En los últimos años, el melanoma (el cáncer de piel más agresivo) se ha convertido en uno de los tumores que mejores noticias ofrece en investigación oncológica. El conocimiento cada vez más detallado sobre los fallos que acumulan las células malignas se ha traducido en nuevas terapias, cada vez más específicas y eficaces, como lo ha demostrado de nuevo el congreso de la Sociedad Europea de Oncología Médica, ESMO 2017, que se celebra en Madrid hasta el martes.

Los dos estudios dados a conocer en este congreso, y publicados en paralelo en la revista ‘The New England Journal of Medicine’ (NEJM), mejoran los actuales tratamientos estándar en pacientes con la forma más avanzada de la enfermedad (en fase III o IV e inoperables).

Uno de los ensayos clínicos, COMBI-AD , ha demostrado que la terapia combinada con dos medicamentos –dabrafenib y trametinib– duplica el tiempo que los pacientes con melanoma en fase III y una mutación en el gen BRAF permanecen libres de enfermedad.

Dabrafenib es un inhibidor de BRAF mientras que trametinib inhibe una vía celular conocida como MEK. En total, 870 pacientes con melanoma en fase III fueron asignados para recibir esta combinación de tratamiento durante 12 meses o bien un placebo (sustancia inactiva) tras una cirugía para extirparles metástasis en los ganglios linfáticos. Al cabo de 2,8 años de seguimiento, el tratamiento redujo el riesgo de recaídas o muerte un 53% en comparación con el placebo (hazard ratio 0,47; intervalo de confianza 95%, 0,39-0,58).

“Estos son los mejores resultados nunca vistos en el tratamiento adyuvante [después de la cirugía] del melanoma en fase III”, señala el Dr. Axel Hauschild, profesor de Dermatología de la Universidad de Kiel (Alemania) e investigador principal del estudio. “El interferón es la terapia aprobada para este escenario, pero sólo mejora la supervivencia relativa sin recaídas un 20%”. A su juicio, estos resultados cambiarán la práctica clínica en este tipo de pacientes con melanoma de alto riesgo.

Como comenta de manera independente el Dr. Oliver Michielin, coordinador del ESMO Melanoma Faculty, “llevamos muchos años intentando desarrollar terapias adyuvantes para el melanoma [que ayuden a prevenir recaídas después de la cirugía para extirpar las metástasis]. La primera de estas revoluciones fue ipilimimumab, presentado en el congreso ESMO de 2016, y que supuso la primera revolución en adyuvancia, aunque con un perfil bastante tóxico”.

A diferencia de ipilimimumab, que es un tipo de terapia inmunológica (es decir, que refuerza el papel del sistema inmune contra las células tumorales), los dos medicamentos usados en este estudio COMBI-AD son dianas dirigidas, es decir, que actúan contra ‘fallos’ específicos de las células tumorales. “Estos resultados suponen una nueva y atractiva opción de tratamiento para los pacientes con mutación en BRAF, que representan aproximadamente la mitad de los pacientes con melanoma”, recuerda el Dr. Michielin. Las diferencias en el perfil de toxicidad entre la inmunoterapia o esta nueva combinación influirán en la elección de tratamiento en cada paciente.

En el segundo de los estudios, también publicado en la revista NEJMⁱⁱⁱ, se analizó un tipo de inmunoterapia (nivolumab) después de la cirugía en pacientes con melanoma en fase III y se compararon los resultados con el fármaco estándar empleado para reducir el riesgo de recaídas en pacientes con melanoma en fase III/IV extirpado quirúrgicamente.

Tanto nivolumab como ipilimumab son dos fármacos inmunoterápicos, es decir, actúan inhibiendo un fallo en el sistema de control del sistema inmunitario que impide a las células defensivas reconocer y destruir el tumor.

