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INMUNOTERAPIA EN CÁNCER: MELANOMA LUIS DE LA CRUZ MERINO Sº ONCOLOGÍA MÉDICA HUVMACARENA (SEVILLA)

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Presentation on theme: "INMUNOTERAPIA EN CÁNCER: MELANOMA LUIS DE LA CRUZ MERINO Sº ONCOLOGÍA MÉDICA HUVMACARENA (SEVILLA)"— Presentation transcript:

1 INMUNOTERAPIA EN CÁNCER: MELANOMA LUIS DE LA CRUZ MERINO Sº ONCOLOGÍA MÉDICA HUVMACARENA (SEVILLA)

2 Este ponente ha dispuesto de total libertad para la elaboración de esta ponencia en la recogida y presentación de datos e información científica actualizada y de interés; sin embargo los principios activos y terapias mencionadas en esta ponencia podrían no estar autorizados en todos los países para las indicaciones comentadas. Pembrolizumab no está aún autorizado en la UE.

3 INDEX MELANOMA: PARADIGM OF IMMUNOGENIC TUMOR - TILs - NEOANTIGENS - IMMUNE SYNAPSES ANTIBODIES AGAINST IMMUNE CHECKPOINTS - Anti-CTLA4 - Anti-PD1 AND COMBOS CONCLUSIONS

4 Alexandrov et al. Nature. Aug 2013

5

6

7 MODULATION OF IMMUNE RESPONSES 7 Melero I, Grimaldi AM, Perez-Gracia JL, Ascierto PA. Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res. 2013 Mar 1;19(5):997-1008

8 Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23

9 Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23

10 Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26

11 Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med. 2011 Jun 30;364(26):2517-26

12 Median OS and Landmark OS Rates to 5 Years Treatment Group Median OS, months [95% CI] Overall survival rate, % [95% CI] 1-year2-year3-year4-year5-year Ipilimumab + DTIC (n=250) 11.2 [9.5-13.8] 47.6 [41.2-53.7] 28.9 [23.3-34.7] 21.3 [16.3-26.6] 19.1 [14.4-24.3] 18.2 [13.6-23.4] Placebo + DTIC (n=252) 9.1 [7.8-10.5] 36.4 [30.4-42.4] 17.8 [13.3-22.8] 12.1 [8.4-16.5] 9.7 [6.4-13.7] 8.8 [5.7-12.8] Maio M, Bondarenko I, Robert C, et al. 17th ECCO- 38th ESMO- 32nd ESTRO European Cancer Congress (ECC 2013). Abst 3704. European Journal of Cancer, Volume 49 Supplement 2, September 2013

13 Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma N Engl J Med. 2014 Dec 4;371(23):2189-99

14 Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma N Engl J Med. 2014 Dec 4;371(23):2189-99

15 Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma N Engl J Med. 2014 Dec 4;371(23):2189-99

16 TargetAntibodyMoleculeDevelopment stage PD-1 BMS-936558Fully human IgG4 Phase III multiple tumors (melanoma, RCC, NSCLCa, HNSCC) MK-3475Humanized IgG4 Phase I-II multiple tumors Phase III NSCLC/melanoma CT-011Humanized IgG1Phase II multiple tumors PD-L1 MEDI-4736Engineered human IgG1Phase I-II multiple tumors MPDL-3280AEngineered human IgG1 Phase I-II multiple tumors Phase III NSCLC MSB0010718CFully human IgG1Phase I solid tumors Clinical Development of Inhibitors of PD-1 Immune Checkpoint www.clinicaltrials.gov

