Transcript INMUNOTERAPIA EN CÁNCER: MELANOMA LUIS DE LA CRUZ MERINO Sº ONCOLOGÍA MÉDICA HUVMACARENA (SEVILLA) Este ponente ha dispuesto de total libertad para la elaboración de.

INMUNOTERAPIA EN CÁNCER: MELANOMA
LUIS DE LA CRUZ MERINO
Sº ONCOLOGÍA MÉDICA
HUVMACARENA (SEVILLA)
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.
INDEX
• MELANOMA: PARADIGM OF IMMUNOGENIC TUMOR
- TILs
- NEOANTIGENS
- IMMUNE SYNAPSES
• ANTIBODIES AGAINST IMMUNE CHECKPOINTS
- Anti-CTLA4
- Anti-PD1 AND COMBOS
• CONCLUSIONS
Alexandrov et al. Nature. Aug 2013
MODULATION OF IMMUNE RESPONSES
Melero I, Grimaldi AM, Perez-Gracia JL, Ascierto PA.
Clinical development of immunostimulatory monoclonal antibodies and opportunities for combination.
7
Clin Cancer Res. 2013 Mar 1;19(5):997-1008
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
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
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
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
Median OS and Landmark OS Rates to 5 Years
Overall survival rate, % [95% CI]
Treatment Group
Median OS,
months
[95% CI]
1-year
2-year
3-year
4-year
5-year
Ipilimumab +
DTIC (n=250)
11.2
[9.5-13.8]
47.6
28.9
21.3
19.1
18.2
[41.2-53.7] [23.3-34.7] [16.3-26.6] [14.4-24.3] [13.6-23.4]
Placebo +
DTIC (n=252)
9.1
[7.8-10.5]
36.4
17.8
[30.4-42.4] [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
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
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
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
Clinical Development of Inhibitors of PD-1
Immune Checkpoint
Target
PD-1
PD-L1
Antibody
Molecule
Development stage
BMS-936558
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
MEDI-4736
Engineered human IgG1
Phase I-II multiple tumors
MPDL-3280A
Engineered human IgG1
Phase I-II multiple tumors
Phase III NSCLC
MSB0010718C
Fully human IgG1
Phase I solid tumors
www.clinicaltrials.gov
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
Maximum Percent Change from Baseline in
Tumor Sizea (Central Review, RECIST v1.1)
100
Change From Baseline in Sum of
Longest Diameter of Target Lesion, %
80
60
40
72%
20
0
-20
-40
-60
-80
IPI-T
IPI-N
-100
aIn
MK-3475
Individual Patients Treated With Pembrolizumab
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.
Time to and Durability of Response (Central Review, RECIST v1.1)
12 months
Individual Patients Treated With Pembrolizumab
MK-3475
6 months
• 88% of responses ongoinga
• Median response duration
not reached (range, 6+ to
76+ weeks)
IPI-T
IPI-N
Complete Response
Partial Response
Progression
On Treatment
10
aOngoing
18 months
30
50
Time, weeks
response defined as alive, progression free, and without new anticancer therapy.
Analysis cut-off date: October 18, 2013.
70
Presented by: Antoni Ribas
90
MK-3475
Cut-off April 2014
Ribas SMR 2014
BMS-936558
Hodi SMR 2014
BMS-936558
BMS-936558
BMS-936558
Hodi SMR 2014
Hodi SMR 2014
Hodi SMR 2014
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
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
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
.
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
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
BMS-936558
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
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
BMS-936558
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
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
BMS-936558
MK-3475
Ribas SMR 2014
MK-3475
MK-3475
Ribas SMR 2014
.
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
Trials Ongoing and closed with results pending…
• NCT01844505/CheckMate 067: Ph 3 trial BMS-936558 or BMS936558+ 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………
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??
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)
M Maio ECCO 2013
Ribas ASCO 2014
Hodi SMR 2014
……….their results are eagerly awaited!!!