST, response evaluation criteria in solid tumors. <br /> Brian Rini, MD, FACP: <br /> In the setting of kidney cancer, the most prominent study presented at the 2014 Genitourinary Cancers Symposium was the SWITCH study, a large, randomized phase III study of 2 different sequences of tyrosine kinase inhibitors in patients with previously untreated advanced or metastatic kidney cancer (N = 365).[1] The 2 agents were sorafenib and sunitinib, which were the first 2 tyrosine kinase inhibitors to be approved globally in this indication. This prospective trial was planned following retrospective data that suggested sorafenib followed by sunitinib might be a better regimen than sunitinib preceding sorafenib.[2,3] <br /> The investigators randomized patients either to the sequence of sorafenib at the standard dose of 400 mg twice daily, followed by second-line sunitinib 50 mg once daily upon progression or toxicity, or to the opposite sequence of starting with daily sunitinib until progression or toxicity and then proceeding to sorafenib as a second-line therapy. <br /> The primary endpoint of this European study was total progression-free survival, defined as the time from randomization to confirmed progression or death on second-line therapy, or on first-line therapy if no second-line treatment was used. Based on the retrospective data in earlier studies, the investigators hypothesized that the sequence of sorafenib followed by sunitinib would be superior to sunitinib followed by sorafenib. <br /> References: <br /> 1. Michel M-S, Vervenne WL, De Santis M, et al. SWITCH: a randomized, sequential, open-label study to evaluate efficacy and safety of sorafenib (So)-sunitinib (Su) versus Su-So in the treatment of metastatic renal cell cancer. Program and abstracts of the 2014 Genitourinary Cancers Symposium; January 30 – February 1, 2014; San Francisco, California. Abstract 393. <br /> 2. Ambring A, Björholt I, Lesén E, Stierner U, Odén A. Treatment with sorafenib and sunitinib in renal cell cancer: a Swedish register-based study. Med Oncol. 2013;30:331. <br /> 3. Eichelberg C, Heuer R, Chun FK, et al. Sequential use of the tyrosine kinase inhibitors sorafenib and sunitinib in metastatic renal cell carcinoma: a retrospective outcome analysis. Eur Urol. 2008;54:1373-1378. <br />
  • mRCC, metastatic renal cell carcinoma; OS, overall survival; So, sorafenib; Su, sunitinib. <br /> Brian Rini, MD, FACP: <br /> As with progression-free survival, there was no significant difference in median overall survival between sequences: 31.5 months for sorafenib followed by sunitinib vs 30.2 months for sunitinib followed by sorafenib (HR: 1.00). These survival times of approximately 30 months match what was seen in the COMPARZ phase III study of first-line sunitinib vs pazopanib[1]; basically, in the modern era, patients who receive multiple tyrosine kinase inhibitors for metastatic kidney cancer have an average survival time of approximately 2.5 years. <br />   <br /> Nicholas J. Vogelzang, MD: <br /> These are remarkable long-term survival data, suggesting that the standard of care for renal cell carcinoma should be sequential therapies; it probably does not matter whether sorafenib is given first or whether sunitinib is given first. As seen in long-term colon cancer trial follow-up, patients should receive all available drugs that will provide them the maximum survival time. <br /> Reference: <br /> 1. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369:722-731. <br />