El estudio CheckMate238 es un ensayo en fase III, randomizado y doble ciego, llevado a cabo con 906 pacientes con melanoma con un alto riesgo de recaídas. El objetivo del estudio era comparar la acción de ambos medicamentos en la supervivencia libre de progresión. Como explican los autores, en este tipo de pacientes medir la supervivencia global es un objetivo complicado porque los pacientes suelen pasar a recibir el tratamiento alternativo en cuanto experimentan una recaída.

El ensayo fue interrumpido antes de tiempo cuando el comité que evalúa los datos observó una clara evidencia de beneficio en el grupo de nivolumab. Al cabo de 18 meses de tratamiento, la tasa de supervivencia libre de recaídas era del 66,% en el grupo de nivolumab y del 52,7% con ipilimumab; mientras que el primer grupo experimentó además una menor tasa de toxicidades y de interrupción del tratamiento por efectos adversos.

El principal autor del trabajo, el Dr. Jeffrey Weber, del NYU Langone Health de Nueva York (Estados Unidos), señala que los resultados del ensayo son claramente favorables a nivolumab en estos pacientes (no sólo por la reducción en las recaídas sino por el mejor perfil de toxicidad del fármaco).

Como comentaban los autores del primer trabajo, aunque ipilimumab está aprobado en Estados Unidos para este escenario, en Europa todavía es una cuestión a debate, debido precisamente a la toxicidad mostrada por ipilimumab.

El director de Investigación Clínica en HM CIOCC, Emiliano Calvo, recalca que durante el congreso se han presentado estudios de combinaciones de fármacos inmunoterápicos innovadores para este tipo de tumor y pone el foco en la combinación de un anticuerpo antiLAG3 y nivolumab para el tratamiento de pacientes con melanoma, algunos de ellos con enfermedad avanzada tras terapia previa con antiPD1/PDL1.

“Además, habrá nuevas aproximaciones para intentar que los tumores no inflamatorios sean más sensibles a la inmunoterapia”, comenta el especialista quien pone como ejemplo la combinación de BiTE (anticuerpo específico de simple cadena) con atezolizumab o la administración local de herpesvirus oncolíticos en pacientes con mesotelioma. No obstante, recuerda, que en este caso se trata de un estudio fase I por lo que la investigación se encuentra en una fase incipiente.

Referencias

[i] Long G.V., Hauschild A., Santinami M, et al. Adjuvant Dabrafenib plus Trametinib in Stage III BRAF-Mutated Melanoma. N Engl J Med. DOI: 10.1056/NEJMoa1708539

[ii] LBA6_PR ‘COMBI-AD: Adjuvant Dabrafenib (D) Plus Trametinib (T) for Resected Stage III BRAF V600E/K– Mutant Melanoma‘ será presentado por el Dr. Axel Hauschild durante el simposio presidencial el lunes 11 September 2017, de 16:30 a 17:45 (CEST) en el Auditorio Madrid.

^{[iii] LBA8_PR ‘Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: a randomized, double-blind, phase 3 trial (CheckMate 238)’ será presentado por el Dr. Jeffrey Weber durante el simposio presidencial el lunes 11 September 2017, de 16:30 a 17:45 (CEST) en el Auditorio Madrid.}

Abstract LBA6_PR ‘COMBI-AD: Adjuvant dabrafenib (D) plus trametinib (T) for resected stage III BRAF V600E/K–mutant melanoma’

