actualización del abordaje terapéutico del cáncer de cérvix€¦ · 92% de las pacientes...
TRANSCRIPT
Ana de Juan Ferré – Oncología Médica
H. U. Marqués de Valdecilla – Santandera
Actualización del Abordaje Terapéutico
del Cáncer de Cérvix
Mesa Redonda 2: Estrategia Terapéutica en Tumores Ginecológicos
Int J Cancer 2017
85% de los nuevos diagnósticos ocurren en países subdesarrollados
2º cáncer en la mujer a nivel mundial; 10º tumor más incidente en España
Edad media: 48 años (47% antes de los 35 años)
70-80% epidermoides; 20-25% adenocarcinomas; <5% resto
2/3 in situ; Citología → descenso de la mortalidad desde 1940 (>70%)
Agente etiológico → virus papiloma humano (VPH), transmisión sexual (ETS)
Nature 2017
Se caracterizan molecularmente 228 CC
14 genes mutaciones recurrentes- 9 conocidos: PIK3CA, EP300,
FBXW7, PTEN, ARID1A, NFE2K2, HLA-B, KRAS, MAPK1
- 5 nuevos SHKBP1, ERBB3, CASP8, HLA-A, TGFBR2
Mutaciones mediadas por APOBEC1026 genes silenciados epigenéticamente (metilaciones)
Amplificaciones de dianas de inmunoterapia (PD-L1, PD-L2) y de BCAR4 (asociado a respuesta con lapatinib)
CC endometrial-like (HPV negativos): KRAS, ARID1A, PTEN
Queratina Queratina Adenocarcinomas
Actualización del Abordaje Terapéutico del Cáncer de Cérvix
Guión
1. Estadificación
1. Cirugía en Enfermedad Localizada
2. Enfermedad Localmente Avanzada
4. Enfermedad Avanzada
FIGO 2009
No se considera la invasión linfo-vascular
ni la afectación ganglionar
“Estadificación Clínica”
basada en tamaño, infiltración vagina, parametrios o
recto/vejiga determinada por EF
Rx tórax, pielografía, cistoscopia o rectoscopia
Papel de RM y PET en países desarrollados
FIGO 2018
La invasión linfo-vascular NO cambia estadificación, sí el tratamiento
IIIC1r
IIIC1p
No se
considera la
extensión, sí
la profundidad
FIGO 2018
QT-RT
Cirugía o RT
QT
Actualización del Abordaje Terapéutico del Cáncer de Cérvix
Guión
1. Estadificación
1. Cirugía en Enfermedad Localizada
2. Enfermedad Localmente Avanzada
4. Enfermedad Avanzada
Histerectomía Radical Abierta o Mínimamente InvasivaPhase III randomized trial of laparoscopic or robotic versus abdominal radical
hysterectomy in patients with early-stage cervical cancer: LACC trial
Ramirez PT, et al. N Engl J Med 2018
Laparoscopic or robotic radical hysterectomy → higher recurrence and worse OS
92% de las pacientes incluidas tenían tumores etapa IB1
Histerectomía Radical Abierta o Mínimamente Invasiva (MIS)Comparative effectiveness of minimally-invasive staging surgery in women with early-stage cervical cancer
Melamed A, et al. N Engl J Med 2018
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Meier and Cox proportional hazard models. To assess whether these findings were due to causal effects, we conducted an interrupted time series to evaluate whether adoption of MIS led to a change in survival.