  • IFN, interferon; IL, interleukin. <br />
  • ORR, overall response rate; PFS, progression-free survival; RCC, renal cell carcinoma. <br />
  • RCC, renal cell carcinoma. <br />
  • CR, complete response; CRC, colorectal cancer; CRPC, castrate-resistant prostate cancer; IV, intravenous; NSCLC, non-small cell carcinoma; PD, progressive disease; PR, partial response; RCC, renal cell carcinoma; q2w, every 2 weeks; SD, stable disease. <br />
  • CI, confidence interval; NE, not estimable; NR, not reached; PFS, progression-free survival; OS, overall survival; RCC, renal cell carcinoma. <br />
  • CI, confidence interval; mRCC, metastatic renal cell carcinoma; NE, not estimable; OS, overall survival. <br />
  • mRCC, metastatic renal cell carcinoma; NSCLC, non-small cell carcinoma. <br />
  • AE, adverse events; RCC, renal cell carcinoma; Tx, treatment. <br />

Nuevos tratº cáncer renal 2014 Nuevos tratº cáncer renal 2014 Presentation Transcript

  • Tratamiento antidiana del Cáncer Renal Santo Estevo, 14 de Junio de 2014 Martín Lázaro Quintela
  • Nuevas estrategias de tratamiento en cáncer renal: impacto en un incremento en la supervivencia global 1. Motzer RJ, et al. J Clin Oncol 2009 Nueva EraNueva Era La selección del tratamiento apropiado para cada subgrupo de paciente y en cada una de las líneas es clave en la SG del paciente OS(años) Numero de líneas de tratamiento en secuencia (N>2)1
  • 1. Sunitinib SmPC, Jan 2014; 2. Sorafenib SmPC, Feb 2013; 3. Bevacizumab SmPC, Feb 2014; 4. Temsirolimus SmPC, Oct 2013; 5. Everolimus SmPC, Nov 2013; 6. Pazopanib SmPC, Dec 2013; 7. Axitinib SmPC, Oct 2013. Targeted agents currently approved for mRCC in Europe
  • Clinical patterns of resistance to targeted therapy Primary refractory (2–3 months of treatment) Adaptive (evasive) resistance Early progressors (6–12 months of treatment) Late progressors Changeintumour measurements(%) Changeintumour measurements(%) Changeintumour measurements(%)Rini and Flaherty. Urol Oncol 2008. Intrinsic resistance
  • Srinivas, ASCO 2011
  • Agent N ORR (%) Median PFS (months) Median OS (months) Sunitinib vs IFN-α1 750 47 vs 12 P<0.001 11 vs 5 P<0.001 26.4 vs 21.8 P=0.051 Temsirolimus vs IFN-α2* 626 8.6 vs 4.8 NS 5.5 vs 3.1 P<0.001 10.9 vs 7.3 P=0.008 Bevacizumab + IFN-α vs IFN-α3,4 649 31 vs 13 P=0.0001 10.2 vs 5.4 P<0.0001 23.3 vs 21.3 P=0.1291 Bevacizumab + IFN-α vs IFN-α5,6 732 26 vs 13 P<0.0001 8.5 vs 5.2 P<0.0001 18.3 vs 17.4 P=0.069 Pazopanib vs placebo7,8 435 30 vs 3† P<0.001 11.1 vs 2.8 P<0.0001 (9.2 vs 4.2† P<0.0001) 22.9 vs 20.5† P=0.224 Tivozanib9 517 33 vs 23† P< 0,014 11.9 vs 9,1† p= 0,042 NA 1. Motzer RJ, et al. J Clin Oncol 2009; 2. Hudes G, et al. N Engl J Med 2007; 3. Escudier B, et al. Lancet 2007; 4. Escudier B, et al. J Clin Oncol 2010; 5. Rini BI, et al. J Clin Oncol 2008; 6. Rini B, et al. J Clin Oncol 2010; 7. Sternberg C, et al. J Clin Oncol 2010; 8. Sternberg C, et al. ESMO 2010; 9. Motzer, et al. ASCO 2012 *Poor risk patients (modified MSKCC criteria); † Treatment-naïve and cytokine refractory populations Agentes frente a mRCC
  • Third-line Post-two VEGF-TKIs Everolimus IIA Post-VEGFR-TKI and mTOR inhibitor VEGFR-TKI IIIB ESMO 2012 guidelines for targeted treatment of mRCC Post-cytokines Axitinib Sorafenib Pazopanib Sunitinib IA IA IIA IIIA Post-TKI Axitinib Everolimus IB IIA Favourable or intermediate risk Sunitinib Bevacizumab + IFN-α Pazopanib IA IA IIB Poor risk Temsirolimus IB First-line Second-line Treatment group Standard recommendation Level of evidence Longer-termsurvival IFN-α, interferon-alpha Escudier et al. Ann Oncol 2012; Corrigendum Ann Oncol 2013. Third-line
