pacientes candidatos tercera linea de tratamiento

PACIENTES CANDIDATOS
TERCERA LINEA DE
TRATAMIENTO
Dr. Fernando Arranz Arija.
Complejo Asistencial de Palencia.
Colabora:
TREATMENT BEYOND THE SECOND LINE
•  Patients who have progressed following an initial
–  molecularly targeted agent and
–  immunotherapy
•  may benefit from treatment with an alternative
targeted agent.
•  Patients should be encouraged to participate in
formal clinical trials whenever possible.
“no se moja”
Decisión basada en:
•  guías-evidencia
•  eficacia
•  seguridad
•  tipo de paciente
•  familiaridad con el fármaco
•  agentes disponibles
2ª OPORTUNIDAD
Tratamientos
disponibles
The International Metastatic
Renal Cell Carcinoma
Database Consortium
(IMDC)
Recibir 2ª y 3ª línea de
tratamiento es factor
independiente de mejor SG.
•  Sólo 1 línea
•  SG 14,9 m
•  SLP 6,7 m
•  Dos líneas
•  SG 21 m
•  SLP 3,4 m
•  Tres o más líneas
•  SG 39,2 m
•  SLP 4 m
SG se cuenta desde diagnostico
SLP desde el inicio de la línea
2015 Genitourinary Cancers Symposium
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J Clin Oncol 33, 2015 (suppl 7; abstr 430)
Everolimus
Sorafenib
Sunitinib
Temsirolimus
Pazopanib
Axitinib
25%
14%
13%
11%
10%
6%.
47,4 m desde dgno
10,5 m en 4ª línea
3,2 m
¿Tenemos evidencia?
¿para qué fármaco?
SORAFENIB
•  OR:23,5 %
•  PFS 4 m.
•  OS 7 m.
Dovitinib versus sorafenib for third-line targeted treatment of patients with
metastatic renal cell carcinoma: an open-label, randomised phase 3 trial
Volume 15, No. 3, p286–296, March 2014
SUNITINIB
.
PAZOPANIB
82% tratados
previamente con
TKI en 1ª línea,
probablemente
Sunitinib
•  Estudio retrospectivo
•  31 pts recibieron pazopanib
•  14 en 2ª linea
•  17 en 3ª linea
•  10 everolimus
•  6 Sorafenib
•  1 Tensirolimus
•  Resultados en 3ª :
•  6 RP EN 2ª LINEA (19%)
• 0% en 3ª linea
•  18 SD (58%)
•  PFS 7,4 m
• 11 m en 2ª línea
•  3,8 m en 3ª línea
•  SG no alcanzada
AXITINIB
he encontrado poco…una publicación de ASCO 2014…
Efficacy of axitinib in patients with metastatic renal
cell carcinoma previously treated with both VEGFRTKI and mTORI.
Journal Of Clinical Oncology, 2014 May 20, Vol.32(15) Suppl S
• 12, 9 male and 3 female
Japanese patients
•  Response to axitinib was
•  PR 2 (17%),
•  SD 8 (66%),
•  PD (17%).
•  The median PFS was 5.2 months.
•  The median OS was not reached
Y de forma indirecta, si SORAFENIB es eficaz y AXITINIB es “superior” en
2ª línea…
2626 Efficacy and safety of axitinib as third line therapy in
metastatic renal cell carcinoma (mRCC): Retrospective
analysis
A. Guida, M. Matias, L. Albiges, L. Derosa, Y. Loriot, C.
Massard, K. Fizazi, B. Escudier
BEVACIZUMAB +/- INTERFERÓN
Activity of Single-Agent Bevacizumab in Patients With Metastatic Renal Cell Carcinoma
Previously Treated With Vascular Endothelial Growth Factor Tyrosine Kinase Inhibitors.
James D. Turnbull1, Julien Cobert2, Tracy Jaffe3, Michael R. Harrison1, 2, 4, Daniel J. George1, 2, 4, 5, Andrew J. Armstrong1, 2, 4, 5, ,
Everolimus With or Without
Bevacizumab in Treating
Patients With Advanced Kidney
Cancer That Progressed After
First-Line Therapy
EVEROLIMUS
2ª vs 3ª
5,4 m. vs 4 m.