A. Hauschild1, M. Santinami2, G.V. Long3, V. Atkinson4, M. Mandala5, V. Chiarion Sileni6, M.S. Nyakas7, C. Dutriaux8, A. Haydon9, C. Robert10, L. Mortier11, J. Schachter12, R. Ji13, P. Zhang13, B. Mookerjee13, J. Legos13, R. Kefford14, R. Dummer15, J. Kirkwood16 1Dermatology, University Hospital Schleswig-Holstein, Kiel, Germany, 2Oncology, Fondazione Istituto Nazionale Tumori, Milan, Italy, 3Melanoma Medical Oncology, Melanoma Institute Australia, The University of Sydney, Royal North Shore and Mater Hospitals, Sydney, Australia, 4Medical Oncology, Princess Alexandra Hospital, Gallipoli Medical Research Foundation, University of Queensland, Queensland, Australia, 5Department of Oncology and Haematology, Papa Giovanni XXIII Cancer Center Hospital, Bergamo, Italy, 6Melanoma Oncology Unit, Veneto Oncology Institute, Padua, Italy, 7Department of Oncology, Rikshospitalet-Radiumhospitalet HF, Oslo, Norway, 8Department of Oncologic Dermatology, Centre Hospitalier Universitaire de Bordeaux, Hôpital Saint-André, Bordeaux, France, 9Medical Oncology, The Alfred Hospital, Melbourne, Australia, 10Dermatology, Institute Gustave Roussy, Paris, France, 11Dermatology, Université de Lille, Lille, France, 12Oncology, Ella Institute for Melanoma, Sheba Medical Center, Tel Hashomer, Israel, 13Medical Oncology, Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, 14Medical Oncology, Macquarie University, Melanoma Institute Australia, Westmead Hospital, and the University of Sydney, Sydney, Australia, 15Dermatology, University Hospital Zürich Skin Cancer Center, Zürich, Switzerland, 16Melanoma Program, Hillman UPMC Cancer Center, University of Pittsburgh, Pittsburgh, PA, USA

Background: Surgery is curative for most patients (pts) with localized melanoma; however, those with regional nodal involvement (stage III disease) are at a higher risk for relapse and death after resection. In phase 3 trials of advanced or metastatic BRAF V600–mutant melanoma, D+T combination therapy improved clinical outcomes and was well tolerated.

Methods: In this randomized, double-blind, placebo-controlled, phase 3 study (COMBI-AD [NCT01682083]), pts with high-risk, stage III, BRAF V600E/K–mutant melanoma without prior anticancer therapy were randomized 1:1 within 12 weeks of complete surgical resection to receive D 150 mg twice daily plus T 2 mg once daily or matching placebos. Pts were treated for 12 months and stratified based on BRAFmutation (V600E vs V600K) and stage (IIIA vs IIIB vs IIIC). The primary endpoint was relapse-free survival (RFS). Secondary endpoints included overall survival (OS), distant metastasis-free survival (DMFS), freedom from relapse (FFR), and safety.

Results: A total of 870 pts (stage IIIA, 18%; IIIB, 41%; IIIC, 40%; unknown, 1%) were randomized (D+T, n = 438; placebo, n = 432). The primary endpoint was met. At the time of the data cutoff for the primary analysis (June 30, 2017; median follow-up, 2.8 years), D+T significantly reduced the risk of disease recurrence or death by 53% vs placebo (HR, 0.47 [95% CI, 0.39-0.58]; median not reached vs 16.6 months, respectively; P<0.001). RFS benefit with D+T was observed across all patient subgroups. D+T also improved secondary endpoints of OS (HR, 0.57 [95% CI, 0.42-0.79]), DMFS (HR, 0.51 [95% CI, 0.40-0.65]), and FFR (HR, 0.47 [95% CI, 0.39-0.57]). With D+T, 97% of pts had an adverse event (AE), 41% had grade 3/4 AEs, and 26% had AEs leading to treatment discontinuation (vs 88%, 14%, and 3%, respectively, with placebo).

Conclusions: Combination D+T adjuvant therapy was associated with improvements in RFS, OS, DMFS, and FFR, and manageable safety in pts with high-risk, resected, stage III, BRAF V600E/K–mutant melanoma. This regimen represents a new adjuvant treatment option in this setting.

Clinical trial identification: ClinicalTrials.gov number: NCT01682083 EudraCT number: 2012-001266-15 Release date: May 31, 2017.