  • Less potent More potent Potency:IC50(nM) VEGFR-1 VEGFR-2 VEGFR-3 Motesanib AMG-706 Sunitinib ABT-869 Pazopanib Sorafenib Vatalanib PTK787 Vandetanib CediranibAxitinibTivozanibA V-951 1,000 100 10 1 0.1 0.01 Figure modified using data from Chow LQM, Eckhardt SG. J Clin Oncol. 2007; Eskens FALM, et al. AACR 2008. Abstract LB-201; Hu-Lowe DD, Clin Cancer Res 2008 Potency to Inhibit VEGF Receptors 1, 2, and 3
  • TIVO-1: PFS y OS Motzer R J et al. JCO 2013;31:3791-3799 PFS OS 29,3 Tivo vs 28,8 Sora11,9 Tivo vs 9,1 Sora
  • RECORD3 Everolimus - sunitinib vs. Sunitinib - everolimus Primary endpoint of first-line PFS non- inferiority was not met for everolimus compared with sunitinib1 First-line study* SWITCH Sorafenib** - sunitinib vs. sunitinib - sorafenib Primary endpoint (Total PFS) demonstrating superiority of sorafenib- sunitinib over sunitinib-sorafenib was not met2 Sequencing studies to date have been inconclusive Limitations •Insufficient patients in second-line to allow for robust analysis of sequencing •Introduction of a number of potential areas of bias 1. Motzer at al. ASCO 2013; 2. Michel et al. ASCO GU 2014; 3. Everolimus SmPC, Nov 2013; 4. Sorafenib SmPC, Feb 2013. *Everolimus is indicated for the treatment of patients with advanced RCC, whose disease has progressed on or after treatment with VEGF-targeted therapy3 ; **Sorafenib is indicated for advanced RCC after IFN α/IL-2 or if unsuitable for IFN-α/IL-2‑ 4 Please refer to prescribing information for each treatment option; DCR, disease control rate
  • SWITCH Phase III Study: Sorafenib → Sunitinib vs Sunitinib → Sorafenib in mRCC • Primary endpoint: total PFS (from randomization to confirmed progression or death during second-line therapy, or first line for pts who did not receive second-line treatment) • Pts enrolled in Germany, Austria, and The Netherlands • Efficacy assessed every 12 wks (per RECIST 1.0) and at end of treatment Michel M, et al. ASCO GU 2014. Abstract 393. Pts with mRCC, unsuitable for cytokines, no prior systemic therapy, ECOG PS 0-1, ≥ 1 lesion Sorafenib 400 mg BID Sunitinib 50 mg QD Progression or intolerable toxicity Sorafenib 400 mg BID Sunitinib 50 mg QD Stratified by MSKCC prognostic group (favorable or intermediate)
  • SWITCH Study of Sorafenib → Sunitinib vs Sunitinib → Sorafenib in mRCC: OS Michel M, et al. ASCO GU 2014. Abstract 393. 100 80 60 40 20 0 0 5 10 15 20 25 30 35 40 45 50 Mos From Randomization ProbabilityofOS(%) Pts at Risk, n So → Su → So 182 183 148 147 123 119 105 95 79 80 58 59 36 37 25 29 17 18 9 12 Median OS So→ Su (n = 182): 31.5 mos (95% CI: 23.3-36.9) Su → So (n = 183): 30.2 mos (95% CI: 23.6-50.1) HR: 1.00; P = .49 55 6 7
  • Evolution in the first-line treatment of mRCC Mediansurvival(months) PFS OS 3–6 6–15* 13–22 18–32* After AfterBefore Before 30 25 20 15 10 5 0 Median survival before and after the introduction of targeted agents (TKIs)1–11 1. Coppin et al. Cochrane Database Syst Rev 2005; 2. Gore et al. Lancet 2010; 3. Motzer et al. N Engl J Med 2007; 4. Escudier et al. Lancet 2007; 5. Rini et al. J Clin Oncol 2008; 6. Motzer et al. N Engl J Med 2013; 7. Motzer et al. J Clin Oncol 2009; 8. Escudier et al. J Clin Oncol 2010; 9. Rini et al. J Clin Oncol 2010; 10. Michel et al. ASCO GU 2014; 11. Motzer et al. ASCO 2013. *With targeted agents as first-line mRCC therapy primarily in favourable/intermediate risk patients
