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Avanços no tratamento sistémico de doentes com melanoma metastizado entre 2011 e 2019
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RESUMO: Contexto prévio: Há cerca de dez anos, os doentes diagnosticados com melanoma em
estadio IV tinham um prognóstico reservado e uma sobrevivência muito curta. As terapêuticas então disponíveis, nomeadamente dacarbazina, temozolomida e outros citotóxicos, isoladamente ou em combinação com cirurgia e/ou radioterapia, não proporcionavam benefícios clínicos significativos. Na última década, a comunidade médica e científica testemunhou uma revolução no tratamento do melanoma em estadio IV com a
introdução da imunoterapia, particularmente dos inibidores de checkpoint, e das terapêuticas alvo, nomeadamente dos inibidores da via da mitogen-activated protein cinase
(MAPKi). Ambas as terapêuticas demonstraram benefícios sustentados em termos de
sobrevivência global em doentes com melanoma metastizado. Nesta análise, pretendemos investigar se o aumento de sobrevivência global observado nos ensaios clínicos de
fase II e III que levaram à aprovação destas terapêuticas, podem ou não ser reproduzidos em contexto de prática clínica diária.
População incluída: Nesta análise retrospectiva, multicêntrica, incluímos doentes diagnosticados com melanoma estadio IV entre 2011 e 2018, e tratados no centro oncológico de Tuebingen, ou noutros centros da Alemanha, e documentados prospectivamente no Registo Central de Melanoma Maligno (CMMR) alemão.
Os seguintes dados foram obtidos através do CMMR: ano de nascimento, sexo, data de
diagnóstico do tumor primário, tipo histológico, localização anatómica, espessura, nível
de clark, presença de ulceração, presença de regressão, data da biópsia do gânglio
sentinela (se aplicável), presença de metástases no gânglio sentinela, estadio à data do
primeiro diagnóstico, e data e localização da recidiva. Outros dados foram posteriormente recolhidos através da consulta do processo clínico: tipo de terapêutica local e sistémica em estadio IV e respectivas datas de início e fim, melhor resposta à terapêutica e respectiva data, de acordo com os critérios RECIST 1.1, data de progressão da
doença, data do último contacto, e causa e data da morte. Todos os doentes incluídos
foram seguidos durante, pelo menos, três meses.
Análise estatística: A sobrevivência livre de progressão (PFS) foi definida como o
tempo entre a data de diagnóstico em estadio IV, data de início da terapia sistémica, ou
data do diagnóstico de metástases cerebrais, dependendo do tipo de população avaliada, e data de progressão da doença, data do último contacto ou data de óbito no caso
dos doentes que não tiveram progressão. A sobrevivência global (OS) foi definida como
o tempo entre a data do diagnóstico em estadio IV, data de início da terapia sistémica,
ou data do diagnóstico de metástases cerebrais, dependendo do tipo de população avaliada, e data do último contacto ou data de óbito.
Usámos estimativas de Kaplan-Meier para o cálculo da PFS e OS. As diferenças entre
grupos foram avaliadas utilizando o teste de log-rank. Quando aplicável, foram calculados hazard ratios (HR) com intervalos de confiança de 95% (95% IC) para quantificar o
impacto na sobrevivência. Quando aplicável, foram também utilizados modelos de regressão logística multivariada para avaliar associações entre variáveis. As associações
entre variáveis foram consideradas estatisticamente significativas para valores de p <
0.05. Para a comparação indirecta entre os MAPKi, foi usado o método de Bucher. Todas as análises foram submetidas e aprovadas pelas Comissões de Ética locais.
Resultados: Seis publicações incluindo dados de 3143 doentes diagnosticados com
melanoma em estadio IV foram compiladas para a elaboração da presente tese. A taxa
de OS aos 3 anos (3-y OS rate) para doentes tratados com quimioterapia em primeira
linha, a terapêutica sistémica mais utilizada em 2011-2014 foi de 15.9% (95% CI: 8.8-23); para doentes tratados com imunoterapia em primeira linha no mesmo período, a 3-
y OS rate foi de 37.4% (95% CI: 16.6-58.2). No período entre 2015-2018, a 3-y OS rate
para doentes tratados com imunoterapia em primeira linha, quase que duplicou em comparação com o período de 2011-2014, e foi de 64.6% (95% CI: 53.2-76) para doentes
com resposta completa, resposta parcial ou doença estável. Para doentes com resposta
completa, a 3-y OS rate foi de 87.7% (95%CI: 70.8-100).