Results: We identified 1,166 (52.5%) women who underwent an RH via laparotomy, and 1,055 had MIS (47.5%). In the MIS group, 833 (79%) had robotic surgery. Patients who received MIS were more often white, were privately insured, were from zip codes with higher income and educational levels, were treated in academic centers, had smaller, lower grade tumors, and more often had adenocarcinomas. All covariates were well-balanced in the propensity-matched cohorts. There was no difference between the groups in rates of parametrial invasion (12% vs 9%, P = 0.09), positive margins (5% vs 5%, P = 0.47), or lymph node involvement (11% vs 9%, P = 0.15). The median follow-up was 51 months for MIS and 53 for laparotomy. Women who had MIS had 48% higher hazard of death from any cause compared to those who had laparotomy (HR = 1.48, 95% CI 1.10–1.98). In an interrupted time series, before adoption of MIS (2000–2006) there was a nonsignificant trend toward improved survival over time (annual percentage change 0.4, 95% CI 0.1–0.8). Adoption of MIS was associated with a significant change of trend (P = 0.02), with 4-year survival declining by 1.0% per year (95% CI 0.3–1.6) after 2006. See Figures 1A and 1B.
Conclusion: Despite minimal evidence of the benefits of MIS, a significant number of women with CeCa undergo MIS RH. Compared with laparotomy, MIS is associated with lower survival for women with early-stage CeCa.
Fig. 1a. Kaplan–Meier survival curves for the propensity-matched IPTW groups. Women who underwent MIS RH had inferior overall survival compared with those who underwent laparotomy (plog rank = 0.02). The probability of death within 4-years of diagnosis was 8.4% among MIS compared with 4.7% among those who had laparotomy.
Fig. 1b. Interrupted time series evaluating the effect of adoption of MIS RH on 4-year relative survival among women with CeCa. The 4-year survival among women receiving RH for CeCa (diamonds) and 95% CI (whiskers) are plotted annually 2000-2010. The proportion of RH undertaken using a MIS approach (circles) is plotted on the right axis. In the years before the adoption of MIS there was a nonsignificant trend toward improved survival (annual percent change [APC] 0.4; 95%CI -0.1 to +0.8). Adoption of MIS was associated with a significant change of temporal trend (p=0.02), with 4-year survival declining by1.0% (95%CI 0.3-1.6) per year annually after 2006.
3 – Late Breaking Abstract Topacio: Preliminary activity and safety in patients (pts) with platinum-resistant ovarian cancer (PROC) in a phase 1/2 study of niraparib in combination with pembrolizumab P.A. Konstantinopoulosa, P. Munsterb, A. Forero-Torezc, R.W. Hollowayd, L. Schwartzberge, U.A. Matulonisa, J. Wangf, W. Guof, B. Dezubef and S. Vinayakg. aDana-Farber Cancer Institute, Boston, MA, USA, bUniversity of California San Francisco, San Francisco, CA, USA, cUniversity of Alabama at Birmingham, Birmingham, AL, USA, dFlorida Hospital Cancer Institute, Orlando, FL, USA, eThe West Clinic, Memphis, TN, USA, fTesaro, Inc., Waltham, MA, USA, gCase Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH, USA
Estudio Retrospectivo
MIS is increasing; 4 year survival decreasing 1%/year;
MIS is associated with lower survival
Cáncer de Cérvix Etapa IB1
Histerectomía Radical Abierta o Mínimamente InvasivaMargul DJ, et al. ASCO 2018
Supervivencia Global según Tipo Cirugía
Supervivencia Global según Tamaño
Influye ¿Técnica quirúrgica; Subgrupos; curva aprendizaje?