  • Real world vs clinical trials Real world Purpose Performance in the real world Regulatory approval Patient typeHeterogeneous Homogeneous Control Not placebo-controlled, not blinded Control arm provides relative efficacy Inclusion criteria Strict (e.g. specific age group, few co-morbidities) Broad (e.g. elderly patients, multiple co-morbidities) Conditions Real and diverse clinical situations Highly controlled, stringent treatment delivery Real world Pivotal clinical trials
  • Evolución de los pacientes que no cumplen criterios para ser incluidos en ensayos clínicos • 768 of 2210 (35%) patients in the International Metastatic RCC Database Consortium (IMDC) were deemed ineligible for clinical trials • First-line results (ineligible patients vs eligible patients) – Response rate: 22% vs 29% (p=0.0005) – mPFS: 5.2 vs 8.6 months (p<0.0001) – mOS: 12.5 vs 28.4 months (p<0.0001) • Second-line results (ineligible patients vs eligible patients) – PFS: 2.8 vs 4.3 months (p=0.0039) Heng D Y C et al. Ann Oncol 2014;25:149-154
  • Progress in advanced kidney cancer, 2007–2014 Patient outcomes Therapeutic options Median PFS 4–5 months Median PFS 9–11 months Median PFS 4–5 months ? ? ~40–60%1,2 ~100% <20%3–5 Eligible patients 1. Levy et al. Eur J Cancer 2013; 2. Sonpavde et al. Eur Urol 2012; 3. Iacovelli et al. Eur J Cancer 2013; 4. Pal et al. ASCO GU 2013; 5. Heng et al. ASCO 2013. Adapted from Larkin. ASCO GU 2014 IFN-α, interferon-alpha Sunitinib Pazopanib IFN-α + bevacizumab Temsirolimus Axitinib (post-sunitinib/cytokine) Everolimus (post-VEGFR-TKI) Sunitinib (post-cytokine) Pazopanib (post-cytokine) Sorafenib (post-cytokine) Everolimus (post-VEGFR-TKI × 2) Neoadjuvant Adjuvant First-line Second-line Third-line
  • Have we improved OS since 2007? 2007/20131,2 2010/20132,3 20134 20135 20146 20146 1. Motzer et al. J Clin Oncol 2009; 2. Motzer et al. N Engl J Med 2013; 3. Sternberg et al. Eur J Cancer 2013; 4. Motzer et al. J Clin Oncol 2013; 5. Motzer et al. ASCO 2013; 6. Michel et al. ASCO GU 2014. MedianOS,months Please refer to local prescribing information for each treatment option Median OS for VEGF-targeted therapies in mRCC in clinical studies Eve. Everolimus; Seq., sequence; Sor, sorafenib; Sun, sunitinib
  • ¿Podemos identificar a los largos respondedores?
  • Complete responses to VEGF-TKIs • Long-lasting CRs can occur after TKI treatment alone or when combined with local treatment • Relapsing patients responded well to further therapy • Median time to CR was 12.6 months in patients receiving TKIs alone, highlighting the importance of maintaining therapy Albiges et al. J Clin Oncol 2012. Sunitinib-treated patients: n=59; sorafenib-treated patients: n=5 CR, complete response
  • CR, complete response; PD, disease progression; PR, partial response; SD, stable disease *Six patients were not evaluable Long-term responders to sunitinib • Retrospective analysis of long-term responders to sunitinib (i.e. patients achieving durable CR or remaining progression-free for >18 months) • 186 patients treated with sunitinib monotherapy (n=89) or in combination (n=97) in 9 clinical trials – Of 180 evaluable patients, 34 patients (19%) achieved long-term response Variable All (N=186)* Long-term responders (n=34) Best objective response CR 4 (2%) 3 (9%) PR 74 (40%) 24 (71%) SD 80 (43%) 7 (21%) PD 22 (12%) 0 OS Number of deaths 152 (82%) 24 (71%) Molina et al. Clin Genitourin Cancer 2013.