Em doentes com mutação BRAFV600 e presença de factores de pior prognóstico, nomeadamente valores elevados de LDH à data de início de tratamento, ECOG PS reduzido e maior volume tumoral, a combinação vemurafenib/cobimetinib demostrou uma
redução não significativa do risco de progressão ou morte em comparação com dabrafenib/trametinib, e encorafenib/binimetinib.
Em comparação com o melanoma cutâneo, os doentes com melanoma ocular beneficiaram menos da terapia sistémica, mesmo quando tratados com nivolumab/ipilimumab.
A sobrevivência global média (mOS) foi de apenas 16.1 meses (95% CI: 12.9-19.3),
ainda assim mais elevada do que a reportada em doentes tratados com quimioterapia
ou monoterapia com anti-PD-1.
Em termos de sobrevivência global, o benefício da imunoterapia e das terapêuticas alvo
na doença intracerebral foi semelhante ao observado na doença extracerebral. Isto foi
particularmente verdade em doentes tratados com nivolumab/ipilimumab. A mOS foi de
19 meses (95% CI: 15.9-22.0) e a 3-y OS rate foi de 30.1% (95% CI: 22.2-37.9) Para os
doentes com resposta completa, a 2-y OS rate foi de 85.6% (95% CI: 69.3-100), muito
semelhante às taxas de sobrevivência observadas em outros doentes em estadio IV,
sem metastização cerebral. Os doentes que receberam nivolumab/ipilimumab e terapêutica local (radiocirugia ou cirurgia) beneficiaram mais em comparação com os doentes que não receberam terapêutica local - a 2-y OS rate foi de 49.5% versus 40.9% (95%
CI: 40.9-58.1 e 26.6-55.2). Este benefício foi observado independentemente do timing em que os doentes receberam terapêutica local, i.e., antes ou depois de iniciar nivolumab/ipilimumab. Conclusões: Os nossos dados da prática clínica diária confirmam uma melhoria em
termos de sobrevivência global em doentes com melanoma em estadio IV, diagnosticados e tratados entre 2011-2019. Estes benefícios deveram-se à introdução de novas
opções terapêuticas, nomeadamente imunoterapia com inibidores de checkpoint e terapêuticas alvo com MAKi. Os nossos resultados mostraram que actualmente, a imunoterapia com inibidores de checkpoint, deve ser oferecida em primeira linha em todos os
doentes com melanoma em estadio IV. Em doentes com mutação BRAFV600 e com
presença de factores de pior prognóstico, terapêutica com MAPKi pode igualmente ser
considerada em primeira linha metastática. Em doentes com metastização cerebral, a
combinação de terapia sistémica e local deve ser discutida e ponderada, em primeira
linha ou posteriormente, sempre que viável.
ABSTRACT: Background: Ten years ago, stage IV melanoma carried a dismal prognosis, with very short survival. The therapies available then, namely dacarbazine, temozolomide, and other chemotherapies, alone or in combination with surgery and/or radiotherapy, were unable to provide clinically significant benefit. In the last decade, the medical community testified a revolution in the treatment of advanced melanoma with the introduction of immune checkpoint inhibitors, and targeted therapy with mitogen-activated protein kinase inhibitors (MAPKi). Both therapies were able to provide sustainable overall survival benefits in stage IV melanoma. Here, we aimed to investigate whether the survival advantages seen in phase II, and III clinical trials investigating the afore mentioned therapies, were reproducible or not in a real-world setting. Patients and methods: In this retrospective, multicentric analysis, we included stage IV melanoma patients, diagnosed between 2011 and 2018, treated in the skin cancer center in Tuebingen, or in other German centers, and prospectively documented in the German Central Malignant Melanoma Registry (CMMR). The following patients’ and tumor data were collected from the CMMR: year of birth, gender, date of primary tumor diagnosis, type of melanoma, localization, tumor thickness, Clark level, presence of ulceration, presence of regression, date of sentinel lymph node biopsy (if applicable), presence of lymph node metastases, stage at first diagnosis and date and localization of recurrence. The following variables were further included, based on patients’ clinical chart review: date and type of local and systemic therapy in stage IV, date and type of best overall