Cáncer de Cérvix Etapa IB1
Histerectomía Radical Abierta o Mínimamente InvasivaMargul DJ, et al. ASCO 2018
Actualización del Abordaje Terapéutico del Cáncer de Cérvix
Guión
1. Estadificación
1. Cirugía en Enfermedad Localizada
2. Enfermedad Localmente Avanzada
4. Enfermedad Avanzada
Cáncer de Cérvix Etapa IIB-IVA (y bulky Ib3 y IIA2)
QT-RT concomitante es el ESTANDAR
Alerta NCI
CDDP 40 mg/m2 semanal
durante 6 semanas
QT-RT frente RT: Metanálisis con 17 ensayos y 4580 pacientesGreen JA, et al. Lancet 2001; J Clin Oncol 2008
Mejor control local (HR 0,61), a distancia (HR 0,57), SLE (HR 0,61) y SG (0,71)
1,-Morris M et al. NEJM 1999;340:1137-43.2,- Rose PG et al. NEJM 1999;340:1144-53.3,- Keys HM et al. NEJM 1999;340:1154-61.4,- Whitney CW et al. JCO 1999;17:1339-48.5,- Peters WA et al JCO 2000;18:1606-13
Ensayos en Marcha
EORTC 55994
QTNA
QT-RT
QTNA
Cirugía
QT-RT
QT
Lo Conocido respecto a la QT en 1ª Línea Enfermedad Avanzada
1. La dosis recomendada de cisplatino es de 50
mg/m2
- Bonomi P. J Clin Oncol 1985
2. Combinación con cisplatino mejor que monoterapia
- Omura GA et al. J Clin Oncol 1997
- Moore DH et al. J Clin Oncol. 2004
- Long HJ et al. J Clin Oncol. 2005
- Monk BJ, et al. J Clin Oncol 2009
3. Carboplatino y paclitaxel como estándar, si
cisplatino previo- Kitagawa R. J Clin Oncol 2015
The GOG experience: 12-month milestone
survival rates in pretreated PRmCC
GOG, Gynecologic Oncology Group, now NRG Oncology; PRmCC, persistent/recurrent metastatic cervical cancer.
Tewari KS, et al. Curr Oncol Rep. 2005;7(6):419-434; Muggia F, et al. Gynecol Oncol. 2004;92(2):639-643; Plaxe SC, et al. Cancer Chemother Pharmacol.
2002;50(2):151-154; Armstrong DK, et al. Invest New Drugs. 2003;21(4):453-457; Fracasso PM, et al. Gynecol Oncol. 2003;90(1):177-180; Brewer CA, et al. Gynecol
Oncol. 2006;100(2):385-388; Rose P, et al. Gynecol Oncol. 2006;102(2):210-213; Garcia AA, et al. Am J Clin Oncol. 2007;30(4):428-431; Miller DS, et al. Gynecol Oncol.
2008;110(1):65-70; Fiorica JV, et al. Gynecol Oncol. 2009;115(2):285-289; Monk BJ, et al. J Clin Oncol. 2009;27(7):1069-1074; Schilder RJ, et al. Int J Gynecol Cancer.
2009;19(5):929-933; National Cancer Institute. http://www.cancer.gov/about-cancer/treatment/clinical-trials/search/view?cdrid=691288. Accessed February 6, 2016.
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Opciones Terapéuticas en Cáncer de Cérvix Avanzado
GOG 240, Tewari KS. NEJM 2014
Obj. Primario: Si la adición de Beva mejora SG; si un régimen sin platino mejora SG
Obj. Secundarios: SLP, Toxicidades, QOL
Diseño factorial 2x2
Lancet 2017
Supervivencia Global
16,8 m frente 13,3 m
Sin diferencias
Calidad de Vida
CECILIA (MO29594): DiseñoA multicentre open-label single-arm phase II study evaluating the safety and efficacy of bevacizumab in
combination with carboplatin and paclitaxel in patients with metastatic, recurrent or persistent cervical cancer
Redondo A, et al. ASCO 2018, #5528
Seguridad de Bevacizumab combinado con carboplatino y paclitaxel,
definido por la frecuencia de fístulas (GI perforación/fístula; GI-vaginales; GU)
150 pacientes de Jul-15 a Dic-16Seguimiento: 11,2 meses (0,1-19,7)
71% RT previa
59% platino previo
20% persistencia
54% recaída
26% debut etapa IV
Metastatic, recurrent or persistent cervical
cancer patients not amenable to curative treatment with surgery
and/or radiation therapy
n=150
Until disease progression, unacceptable
toxicity or withdrawal of consent
Paclitaxel 175mg/m2 q3w*
Carboplatin AUC5 q3w*
Bevacizumab 15mg/kg q3w
CECILIA (MO29594): DiseñoA multicentre open-label single-arm phase II study evaluating the safety and efficacy of bevacizumab in
combination with carboplatin and paclitaxel in patients with metastatic, recurrent or persistent cervical cancer
Redondo A, et al. ASCO 2018, #5528
Todas las fístulas,
menos una,
QT-RT previa
Y muchas tenían
Secuelas RT
HPV (Human papillomavirus)
VPH es un virus DNA de la familia Papovaviridae
De transmisión sexual
120 tipos descritos
Inhibe
Degrada
VPH 16 y 18
Responsables del 70% de CC
Vacunas Terapéuticas basadas en Vectores Vivos Atenuados GOG 0265A prospective Phase 2 trial of the Listeria-based HPV inmunotherapy axalimogene filolisbac (AXAL)
in 2ª-3ª line metastatic cervical cancer: An NRG Oncology Group trial
GOG/NRG-0265: Study design and eligibility
†N = total 54 enrolled, as a result of clinical hold interruption during Stage 2.