  • Factors associated with long-term response • Univariate analysis showed the following factors were associated with long-term response: – Absence of bone or lung metastases – Favourable MSKCC risk status All (N=186) Long-term responders (n=34) Univariate logistic analysis (Yes vs No) Odds Ratio (95% CI) p-value Site of disease Bone 50 (27%) 5 (51%) 0.41 (0.15–1.12) 0.08 Lung 131 (70%) 18 (53%) 0.39 (0.18–0.84) 0.02 Liver 41 (22%) 4 (12%) 0.41 (0.14–1.26) 0.12 > 2 metastatic sites 140 (75%) 22 (65%) 0.53 (0.24–1.19) 0.12 Previous treatment 72 (39%) 15 (44%) 1.32 (0.62–2.79) 0.48 Clear cell histologic type 164 (88%) 31 (91%) 1.48 (0.41–5.30) 0.55 MSKCC risk group Favourable 91 (49%) 22 (65%) 2.21 (1.02–4.78) 0.045 Intermediate/poor 95 (51%) 12 (35%) 1.0 (reference) Molina et al. Clin Genitourin Cancer 2013.
  • Nuevos agentes dirigidosNuevos agentes dirigidos Nuevas aproximaciones Nuevas aproximaciones Nuevos enfoques en el tratamiento del Cáncer Renal metastásico
  • Nuevos agentes que no han cumplido las expectativas Ang1/2, angiopoietin 1/2; FGF, fibroblast growth factor; PDGF, platelet-derived growth factor Ramucirumab Aflibercept Dovitinib BIBF 1120, Lenvatanib Tivozanib, Cediranib FGF receptor VEGF receptor PDGF receptor Tie2 receptor AKT MK-2206 FGF VEGF PDGF Ang1/2 AMG 386 Figlin et al. J Urol 2012 PI3K inhibitors
  • Nuevos agentes: c-MET HGFHGF PP SRCSRC PLCPLC GAB1GAB1 RASRAS P13KP13K MEKMEK ERKERK AKTAKT mTORmTOR PP PP PP TKI no selectivo Crizotinib TKI no selectivo Crizotinib TKI selectivo MET Tivantinib Foretinib Cabozantinib TKI selectivo MET Tivantinib Foretinib Cabozantinib HGFHGF
  • Estudios con agentes frente a c-MET Completed Phase I and II studies Agent Study type Results Foretinib (XL 880)1 Phase II, 74 patients with pRCC PFS: 9.3 months OS: NR Tivantinib (ARQ 197)2 One patient with RCC SD over 4 months Ongoing Phase II and III studies3 Agent Study type Current status CREATE study, crizotinib Phase II EORTC Type 1 pRCC type Ongoing AcSé, crizotinib Phase II, pRCC Ongoing METEOR study, cabozantinib (XL 184) Phase III, second-line vs everolimus, ccRCC Ongoing Cabozantinib (XL 184) Phase II, pRCC Study opening September 2013 Cabozantinib (XL 184) Phase II, first-line vs sunitinib, ccRCC Ongoing 1. Choueiri et al. JCO 2013; 2. Yap et al. JCO 2011; 3. www.clinicaltrials.gov
  • Cabozantinib Fase II 25 pacientes Más de una línea SLP: 14.7 meses RR 28% Figlin, Int J Cancer 2013;133:788-796
  • Nuevos agentes dirigidos Nuevos agentes dirigidos Nuevos agentes de inmunoterapia Nuevos agentes de inmunoterapia Nuevas aproximaciones Nuevas aproximaciones Nuevos enfoques en el tratamiento del Cáncer Renal metastásico
  • Nuevas dianas: Programmed death (PD)-1 pathway PD-1 regula la función de los linfocitos T uniéndose con su ligando (PD-L1) Ileana et al. Bul Cancer 2013