response, according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), date of progressive disease, date of last contact, cause of death, and death date. Patients included had a minimum follow-up of three months. Progression free survival (PFS) was defined as the time between date of stage IV diagnosis, start date of systemic therapy, or date of melanoma brain metastases (MBM) diagnosis, depending on the type of population evaluated, and date of progressive disease, or last contact or death, for the patients that didn’t progress. Overall survival (OS) was defined as the time between stage IV diagnosis, start date of systemic therapy, or date of MBM diagnosis, depending on the type of population evaluated, and date of last contact or death. Kaplan-Meier estimates were used for the calculation of PFS and OS. Differences between groups were assessed using the log-rank test. When applicable, hazard ratios (HR) with 95% confidence intervals (CI) were calculated to quantify the impact on survival. Multivariate logistic regression models were used to examine associations between variables, when appropriate. Results were reported as two-sided p values with 95% CIs. All p-values presented are two-sided tests of statistical significance at 0.05. For the indirect comparison between MAPKi, the Bucher method was used. All analyses were submitted to and approved by the local Ethics Committee. Results: Six publications reporting data from 3143 stage IV melanoma patients were included in this thesis. The 3-years (3-y) OS rate for patients treated with first-line chemotherapy, the most used systemic therapy in 2011-2014 was 15.9% (95% CI: 8.8-23). For patients treated with first-line immunotherapy in the same period, the 3-y OS rate was 37.4% (95% CI: 16.6-58.2). In the period of 2015-2018, the 3-y OS rate for patients treated with first-line immunotherapy almost duplicated compared to the 2011-2014 period, and was 64.6% (95% CI: 53.2–76) for patients achieving a complete response (CR), partial response (PR) or stable disease (SD). For patients achieving a CR, the 3-y OS rate was 87.7% (95% CI: 70.8–100). In patients harboring a BRAFV600 mutation, and with presence of worse prognostic factors, namely elevated baseline lactate dehydrogenase (LDH), worse Eastern Cooperative Oncology Group Performance Status (ECOG PS) and higher tumor volume, the combination of vemurafenib plus cobimetinib showed a non-significant lower risk for progression or death, compared to dabrafenib plus trametinib, and encorafenib plus binimetinib. Compared to cutaneous melanoma, patients with uveal melanoma derived less benefit from systemic therapy, even when treated with combined immunotherapy. The median OS (mOS) was only 16.1 months (95% CI: 12.9–19.3), but still higher than those reported for both chemotherapy and programmed cell death protein 1 (PD-1) monotherapy in this sub-group. The benefit observed in intracerebral disease was similar to the benefit in extracerebral disease, when combined immunotherapy (nivolumab plus ipilimumab) was used. The mOS in patients with MBM was 19 months (95% CI: 15.9-22.0). For the whole collective of patients receiving nivolumab plus ipilimumab, the 3-y OS rate was 30.1% (95% CI: 22.2-37.9). For patients achieving a CR, the 2-y OS rate was 85.6% (95%CI: 69.3-100), very similar to other stage IV patients. Patients receiving combined immunotherapy and local therapy (surgery or stereotactic radiotherapy) had a better outcome when compared to patients that didn’t receive local therapy – the 2-y OS rate was 49.5% versus 40.9 % (95%CI: 40.9-58.1 and 26.6-55.2). This benefit was observed regardless the timing of local therapy, i.e., before or after starting nivolumab plus ipilimumab. Conclusions: Our real-world data confirmed the improvement of survival outcomes in stage IV melanoma patients with the introduction of immune checkpoint inhibitors, and MAPKi in the last decade. Results show that, currently, PD-1 based immunotherapy should be offered as first-line therapy in stage IV melanoma. In patients with BRAFV600 mutation and worse prognostic features, first-line systemic therapy with MAPKi could be considered. In patients with MBM, combination of systemic immunotherapy and local therapy should be offered, when feasible.