Eve vs Placebo
4 m. vs 1,8 m.
Y apoyado por múltiples estudios retrospectivos …
• 
Albiges L, Bergmann L, Eymard JC , et al. Everolimus for Patients With Metastatic Renal Cell Carcinoma (mRCC) Refractory to Anti‐VEGF
Therapy: Preliminary Results of a Pooled Analysis of Noninterventional Studies. Presented at the 2013 Genitourinary Cancers Symposium,
Orlando, Florida, February 14—16, 2013. Abstract 392.
• 
Alimohamed N, Lee JL, Srinivas S et al. A Population‐Based Overview of Sequences of Targeted Therapy in Metastatic Renal Cell Carcinoma.
Clin Genitourin Cancer. 2014 Aug;12(4):e127-31
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Buchler T, Bortlicek Z, Poprach A, Kubackova K, Kiss I, Zemanova M, Fiala O, Dusek L, Vyzula R, Melichar B; on behalf of the Czech Renal
Cancer Cooperative Group. Efficacy of everolimus in second‐ and third‐line therapy for metastatic renal cell carcinoma: A registry‐based
analysis. Urol Oncol. 2014 Mar 11. pii: S1078‐1439(13)00509‐7. doi: 10.1016/j.urolonc.2013.12.007. [Epub ahead of print].
• 
Busch J, Seidel C, Erber B, et al. Retrospective comparison of triple‐sequence therapies in metastatic renal cell carcinoma. Eur Urol. 2013
Jul;64(1):62-70.
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Calvani N, Morelli F, Chiuri V, et al. Prolonged exposure to tyrosine kinase inhibitors or early use of everolimus in metastatic renal cell
carcinoma: are the two options alike? Med Oncol. 2013;30(2):578.
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Harada KH, Miyake HM and Fujisawa MF. Sequential use of mammalian taget of rapamycin inhibitors in patients with metastatic renal cell
carcinoma following failure of tyrosin kinase inhibitors. The journal of Urology 2014; 191 4S
• 
Harrison MR, George DJ, Walker MS et al., “Real World” Treatment of Metastatic Renal Cell Carcinoma in a Joint Community‐Academic
Cohort: Progression‐Free Survival Over Three Lines of Therapy. Clin Genitourin Cancer. 2013 Dec;11(4):441‐50.
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Lacovelli R, Cartenì G, Sternberg CN, et al. Clinical outcomes in patients receiving three lines of targeted therapy for metastatic renal cell
carcinoma: Results from a large patient cohort. European Journal of Cancer 2013;49:2134–2142.
• 
Kumano M, Miyake H, Harada K et al. Sequential use of mammalian target of rapamycin inhibitors in patients with metastatic renal cell
carcinoma following failure of tyrosine kinase inhibitors. Med Oncol. 2013;30(4):745.
• 
Maj‐Hes A, Medioni J, Scotte F, et al. Rechallenge with mTOR inhibitors in metastatic renal cell carcinoma patients who progressed on
previous mTOR inhibitor therapy. Oncology 2013;85:8–13.
• 
Pal S, Malangone E, Bhurke S, et al. Real World Treatment Patterns in Third‐line Patients with Metastatic Renal Cell Carcinoma (mRCC) –The
Changing andscape in the United States. Presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium,
February 14–16, 2013, Orlando, FL.