  • PD-L2–mediated inhibition of TH2 T cells Stromal PD-L1 modulation of T cells Reprinted from Clinical Cancer Research. 2013;19(5):1021-1034. Sznol M, et al. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. With permission from AACR. Blockade of PD-1 Binding to PD-L1 (B7-H1) and PD-L2 (B7-DC) Revives T Cells • PD-L1 expression on tumor cells is induced by γ-interferon • In other words, activated T cells that could kill tumors are specifically disabled by those tumors PD-1 PD-L1 PD-L2 T-cell receptor MHC-1 CD28 Shp-2 B7.1 IFN-γ–mediated upregulation of tumor PD-L1 PD-L1/PD-1–mediated inhibition of tumor cell killing Priming and activation of T cells Immune cell modulation of T cells Tumor cell IFN-γR IFN-γ Tumor-associated fibroblast M2 macrophage Treg cell Th2 T cell Other NFκB P13K CD8+ cytoxic T lymphocyte T-cell polarization TGF-β IL-4/13 Can you generate tumor-killing T cells? Dendritic cell Antigen priming Can the T cells get to the tumor? T-cell trafficking Can the T cells see the tumor? Peptide-MHC expression Can the T cells be turned off? Inhibitory cytokines Can the T cells be turned off? PD-L1 expression on tumor cells
  • Nuevas dianas: Programmed death (PD)-1 pathway • PD-L1 puede estar sobreexpresado en mRCC y asociado con: – Patología desfavorable – Comportamiento agresivo del tumor – Pobre supervivencia Thompson et al. Clin Cancer Res 2007; Thompson et al. PNAS 2004 A B C D Tumor PD-L1 Negative Positive 0 1 2 3 4 5 6 7 8 9 10 0 20 40 60 80 100 Cancer-specificSurvival N=306 Patients Years from nephrectomy to last follow-up
  • Agentes Anti-PD1/anti-PD-L1 en desarrollo Company Agent Structure Status Amplimune/GSK AMP-224 Fc fusion protein to PD-L2 Phase I Bristol Myers Squibb Nivolumab Fully human, IgG 4 Ab Phase III RCC, others solid tumours Curetech/Teva CT-011 Humanized monoclonal Phase II melanoma, RCC Genentech/Roch e MPDL3280A PDL-1 Ab Phase I Merck MK-3475 Humanized, IgG 4 ab Phase I McDermott. ASCO GU 2012 (educational session)
  • Targeting PD-L1: MPDL3280A Phase Ia Efficacy Summary in RCC RECIST 1.1 ORR, % SD of ≥ 24 Wks, % 24-Wk PFS, % Overall population (N = 140) 21 16 45 RCC* (n = 47) 13 32 53 Clear cell (n = 40) 13 35 57 Nonclear cell (n = 6) 17 0 20 Cho DC, et al. ASCO 2013. Abstract 4505. Correlación entre status de PDL-1 y eficacia
  • MPDL3280A Phase Ia: Tumor Burden Over Time in Patients With RCCChangeinSumofLongestDiameters (SLD)FromBaseline(%) Days on Study 100 50 -50 0 21 42 63 84 105 0 126 147 168 189 210 231 252 273 294 315 336 357 378 399 420 -100 441 New lesions Discontinued study 20 mg/kg (n = 13) 10 mg/kg (n = 12) 3 mg/kg (n = 2) 15 mg/kg (n = 18) Patients first dosed at 3-20 mg/kg prior to August 1, 2012, with at least 1 postbaseline evaluable tumor assessment; data cutoff February 1, 2013. Cho DC, et al. ASCO 2013. Abstract 4505.
  • Phase I Nivolumab Multidose Regimen • Eligibility: advanced melanoma, NSCLC, RCC, CRC, or CRPC with PD after 1-5 systemic therapies Day 1* 15* 29* 43* 57 Follow-up q8w x 6 (48 wks) Treat to confirmed CR, worsening PD, unacceptable toxicity, or 12 cycles (96 wks) Off study *Dose administered IV q2w. Scans done at baseline and following each 8-wk treatment cycle. Rapid PD or clinical deterioration Unacceptable toxicity CR/PR/SD or PD but clinically stable 8-wk treatment cycle Drake CG, et al. ASCO 2013. Abstract 4514.
  • Nivolumab: Outcomes in Patients With Metastatic RCC Dose, mg/kg Objective Response Rate, % (n/N) Median DoR, Wks (Range) SD Rate, % (n/N) ≥ 24 Wks ≥ 48 Wks All doses 29.4 (10/34) 56.1 (36.6-126.7+) 26.5 (9/34) 5.9 (2/34) 1 27.8 (5/18) 56.1 (40.1-76.1+) 22.2 (4/18) 5.6 (1/18) 10 31.3 (5/16) 56.1 (36.6-126.7+) 31.3 (5/16) 6.3 (1/16) Drake CG, et al. ASCO 2013. Abstract 4514.