Legal entity responsible for the study: GlaxoSmithKline

Funding: GlaxoSmithKline

Disclosure: A. Hauschild: Clinical trial support or speaker´s honoraria or consultancy fees from Amgen, BMS, MerckSerono, MSD, Novartis, OncoSec, Philogen, Pierre Fabre, Provectus, Regeneron, Roche during the conduct of the study; G.V. Long: Personal fees as a consultant advisor to BMS, Novartis, Roche, Amgen, Merck MSD, Pierre Fabre, and Array outside the submitted work; V. Atkinson: Travel reimbursement and advisory board speaker's fees from MSD, BMS, and Novartis, speaker's fees from Roche, and advisory board fees from Pierre Fabre outside the submitted work. M. Mandala: Advisory board, lectures, and research activity fees from Roche; and advisory board and lecture fees from Novartis, MSD, and BMS outside the submitted work; V. Chiarion Sileni: Assistance with manuscript preparation from ArticulateScience, LLC, and advisory board fees from BMS, MSD, Roche, Novartis, and Merck Serono during the conduct of the study; M.S. Nyakas, C. Dutriaux: Assistance with manuscript preparation from ArticulateScience, LLC, during the conduct of this study; A. Haydon: Lecture fees from Novartis during the conduct of the study; C. Robert: Advisory board fees from BMS, MSD, Novartis, and Roche during the conduct of the study. L. Mortier: Assistance with manuscript preparation from ArticulateScience, LLC, and medical board fees from Novartis during the conduct of this study; and medical board fees from Roche outside the submitted work;R. Ji, P. Zhang: Employment by Novartis during the conduct of the study; B. Mookerjee: Employment and stock options from Novartis and stock options from GlaxoSmithKline during the conduct of the study; employment and stock options from Novartis and GlaxoSmithKline outside the submitted work; J. Legos: Employment by and shareholder of Novartis and non-financial support from ArticulateScience, LLC, during the conduct of the study; R. Kefford: Institutional reimbursement advisory boards fees from Novartis during the conduct of the study and institutional reimbursement advisory boards fees from BMS, Merck, Amgen, and Teva outside the submitted work; R. Dummer: Intermittent, project-focused consulting and/or advisory relationships with Novartis, MSD, BMS, Roche, Amgen, Takeda, and Pierre Fabre outside the submitted work; J. Kirkwood: Grants from Merck and Prometheus and personal fees from Prometheus, BMS, Novartis, Roche, Genentech, EMD Serono, and ArrAY Biopharma outside the submitted work. All other authors have declared no conflicts of interest.

Keywords: adjuvant, dabrafenib, trametinib, BRAF V600–mutant melanoma

Abstract LBA8_PR ‘Adjuvant therapy with nivolumab (NIVO) versus ipilimumab (IPI) after complete resection of stage III/IV melanoma: a randomized, double-blind, phase 3 trial (CheckMate 238)’

J. Weber1, M. Mandala2, M. Del Vecchio3, H. Gogas4, A.M. Arance5, L.C. Cowey6, S. Dalle7, M. Schenker8, V. Chiarion-Sileni9, I. Márquez-Rodas10, J.-J. Grob11, M. Butler12, M.R. Middleton13, M. Maio14, V. Atkinson15, P. Queirolo16, V. de Pril17, A. Qureshi17, J. Larkin18, P.A. Ascierto19 1Perlmutter Cancer Center, NYU Langone Health, New York, USA, 2Oncology, Papa Giovanni XIII Hospital, Bergamo, Italy, 3Medical Oncology, National Cancer Institute, Milan, Italy, 4Oncology, University of Athens, Athens, Greece, 5Oncology, Hospital Clinic de Barcelona, Barcelona, Spain, 6Oncology, Texas Oncology-Baylor Charles A. Sammons Cancer Center, Dallas, TX, USA, 7Oncology, Hospices Civils de Lyon, Pierre Bénite, France, 8Oncology, Oncology Center sf. Nectarie Ltd., Craiova, Romania, 9Oncology, Oncology Institute of Veneto IRCCS, Padua, Italy, 10Medical Oncology, Hospital Gregorio Marañón, Madrid, Spain, 11Medical Oncology, Hospital de la Timone, Marseille, France, 12Oncology, Princess Margaret Cancer Centre, Toronto, ON, Canada, 13Oncology, Churchill Hospital, University of Oxford, Oxford, UK, 14Center for Immuno-Oncology, University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy, 15Oncology, Gallipoli Medical Research Foundation and Princess Alexandra Hospital, and University of Queensland, Queensland, Australia, 16Oncology, IRCCS AOU San Martino - IST, Genova, Italy, 17Global Clinical Research - Oncology, Bristol-Myers Squibb, Princeton, NJ, USA, 18Oncology, The Royal Marsden Hospital, London, UK, 19Oncology, Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy.

