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INMUNOTERAPIA EN CÁNCER: MELANOMA

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Presentation on theme: "INMUNOTERAPIA EN CÁNCER: MELANOMA"— 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
Melero I, Grimaldi AM, Perez-Gracia JL, Ascierto PA. Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination. Clin Cancer Res Mar 1;19(5): 7

8 Hodi FS, O'Day SJ, McDermott DF, et al.
Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 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 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 Jun 30;364(26):

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

12 Median OS and Landmark OS Rates to 5 Years
Treatment Group Median OS, months [95% CI] Overall survival rate, % [95% CI] 1-year 2-year 3-year 4-year 5-year Ipilimumab + DTIC (n=250) 11.2 [ ] 47.6 [ ] 28.9 [ ] 21.3 [ ] 19.1 [ ] 18.2 [ ] Placebo + DTIC (n=252) 9.1 [ ] 36.4 [ ] 17.8 [ ] 12.1 [ ] 9.7 [ ] 8.8 [ ] Maio M, Bondarenko I, Robert C, et al. 17th ECCO- 38th ESMO- 32nd ESTRO European Cancer Congress (ECC 2013). Abst 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 Dec 4;371(23):

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

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

16 Clinical Development of Inhibitors of PD-1 Immune Checkpoint
Target Antibody Molecule Development stage PD-1 BMS Fully human IgG4 Phase III multiple tumors (melanoma, RCC, NSCLCa, HNSCC) MK-3475 Humanized IgG4 Phase I-II multiple tumors Phase III NSCLC/melanoma CT-011 Humanized IgG1 Phase II multiple tumors PD-L1 MEDI-4736 Engineered human IgG1 MPDL-3280A Phase III NSCLC MSB C Fully human IgG1 Phase I solid tumors

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 Robert16 1University of California, Los Angeles, CA; 2Dana-Farber Cancer Institute, Boston, MA; 3Crown Princess Mary Cancer Centre, Westmead Hospital and Melanoma Institute Australia, Sydney, Australia; 4University of Sydney, Sydney, Australia; 5The Angeles Clinic and Research Institute, Los Angeles, CA; 6University of California, San Francisco, CA; 7Memorial Sloan-Kettering Cancer Center, New York, NY; 8MD Anderson Cancer Center, Houston, TX; 9Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA; 10South Texas Accelerated Research Therapeutics, San Antonio, TX; 11Princess Margaret Hospital, Toronto, Ontario; 12H. Lee Moffitt Cancer Center, Tampa, FL; 13Mayo Clinic, Rochester, MN; 14University of Pittsburgh, Pittsburgh, PA; 15Merck & Co., Inc., Whitehouse Station, NJ; 16Institut Gustave-Roussy, Villejuif, France 17

18 Maximum Percent Change from Baseline in Tumor Sizea (Central Review, RECIST v1.1)
Individual Patients Treated With Pembrolizumab -100 -80 -60 -40 -20 20 40 60 80 100 Change From Baseline in Sum of Longest Diameter of Target Lesion, % IPI-T IPI-N 72% Only patients with measurable disease at baseline per RECIST v1.1 per central review and ≥1 postbaseline assessment are shown (n = 317). 227 of the 317 patients had tumor shrinkage (72%), including 123 who had shrinkage of ≥50% (39%) MK-3475 aIn 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. 18

19 Individual Patients Treated With Pembrolizumab
Time to and Durability of Response (Central Review, RECIST v1.1) IPI-T IPI-N Complete Response Partial Response Progression On Treatment Time, weeks 10 30 50 70 90 Individual Patients Treated With Pembrolizumab 12 months 6 months 18 months MK-3475 88% of responses ongoinga Median response duration not reached (range, 6+ to 76+ weeks) Only confirmed best responses are displayed. Therefore, for patients who experienced PR before CR, only CR is shown. Duration of response ranged from 6+ to 76+ weeks for IPI-T patients and 6+ to 74+ weeks for IPI-N patients The median time to confirmed response was 28 weeks in B1 (range, 12-72), 24 weeks in B2 (1 at week 12, 1 at week 36), and 26 weeks in D (two at week 16, 1 each at week 36 and 37) aOngoing response defined as alive, progression free, and without new anticancer therapy. Analysis cut-off date: October 18, 2013. Presented by: Antoni Ribas 19

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

21 BMS Hodi SMR 2014

22 BMS BMS BMS Hodi SMR 2014

23 Hodi SMR 2014

24 Hodi SMR 2014

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

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

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

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

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

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

34 BMS

35 MK-3475 Ribas SMR 2014

36 MK-3475 MK-3475 Ribas SMR 2014

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

38 Trials Ongoing and closed with results pending…
NCT /CheckMate 067: Ph 3 trial BMS or BMS 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 lirilumab (anti-KIR) * BMS anti-LAG3 * BMS anti-CD137 MK-3475 in melanoma brain metastases (PN027). Yale Univ. Adjuvant therapy of melanoma……… 022 y 029: las primeras partes solo participan centros de USA. 38

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 (NCT , NCT ) - Ph 3 study to evaluate two different dosing schedules of pembro (MK- 3475) compared to ipi (MK /KEYNOTE 006) ……….their results are eagerly awaited!!! M Maio ECCO 2013 Ribas ASCO 2014 Hodi SMR 2014


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