  • Median OS for Patients With mRCC Treated With Nivolumab 1-yr OS: 70% 2-yr OS: 50% Drake CG, et al. ASCO 2013. Abstract 4514. 100 80 60 40 20 0 OS(%) Mos Since Treatment Initiation 510 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 Pts at Risk, n 034 33 28 28 23 19 14 12 8 8 8 8 8 5 2 0 0 Died/Treated 15/34 Median, Mos (95% CI) > 22 (13.60 - NE)
  • Change in Target Lesions From Baseline After Nivolumab Therapy • Unconventional “immune-related” responses in patients with NSCLC, Melanoma, and mRCC Melanoma First occurrence of new lesion RCC NSCLC Wks Since Treatment Initiation %ChangeFromBaselinein TargetTumorLesion Hodi FS, et al. 12th International Congress on Targeted Anticancer Therapies. Abstract O2.3. 100 80 60 40 20 0 -20 -40 -60 -80 -100 1600 10 20 30 40 50 60 70 80 90 100110120130140150
  • Nivolumab Phase II Dose-Ranging Study • Pts with clear-cell mRCC (≥1 VEGF TKI; ≤ 3 previous systemic therapies) – Randomized to receive nivolumab 0.3, 2, or 10 mg/kg IV every 3 wks Motzer RJ, et al. ASCO 2014. Abstract 5009. Outcome Nivolumab Dose 0.3 mg/kg (n = 60) 2 mg/kg (n = 54) 10 mg/kg (n = 54) ORR, % 20 22 20 Median PFS, mos 2.7 4.0 4.2 Median OS, mos 18.2 25.5 24.7 Tx-related AEs, % 75 67 78 Grade 3/4 AEs,* % 5 17 13 *No grade 3 or 4 pneumonitis reported.
  • Nuevos agentes: Ensayos fase III de vacunas + SOC versus SOC AGS-003, autonomous dendritic cell product; IMA901, consists of multiple tumour-associated peptides SOC, standard of care Sunitinib + AGS-003Sunitinib + AGS-003 SunitinibSunitinib Diagnosis of advanced kidney cancer Diagnosis of advanced kidney cancer Surgery Tumour sample taken Surgery Tumour sample taken Blood donation Blood donation Standard treatment with sunitinib Begins 6 weeks after first dose of sunitinib Standard treatment with sunitinib Begins 6 weeks after first dose of sunitinib Eligibility criteria:  Metastatic and/or locally advanced ccRCC  Favourable/intermediat e risk HLA-A*02- positive  No prior systemic therapy Sunitinib Sunitinib + IMA901 + GM-CSF R A N D O M I Z E D ADAPT Study IMPRINT trial ADAPT study trial highlights. Available at: http://adaptkidneycancer.com. Accessed September 19, 2013; www.clinicaltrials.gov (NCT01582672); www.clinicaltrials.gov (NCT01265901)
  • Overnight Shipment Overnight Shipment 1-2 Day Shipment How is AGS-003 Produced for Each Patient? •RNA that encodes autologous RCC antigens is isolated and amplified from a small tumor specimen (~ 200mg) isolated during nephrectomy •Monocytes isolated from a single leukapheresis are differentiated into DCs •Within the central manufacturing facility in Durham NC, the DCs are co-electroporated with RCC and CD40L RNA, vialed and cyropreserved for shipment •One production run yields up to 5 years of treatment per patient(24 doses)
  • N=21
  • Figlin, 2011 Int KC Symp
  • ADAPT Study Design Stratification based upon number of risk factors (1, 2, 3, or 4) Pre-treatment Induction Booster • Open-label design, no placebo-control or requirement for leukapheresis on Arm B • 80% power to detect ≥ 6 month OS improvement (HR: 0.708) Diagnosis, Nephrectomy, Screening ↓ Registration; Leukapheresis (Arm A only) Arm A: AGS-003 (8 doses) plus Standard treatment* for 48 weeks (N = 300) ≥ SD Pre-treatment Induction Booster Arm B: Standard treatment* for 48 weeks (N = 150) AGS-003 quarterly + Standard treatment* until PD Standard treatment* until PD ≥ SD * Standard treatment initiates with 6-week sunitinib cycles (50mg daily, 4 weeks on, 2 weeks rest.) Other compatible agents may be substituted for intolerance and/or early PD prior to week 48.