• 
Maute L, Grünwald V, Weikert S, Kube U, Gauler T, Kahl C, Burkholder I, Bergmann L. Therapy of mRCC beyond mTORinhibition in clinical
practice: results of a retrospective analysis. J Cancer Res Clin Oncol. 2014 Feb 21. [Epub ahead of print]
Y también datos para 2ª oportunidad con m-TOR
Tensirolimus/Everolimus
•  12 pacientes
•  3ª o 4ª línea de tratamiento tras
•  1 ó 2 anti VEGF
•  1 mTOR
•  Recibieron un 2 y 3 er mTOR
•  7 EVE-----TEN
•  5 TEN-----EVE
•  Independiente de la secuencia:
•  50 % respondieron a Everolimus
•  33 % respondieron a Tensirolimus
Sin embargo, everolimus
parece haber perdido fuerza
últimamente
CABOZANTINIB
NIVOLUMAB
NIVOLUMAB
ORIGINAL ARTICLE
Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma
Robert J. Motzer, M.D., Bernard Escudier, M.D., David F. McDermott, M.D., Saby George, M.D., Hans J. Hammers, M.D., Ph.D., Sandhya Srinivas, M.D., Scott S. Tykodi, M.D.,
Ph.D., Jeffrey A. Sosman, M.D., Giuseppe Procopio, M.D., Elizabeth R. Plimack, M.D., Daniel Castellano, M.D., Toni K. Choueiri, M.D., Howard Gurney, M.D., Frede Donskov,
M.D., Ph.D., Petri Bono, M.D., Ph.D., John Wagstaff, M.D., Thomas C. Gauler, M.D., Takeshi Ueda, M.D., Ph.D., Yoshihiko Tomita, M.D., Fabio A. Schutz, M.D., Christian
Kollmannsberger, M.D., James Larkin, M.D., Ph.D., Alain Ravaud, M.D., Ph.D., Jason S. Simon, Ph.D., Li-An Xu, Ph.D., Ian M. Waxman, M.D., and Padmanee Sharma, M.D.,
Ph.D. for the CheckMate 025 Investigators
N Engl J Med 2015; 373:1803-1813November 5, 2015DOI: 10.1056/NEJMoa1510665
56 pts
Quimioterapia
Wien Klin Wochenschr. 2005 Jan;117(1-2):63-5.
Major response and clinical benefit following
third-line treatment for Bellini duct
carcinoma.
(CDDP-GEM tras IL/IF y Talidomida)
Fakhrai N1, Haitel A, Balassy C, Zielinski CC, Schmidinger M.
Tratamiento soporte/paliativo
Clinical Trial Participants With Metastatic Renal Cell Carcinoma
Differ From Patients Treated in Real-World Practice
JOP Nov 1, 2015:491-497; published online onSeptember 1, 2015,
ESTUDIO RETROSPECTIVO
DE UN CENTRO CON GRAN
VOLUMEN
“24 pts”
Conclusiones
•  Los agentes anti-diana han mejorado el pronóstico del CR
de forma muy importante, sin embargo, la aparición de
resistencias es la norma
•  En caso de resistencia se puede tratar por una vía
alternativa, aunque
•  Se acumulan los datos que apoyan el re-tratamiento
posterior de la misma vía inicial, sobre todo si:
•  RO a tratamiento previo
•  Largo periodo de SLP en tratamientos con TKI
•  RO 17 %, SD 50%
•  En pacientes respondedores, respuestas
prolongadas de 9 m
•  Esperamos con interés los resultados de ensayos
aleatorizados y de tratamientos inmunomoduladores.
Molecular Subtypes of Clear Cell Renal Cell Carcinoma Are Associated
with Sunitinib Response in the Metastatic Setting
1. Benoit Beuselinck1,2,3,5, Sylvie Job6, Etienne Becht2,3,4, Alexandra Karadimou1,2,3, Virginie Verkarre2,7, Nicolas Giraldo2,4 Nathalie Rioux-Leclercq8, Vincent Molinié9, Mathilde Sibony2,10, Reza Elaidi5, Corinne Teghom5, Jean-Jacques Patard11,Arnaud Méjean2,5, Wolf Herman Fridman2,3,4, Jessica Zucman-Rossi1,2,3,5,*
•  4 TIPOS MOLECULARES DISTINTOS, CON DISTINTO
MICROAMBIENTE, y CON DISTINTA RESPUESTA A
INMUNOTERAPIA Y A SUNITINIB