*Stage 2 amended to allow continuous (>3) dosing of AXAL.
AXAL, axalimogene filolisbac; CFU, colony-forming units; GOG PS, Gynecologic Oncology Group performance status; HPV, human papillomavirus;
ORR, objective response rate; OS, overall survival; PFS, progression-free survival; PRmCC, persistent/recurrent metastatic cervical cancer; RECIST,
Response Evaluation Criteria In Solid Tumors.
8
N 63, ≥ 18 años, PS 0/1, enfermedad medible (RECIST 1.1); Ca. cérvix enf. avanzada, ≥ 1 línea
de QT (se permitía beva previo)
Objetivo 1arios: Tasa supervivencia a 12 m y seguridad/tolerabilidad; 2arios: SLP, SG y respuestas
Overall (N = 50)
Median age (range), years 46 (29–70)
Race, n (%)
White 37 (74)
GOG PS, n (%)
0 vs 1 31 (62) vs 19 (38)
FIGO stage at diagnosis, n (%)
IA
IB
IIA
IIB
IIIB
IV
Not available
1 (2)
18 (36)
3 (6)
14 (28)
4 (8)
10 (20)
1 (2)
Prior lines of systemic-dose therapy, n (%)
1
2
3
24 (48)
22 (44)
4 (8)
Prior bevacizumab, n (%) 28 (56)
Prior pelvic radiation, n (%) 43 (86)
Demographics and baseline characteristics
Note: Prior lines of therapy do not include chemotherapy given as part of curative treatment.
FIGO, International Federation of Gynecology and Obstetrics; GOG PS, Gynecologic Oncology Group performance status.
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Treatment-emergent adverse event summary
• All t
r
ea ted patients (N = 50 ) ex perienced ≥1 AE;; s a fety findings from both
stages of the study were consistent
AE Grade 1–4 Grade 1–2 Grade 3 Grade 4
Patients with
≥1 TRAE, n (%)48 (96) 28 (56) 18 (36) 2 (4)*
TRAEs occurring in ≥30% of patients
Fatigue 26 (52) 26 (52) - -
Chills 26 (52) 26 (52) - -
Anemia 24 (48) 19 (38) 5 (10) -
Nausea 16 (32) 16 (32) - -
Fever 15 (30) 15 (30) - -
*The observed grade 4 TRAEs recorded in 2 patients were considered possibly related (lung infection [klebsiella related] and
sepsis; same patient) or probably related (hypotension and cytokine related symptoms; same patient) to treatment.
AE, adverse event; TRAE; treatment-related AE.
12
GOG 0265A prospective Phase 2 trial of the Listeria-based HPV inmunotherapy axalimogene filolisbac (AXAL)
in second- and third-line metastatic cervical cancer: An NRG Oncology Group trial
CI, confidence interval; OS, overall survival.