  • ¿El futuro está en tratamientos guiados por marcadores? Setting Tumour markers Treatment choice First-line therapy PDL1 expression Anti-PD1-based therapy PDL1-/VHL null, BAP-1 WT Selective VEGF inhibitor PDL1-/VHL null, BAP-1 mutant VEGF inhibitor + agent ‘X’ mTOR activation, high LDH TOR inhibitor Other mutation Specific inhibitor Second-line therapy Not necessary BAP-1, BRCA1 associated protein-1; LDH, lactate dehydrogenase; mTOR, mammalian target of rapamycin; PD1, programmed cell death 1; PDL1, programmed death ligand 1; TOR, target of rapamycin; VEGF, vascular endothelial growth factor; VHL, Von Hippel–Lindau. Atkins. IKCS 2012; Future leaders of RCC investigation
  • Estrategias de combinación Estrategias de combinación Nuevos agentes dirigidos Nuevos agentes dirigidos Nuevos agentes de inmunoterapia Nuevos agentes de inmunoterapia Nuevas aproximaciones Nuevas aproximaciones Nuevos enfoques en el tratamiento del Cáncer Renal metastásico
  • Tratamiento de combinación: pasado, presente y futuro Pasado Presente Futuro New studies combining immunotherapies with existing targeted agent •CA209-016 BMS-936558 + sunitinib/ sunitinib/pazopanib/ipilimumab 4 Early combination therapy slides were unsuccessful •INTORACT Bevacizumab + temsirolimus1 •BEST Sorafenib + temsirolimus2 •RECORD 2 Bevacizumab + everolimus3 1. Rini et al. ESMO 2012; 2. McDermott et al. JCO 2013; 3. Hainsworth et al. JCO 2010; 4. www.clinicaltrials.gov (NCT01472081)
  • Estrategias de combinación Estrategias de combinaciónNuevos escenariosNuevos escenarios Nuevos agentes dirigidos Nuevos agentes dirigidos Nuevos agentes de inmunoterapia Nuevos agentes de inmunoterapia Nuevas aproximaciones Nuevas aproximaciones Nuevos enfoques en el tratamiento del Cáncer Renal metastásico
  • Neoadyuvancia en cáncer renal NCT01069770 Sunitinib NCT01404104 Temsirolimus NCT01263769 Axitinib NCT000727532 Sorafenib NCT01361113 Pazopanib
  • Adyuvancia en cáncer renal SORCE Sorafenib PROTECT Pazopanib S-TRAC Sunitinib ASSURE Sunitinib vs sorafenib vs placebo ATLAS Axitinib EVEREST Everolimus
  • Nefrectomía en enfermedad metastásica CARMENA Nephrectomy + sunitinib vs nephrectomy alone SURTIME Surgery prior/after sunitinib
  • PI: Arnaud Mejean (CCAFU, HEGP, Paris, France) CARMENA: Estudio fase III sunitinib versus nefrectomía + sunitinib Objetivo primario: ¿Es sunitinib no inferior a la combinación nefrectomía + sunitinib en supervivencia global? Nephrectomy Sunitinib 50 mg/day (Schedule 4/2) Sunitinib 50 mg/day (Schedule 4/2) R A N D O M I Z A T I O N N=576 Metastatic clear-cell RCC www.clinicaltrials.gov (NCT00930033)
  • SURTIME: Estudio fase III comparando nefectomía inmediata versus diferida • Objetivo primario: PFS • Objetivos secundarios: OS, association with prognostic gene and protein expression profiles Nephrectomy Sunitinib 50 mg/day (Schedule 4/2) Nephrectomy Sunitinib 50 mg/day (Schedule 4/2) N=458 Eligibility criteria Synchronous mRCC and primary tumour in situ R A N D O M I Z A T I O N www.clinicaltrials.gov (NCT01099423) PI: Axel Bex (NCI, Amsterdam, Netherlands)
  • Conclusiones • Los tratamientos antidiana han cambiado el tratamiento del cáncer renal en los últimos años • Los tratamientos antivegf permanecen con¡mo el SoC en primera línea en pacientes de riesgo favorable o intermedio • VEGFR- y mTOR-targeted son opciones en segunda línea • Futuro • Fármacos contra nuevas dianas • Marcadores predictivos • Combinaciones de los nuevos fármacos • Nuevos escenarios