17 Efficacy and Safety of the Anti-PD-1 Monoclonal Antibody MK-3475 in 411 Patients With Melanoma Antoni Ribas, 1 F. Stephen Hodi, 2 Richard Kefford, 3,4 Omid Hamid, 5 Adil Daud, 6 Jedd D. Wolchok, 7 Wen-Jen Hwu, 8 Tara C. Gangadhar, 9 Amita Patnaik, 10 Anthony M. Joshua, 11 Peter Hersey, 4 Jeffrey Weber, 12 Roxana Dronca, 13 Hassane Zarour, 14 Kevin Gergich, 15 Xiaoyun (Nicole) Li, 15 Robert Iannone, 15 S. Peter Kang, 15 Scot Ebbinghaus, 15 Caroline Robert 16 1 University of California, Los Angeles, CA; 2 Dana-Farber Cancer Institute, Boston, MA; 3 Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia, Sydney, Australia; 4 University of Sydney, Sydney, Australia; 5 The Angeles Clinic and Research Institute, Los Angeles, CA; 6 University of California, San Francisco, CA; 7 Memorial Sloan-Kettering Cancer Center, New York, NY; 8 MD Anderson Cancer Center, Houston, TX; 9 Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA; 10 South Texas Accelerated Research Therapeutics, San Antonio, TX; 11 Princess Margaret Hospital, Toronto, Ontario; 12 H. Lee Moffitt Cancer Center, Tampa, FL; 13 Mayo Clinic, Rochester, MN; 14 University of Pittsburgh, Pittsburgh, PA; 15 Merck & Co., Inc., Whitehouse Station, NJ; 16 Institut Gustave-Roussy, Villejuif, France

18 Maximum Percent Change from Baseline in Tumor Size a (Central Review, RECIST v1.1) a In patients with measurable disease at baseline by RECIST v1.1 by central review and ≥1 postbaseline assessment (n = 317). Percentage changes >100% were truncated at 100%. Analysis cut-off date: October 18, 2013. 72% MK-3475

19 Time to and Durability of Response (Central Review, RECIST v1.1) Presented by: Antoni Ribas a Ongoing response defined as alive, progression free, and without new anticancer therapy. Analysis cut-off date: October 18, 2013. 88% of responses ongoing a Median response duration not reached (range, 6+ to 76+ weeks) MK-3475

20 Ribas SMR 2014 Cut-off April 2014 MK-3475

21 BMS-936558 Hodi SMR 2014

22 BMS-936558

23 Hodi SMR 2014

24

25 Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33

26 Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33

27 27 Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013 Jul 11;369(2):122-33

28 . Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30

29 BMS-936558. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30

30 BMS-936558. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30

31 BMS-936558. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30

32 BMS-936558. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30

33 BMS-936558. Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015 Jan 22;372(4):320-30

34 BMS-936558

35 Ribas SMR 2014 MK-3475

36 Ribas SMR 2014 MK-3475

37 . Tumeh PC, Harview CL, Yearley et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance Nature. 2014 Nov 27;515(7528):568-71

38 NCT01844505/CheckMate 067: Ph 3 trial BMS-936558 or BMS- 936558+ ipilimumab vs ipilimumab alone KEYNOTE 006: Ph 3 trial MK-3475 two doses vs ipilimumabone Combinations with emerging approaches in melanoma –Talimogene Laherparepvec (T-VEC) combination * MK-3475 With or Without T-VEC in Unresected Melanoma –Other new immunotherapeutic drugs * BMS-936558 + lirilumab (anti-KIR) * BMS-936558 + anti-LAG3 * BMS-936558 + anti-CD137 MK-3475 in melanoma brain metastases (PN027). Yale Univ. Adjuvant therapy of melanoma……… Trials Ongoing and closed with results pending…

39 ANTI-CTLA4 AND ANTI-PD1 PITFALLS IN CLINICAL DEVELOPMENT Weaknesses of clinical trials: - Brain mets up to 40% advanced melanoma pts: underrepresented - Autoimmunity diseases up to 8% population: excluded - What should we do with this patients? Absence of predictive biomarkers (by now…) - PD-L1 does not seem a reliable biomarker, not exclude PD-L1- patients from therapy!!! Optimal duration of anti-CTLA4 and anti-PD1 treatment in responders unknown How much time will we need to use anti-PD1 therapy in daily practice? Which will be the cost??

40 IMMUNOTHERAPY IN MELANOMA CONCLUSIONS 5 years OS of anti-CTLA4 = 18-20% 2 years OS of anti-PD1 = 50%.... AND extremely well tolerated 2 years OS anti-CTLA4+ anti-PD1 = 80% … BUT far more toxic (63% G3/4 toxicity, 23% discontinuations) and in a more favourable population (>50% non pretreated) to shed light in this maremagnum… - Ph 3 concurrent nivo + ipi combination vs nivo vs ipi (NCT01844505, NCT01927419) - Ph 3 study to evaluate two different dosing schedules of pembro (MK- 3475) compared to ipi (MK-3475-006/KEYNOTE 006) ……….their results are eagerly awaited!!! M Maio ECCO 2013 Ribas ASCO 2014 Hodi SMR 2014


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