ABSTRACT: Background: Ten years ago, stage IV melanoma carried a dismal prognosis, with very short survival. The therapies available then, namely dacarbazine, temozolomide, and other chemotherapies, alone or in combination with surgery and/or radiotherapy, were unable to provide clinically significant benefit. In the last decade, the medical community testified a revolution in the treatment of advanced melanoma with the introduction of immune checkpoint inhibitors, and targeted therapy with mitogen-activated protein kinase inhibitors (MAPKi). Both therapies were able to provide sustainable overall survival benefits in stage IV melanoma. Here, we aimed to investigate whether the survival advantages seen in phase II, and III clinical trials investigating the afore mentioned therapies, were reproducible or not in a real-world setting. Patients and methods: In this retrospective, multicentric analysis, we included stage IV melanoma patients, diagnosed between 2011 and 2018, treated in the skin cancer center in Tuebingen, or in other German centers, and prospectively documented in the German Central Malignant Melanoma Registry (CMMR). The following patients’ and tumor data were collected from the CMMR: year of birth, gender, date of primary tumor diagnosis, type of melanoma, localization, tumor thickness, Clark level, presence of ulceration, presence of regression, date of sentinel lymph node biopsy (if applicable), presence of lymph node metastases, stage at first diagnosis and date and localization of recurrence. The following variables were further included, based on patients’ clinical chart review: date and type of local and systemic therapy in stage IV, date and type of best overall response, according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1), date of progressive disease, date of last contact, cause of death, and death date. Patients included had a minimum follow-up of three months. Progression free survival (PFS) was defined as the time between date of stage IV diagnosis, start date of systemic therapy, or date of melanoma brain metastases (MBM) diagnosis, depending on the type of population evaluated, and date of progressive disease, or last contact or death, for the patients that didn’t progress. Overall survival (OS) was defined as the time between stage IV diagnosis, start date of systemic therapy, or date of MBM diagnosis, depending on the type of population evaluated, and date of last contact or death. Kaplan-Meier estimates were used for the calculation of PFS and OS. Differences between groups were assessed using the log-rank test. When applicable, hazard ratios (HR) with 95% confidence intervals (CI) were calculated to quantify the impact on survival. Multivariate logistic regression models were used to examine associations between variables, when appropriate. Results were reported as two-sided p values with 95% CIs. All p-values presented are two-sided tests of statistical significance at 0.05. For the indirect comparison between MAPKi, the Bucher method was used. All analyses were submitted to and approved by the local Ethics Committee. Results: Six publications reporting data from 3143 stage IV melanoma patients were included in this thesis. The 3-years (3-y) OS rate for patients treated with first-line chemotherapy, the most used systemic therapy in 2011-2014 was 15.9% (95% CI: 8.8-23). For patients treated with first-line immunotherapy in the same period, the 3-y OS rate was 37.4% (95% CI: 16.6-58.2). In the period of 2015-2018, the 3-y OS rate for patients treated with first-line immunotherapy almost duplicated compared to the 2011-2014 period, and was 64.6% (95% CI: 53.2–76) for patients achieving a complete response (CR), partial response (PR) or stable disease (SD). For patients achieving a CR, the 3-y OS rate was 87.7% (95% CI: 70.8–100). In patients harboring a BRAFV600 mutation, and with presence of worse prognostic factors, namely elevated baseline lactate dehydrogenase (LDH), worse Eastern Cooperative Oncology Group Performance Status (ECOG PS) and higher tumor volume, the combination of vemurafenib plus cobimetinib showed a non-significant lower risk for progression or death, compared to dabrafenib plus trametinib, and encorafenib plus binimetinib. Compared to cutaneous melanoma, patients with uveal melanoma derived less benefit from systemic therapy, even when treated with combined immunotherapy. The median OS (mOS) was only 16.1 months (95% CI: 12.9–19.3), but still higher than those reported for both chemotherapy and programmed cell death protein 1 (PD-1) monotherapy in this sub-group. The benefit observed in intracerebral disease was similar to the benefit in extracerebral disease, when combined immunotherapy (nivolumab plus ipilimumab) was used. The mOS in patients with MBM was 19 months (95% CI: 15.9-22.0). For the whole collective of patients receiving nivolumab plus ipilimumab, the 3-y OS rate was 30.1% (95% CI: 22.2-37.9). For patients achieving a CR, the 2-y OS rate was 85.6% (95%CI: 69.3-100), very similar to other stage IV patients. Patients receiving combined immunotherapy and local therapy (surgery or stereotactic radiotherapy) had a better outcome when compared to patients that didn’t receive local therapy – the 2-y OS rate was 49.5% versus 40.9 % (95%CI: 40.9-58.1 and 26.6-55.2). This benefit was observed regardless the timing of local therapy, i.e., before or after starting nivolumab plus ipilimumab. Conclusions: Our real-world data confirmed the improvement of survival outcomes in stage IV melanoma patients with the introduction of immune checkpoint inhibitors, and MAPKi in the last decade. Results show that, currently, PD-1 based immunotherapy should be offered as first-line therapy in stage IV melanoma. In patients with BRAFV600 mutation and worse prognostic features, first-line systemic therapy with MAPKi could be considered. In patients with MBM, combination of systemic immunotherapy and local therapy should be offered, when feasible.
Descrição
Palavras-chave
Melanoma Estadio IV Terapêutica sistémica Sobrevivência global Melanoma Stage IV Systemic Therapy Overall Survival