Background: NIVO and IPI are immune checkpoint inhibitors approved for advanced melanoma. IPI is also approved in the US for resected stage III melanoma, based on a phase 3 trial demonstrating an improvement in recurrence-free survival (RFS). We report the first results of a phase 3 trial designed to evaluate NIVO vs IPI for resected stage III/IV melanoma at high risk of recurrence.

Methods: In this randomized, double-blind trial, eligible patients (pts) included those ≥15 yrs of age who underwent complete resection of stage IIIb/c or IV melanoma. 906 pts were randomized (stratified by stage and PD-L1 status) 1:1 to receive NIVO 3 mg/kg (n=453) every 2 wks or IPI 10 mg/kg (n=453) every 3 wks for 4 doses, then every 12 wks (from week 24) for up to 1 yr, disease recurrence, or unacceptable toxicity. The primary endpoint was RFS in the intent-to-treat population.

Results: Overall, 34%/47%/19% of pts had stage IIIb/IIIc/IV; 32%, ulcerated primary; 48%, macroscopic lymph node involvement; and 42%, BRAF mutation. At a median follow-up of 18.5 mo, NIVO significantly improved RFS vs IPI (Table). Results from prespecified subgroup analyses demonstrated consistent hazard ratios favoring NIVO.

	NIVO (N=453)	IPI (N=453)
18-mo RFS rates (95% CI)	66.4% (61.8–70.6)	52.7% (47.8–57.4)
Median RFS	Not reached	Not reached
HR (95% CI)	0.65 (0.51–0.83)
Log-rank	P < 0.0001

Treatment-related grade 3/4 adverse events (AEs) occurred in 14% of pts in the NIVO group and 46% of pts in the IPI group; AEs of any grade led to discontinuation in 10% and 43%, respectively. Organ systems with the highest frequency of treatment-related grade 3/4 select (immune-related) AEs in the NIVO and IPI arms were gastrointestinal (2.0% vs 6.8%), hepatic (1.8% vs 10.8%), and skin (1.1% vs 6.0%). No deaths due to study drug toxicity were reported for NIVO, but 2 (0.4%) were reported for IPI (colitis and medullary aplasia) >100 days post-IPI.

Conclusions: NIVO as adjuvant therapy significantly improved RFS vs IPI for pts with stage III/IV melanoma at high risk of recurrence and demonstrated a superior safety profile. Acknowledgement: The co-senior authors for this abstract are Dr. J. Larkin and Dr. P.A. Ascierto.