• Represents a 52%
improvement vs logistic
model-predicted milestone
survival rate of 24.5%
• The probability of this
survival advantage being
detected by chance vs a
true treatment effect was
0.02
• 8 patients remain alive as of
January 31, 2017
12-month and median overall survival1
0.9
0.4
0.2
0.0
0 2 4 6 8 10 12 14 16 18 20 22 24
Ove
rall
su
rviv
al
Months
26 28 30 32 34 36 38 40 42
0.8
0.7
0.6
0.5
0.3
0.1
12-month OS rate: 38%,
range 12.02–40.6 months
(n = 19/50; primary endpoint)
50 47 35 25 22 21 19 13 9 4 3 3 3 3 3 3 2 1 1 1 1 0
Number of patients: 50
Events: 42 (84%)
Censored: 8 (16%)
Median OS: 6.2 months
95%CI: (4.4–12.3)
No. at risk:
13
ON HOLD
FDA
Pembrolizumab (anti-PD-1): KEYNOTE-158 (Fase II, n 98)Chung HC, et al. J Clin Oncol 2019
Características pacientes
- Edad 46 (24-75)
- PS 1 65,3%; M1 93,9%;
- PD-L1 +: 83%
- 92% epidermoides y 6% adenoc
- Líneas previas
1 → 35%; ≥2 → 65%
Respuestas globales
- Respuestas 13% (7,3-21,6)- RC 3, RP 10, EE 17
- DOR no alcanzada
Las respuestas SÓLO en PD-L1 (n 77): 16%
SLP 2,1 m y SG 9,4 m
CC avanzado
Progresión ≥ 1 línea QT
PS 0 o 1
Pembrolizumab 200 mg/3 s
2 años o hasta prog o tox
PD-L1 (CPS, combined positive score) ≥1Objetivo primario → Respuestas
Objetivo secundarios → DOR, SLP, SG, toxicidad
Mediana seguimiento 11,7 m (0,6-22,7)
GEICO Study design
Standard Concurrent Chemo-Radiation
R1:2
No Further Treatment
*TSR-0428 for 24 months≤12 weeks
*TSR-042: is an anti-PD1 IgG4 humanized monoclonal antibody that binds with high affinity to PD-1. TSR-042 will be administered using a 30 minute IV
infusion (with a -5 minute and +15 minute window permitted). Patients will receive a fixed 500 mg TSR-042 dose Q3W for the first 4 doses followed by a fixed 1000 mg TSR-042 dose Q6W for the remainder of the study.
PR / CR
Stratification Factors• Histology( squamous vs adenosquamous adenocarcinoma• FIGO Stage: IB2, IIA2 or IIB wIth pelvic positive lymph nodes vs III/IVA vs
any Stage with positive ParaAortic Lymph nodes• Partial Response vs Complete Response by RECIST Criteria v1.1
N=132
A RANDOMIZED, OPEN LABEL, PHASE II TRIAL OF ANTI-PD1, TSR-042, AS
MAINTENANCE THERAPY FOR PATIENTS WITH HIGH-RISK LOCALLY ADVANCED
CERVICAL CANCER AFTER CHEMO-RADIATION
Protocol Number: GEICO-78-CCoordinating Investigator: Ana Oaknin, MD, PhD
Anti-PD-1
ENGOT-Cx10/GEICO 68-C/BEATcc Trial:
Dra. Oaknin
Conclusiones
1. Estadificación (FIGO 2018) No se considera extensión en etapas Ia
Se subdivide etapas IB (IB1, IB2, IB3)
Se considera afectación ganglionar (IIIC1 y IIIC2)
1. Cirugía en Enfermedad Localizada Cirugía abierta frente MIS
2. Enfermedad Localmente Avanzada Estándar QT-RT
Estudios con mantenimiento en marcha
4. Enfermedad Avanzada Incorporación de Bevacizumab
La inmunoterapia se incorpora
Impacto de la Vacunación
For invasive cancer in
women aged 20–29, we
project a 63%reduction in rates by
2025 with 80% vaccine
coverage and no cross-
protection
Muchas Gracias