Clinical trial identification: NCT02388906

Legal entity responsible for the study: Bristol-Myers Squibb

Funding: Bristol-Myers Squibb

Disclosure: J. Weber: Celldex, Ichor Medical Systems, cCam Biotherapeutics, Lion Biotechnologies, Pieris Pharmaceuticals, Altor BioScience, Bristol-Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, Abbvie, Eisai, CytomX Therapeutics, Nektar, Novartis, Medivation: consulting or advisory role; Bristol-Myers Squibb, GlaxoSmithKline, Daiichi Sankyo, Pieris Pharmaceuticals, cCam Biotherapeutics, Lion Biotechnologies, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech, Novartis: travel, accommodations, expenses; Named on a patent submitted by Moffitt Cancer Center for an IPILIMUMAB biomarker; Altor BioScience, Celldex, CytomX Therapeutics: stock and other ownership interests; Bristol-Myers Squibb, Merck, Genentech, Abbvie, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Eisai, Altor BioScience, Altor BioScience, Amgen, Roche, Ichor Medical Systems, Celldex, cCam Biotherapeutics, Pieris Pharmaceuticals, CytomX Therapeutics, Nektar, Novartis, Medivation: honoraria; Bristol-Myers Squibb, Merck, Gla; M. Mandala: Roche: personal fees, grant; BMS, MSD, Novartis: personal fees; M. Del Vecchio: BMS: personal fees, honoraria; Roche: personal fees, honoraria, advisory board, research

funding; GSK: personal fees, honoraria; H. Gogas: Roche, Amgen MSD, BMS, Novartis: consulting or advisory role, research funding; BMS, Roche, MSD: travel accommodations, expenses; A.M. Arance: GSK, Roche, : personal fees, Consultant, speakers' bureau; BMS: personal fees & non-financial support, Speakers' bureau, travel funding; L.C. Cowey: BMS, Genentech: grant, personal fees, consultant, Speaker, Research funding; Merck, GSK:

grant, consultant, Research funding; S. Dalle: BMS: research grants and travel expenses; BMS, MSD, Novartis, Roche: principal investigator; V. Chiarion-Sileni: BMS, Roche, GSK: personal fees, consulting, speakers' bureau, travel; MSD: personal fees, consulting, travel; I. Márquez-Rodas: Novartis, Roche, MSD, BMS: honoraria; Novartis, Roche, MSD, BMS, Amgen, Bioncotech: consulting or advisory role; MSD, BMS, Amgen: travel, accommodations, expenses

J.-J. Grob: BMS: personal fees, consultant, speakers' bureau, research funding; GSK: personal fees, consultant, speakers' bureau; Novartis: personal fees, consulting; Roche: personal fees, non-financial support, consulting, speakers' bureau, research funding, travel; Merck, Amgen: personal fees, consulting M. Butler: Bristol Myers Squib, EMD Serono, Immunocore, Immunovaccine: personal fees, advisory boards; Merck: grant, personal fees, advisory boards, grant support for clinical trial; M.R. Middleton: Amgen, Bristol-Myers Squibb, Clovis, GlaxoSmithKline, Immunocore (uncompensated), Merck, Roche (all compensated): consulting or advisory role; Amgen, AstraZeneca, Bristol-Myers Squibb, Clovis, Eisai, GlaxoSmithKline, Immunocore, Medimmune, Merck, Pfizer, Roche, Vertex: research funding;

Merck, Roche: travel, accommodations, expenses; M. Maio: BMS, Roche, MedImmune, MSD, GSK: honoraria, consulting or advisory role, travel accommodations, expenses; BMS, MedImmune: research funding; V. Atkinson: BMS, MSD, Novartis: honoraria, consulting or advisory role, speakers' bureau, travel accommodations, expenses P. Queirolo: Roche, MSD, BMS, Novartis: personal fees; V. de Pril, A. Qureshi: employment – Bristol-Myers Squibb and stock/ownership – Bristol-Myers Squibb J. Larkin: BMS, MSD, Novartis, Pfizer: research funding; BMS, MSD, Pfizer, Eisai, GSK, Roche: travel, accommodations, expenses; P.A. Ascierto: Bristol-Myers Squibb, Roche-Genentech: grant, personal fees, honoraria, consultant, institutional research funding; GSK: personal fees, honoraria, consultant; MSD, personal fees, consultant; Ventana: grant, consultant, institutional research funding; Novartis: Consultant All other authors have declared no conflicts of interest.

Keywords: adjuvant, nivolumab, recurrence-free surviva l, phase 3

Fuente: Berbés Asociados