Asunto(s)

Anilidas , Carcinoma Hepatocelular , Ipilimumab , Neoplasias Hepáticas , Nivolumab , Piridinas , Humanos , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Nivolumab/farmacología , Nivolumab/uso terapéutico , Piridinas/farmacología , Piridinas/uso terapéutico , Anilidas/farmacología , Anilidas/uso terapéutico , Ipilimumab/uso terapéutico , Ipilimumab/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología

RESUMEN

Inactivation of the cyclin-dependent kinase inhibitor 2A (CDKN2A) gene is considerably more frequent in squamous cell lung cancer (SqCLC) than in other subtypes of lung cancer and may be a promising target for this histology. Here, we present the course of diagnosis and treatment of a patient with advanced SqCLC, harboring not only CDKN2A mutation but also PIK3CA amplification, Tumor Mutational Burden-High (>10 mutations/megabase), and a Tumor Proportion Score of 80%. After disease progression on multiple lines of chemotherapy and immunotherapy, he responded favorably to treatment with the CDK4/6i Abemaciclib and later achieved a durable partial response to immunotherapy rechallenge with a combination of anti-PD-1 and anti-CTLA-4, nivolumab, and ipilimumab.

Asunto(s)

Carcinoma de Pulmón de Células no Pequeñas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Células Escamosas/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa Clase I/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Células Epiteliales , Inmunoterapia , Ipilimumab/uso terapéutico , Neoplasias Pulmonares/genética , Mutación , Nivolumab/uso terapéutico

RESUMEN

INTRODUCTION: Dual immunotherapy (ipilimumab/nivolumab, IO/IO) and immunotherapy/tyrosine kinase inhibitor (IO/TKI) combinations (e.g. pembrolizumab/axitinib) are approved for the first-line treatment of intermediate/poor risk metastatic renal cell carcinoma (RCC), but there is limited comparative data between these two options. We sought to understand how oncologists decide between IO/IO vs. IO/TKI. METHODS: We sent a 10-question electronic survey centered on a patient scenario of intermediate/poor risk metastatic RCC to 294 academic/disease-focused and general oncologists in the US. RESULTS: We received 105 responses (36% response rate): 61% (64) of providers chose IO/IO, 39% (41) chose IO/TKI. 78% (82) of oncologists were academic or disease-focused, 22% (23) were general. Academic/disease-focused oncologists were significantly more likely to choose IO/IO (56/82, 68%) than general oncologists (8/23, 35%), P = .004. Among those who chose IO/IO, the perceived main issue with IO/TKI was: long-term toxicities - 31% (20), short-term toxicities - 28% (18), less effective - 28% (18), less convenient - 8% (5). Among those who chose IO/TKI, the perceived main issue with IO/IO was: short-term toxicities - 43% (17), less effective - 28% (11), long-term toxicities - 15% (6), and risk of death - 10% (4). 88% (92) of providers would be comfortable enrolling patients into a phase III trial comparing IO/IO vs. IO/TKI. We found no associations between therapy chosen by a provider and participation as PI in a trial of IO/IO or IO/TKI, or receipt of outside funding from an IO/IO or IO/TKI company. CONCLUSION: In response to a patient scenario of intermediate/poor risk metastatic RCC, 61% of providers chose IO/IO, 39% chose IO/TKI. There was a significant association between type of practice and choice of therapy, with academic/disease-focused oncologists more likely to choose IO/IO. The majority of oncologists would be comfortable enrolling patients into a phase III trial comparing IO/IO vs. IO/TKI.

Asunto(s)

Carcinoma de Células Renales , Neoplasias Renales , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Inmunoterapia , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Inhibidores de Proteínas Quinasas , Ensayos Clínicos Fase III como Asunto

RESUMEN

PURPOSE: We retrospectively analysed overall survival (OS) and potential predictive biomarkers of OS in patients with metastatic melanoma treated with ipilimumab plus nivolumab in a single institution. METHODS AND PATIENTS: Electronic medical records of patients with advanced melanoma receiving ≥ 1 dose of a combined ipilimumab plus nivolumab regimen between March 3, 2016 and March 7, 2020 in a single institution, were reviewed. OS was analysed using the Kaplan-Meier method. Sub-group analyses were conducted to examine several endpoints according to relevant clinical, molecular and pathological variables using logistic and Cox models. RESULTS: Forty-four cases were reviewed, 38 (86.4%), of whom had cutaneous melanoma, 21 (47.7%) were BRAF mutant, 21 (47.7%) presented high lactate dehydrogenase (LDH) values, 23 (52.3%) had ≥ 3 disease sites, and 10 (22.7%) patients had brain metastases. The median follow-up was 37.7 months, and the median OS was 21.1 months (95% CI 8.2-NR). In the multivariate analysis, the OS was significantly longer in patients with an Eastern Cooperative Oncology Group (ECOG) score of 0, LDH ≤ upper limit of normal, absence of liver metastases and neutrophil-to-lymphocyte ratio (NLR) < 5 (all p ≤ 0.05, log-rank test). These factors allowed the classification of patients into three prognostic risk groups (low/intermediate/high risk) for death. CONCLUSION: Overall survival of real-world patients from our cohort receiving ipilimumab plus nivolumab was lower than in previous studies. The ECOG score, LDH values, the presence of liver metastases and the NLR were independent prognostic factors for survival.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Ipilimumab/uso terapéutico , Melanoma/tratamiento farmacológico , Nivolumab/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Adulto , Anciano , Femenino , Humanos , Masculino , Melanoma/mortalidad , Melanoma/secundario , Persona de Mediana Edad , Estudios Retrospectivos , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Tasa de Supervivencia , Resultado del Tratamiento

RESUMEN

PURPOSE: Combination immunotherapy with nivolumab and ipilimumab has a high initial response rate in advanced melanoma; however, up to 55% of patients later progress. The efficacy and safety of ipilimumab re-induction in the setting of acquired resistance (AR) to combination immunotherapy is unknown. METHODS: Patients with advanced melanoma who initially achieved a complete response, partial response or sustained stable disease to induction combination immunotherapy then progressed and were reinduced with ipilimumab (alone or in combination with anti-PD-1) and were analysed retrospectively. Demographics, disease characteristics, efficacy and toxicity were examined. RESULTS: Forty-seven patients were identified from 12 centres. The response rate to reinduction therapy was 12/47 (26%), and disease control rate was 21/47 (45%). Responses appeared more frequent in patients who developed AR after ceasing induction immunotherapy (30% vs. 18%, P = 0.655). Time to AR was 11 months (95% confidence interval [CI], 8-15 months). After a median follow-up of 16 months (95% CI, 10-25 months), responders to reinduction had a median progression-free survival of 14 months (95% CI, 13, NR months), and in the whole cohort, the median overall survival from reinduction was 17 months (95% CI, 12-NR months). Twenty-seven (58%) immune-related adverse events (irAEs) were reported; 18 (38%) were grade 3/4, and in 11 of 27 (40%), the same irAE observed during induction therapy recurred. CONCLUSIONS: Reinduction with ipilimumab ± anti-PD-1 has modest clinical activity. Clinicians should be attentive to the risk of irAEs, including recurrence of irAEs that occurred during induction therapy. Future studies are necessary to determine best management after resistance to combination immunotherapy.

Asunto(s)

Anticuerpos Monoclonales/uso terapéutico , Quimioterapia de Inducción/métodos , Ipilimumab/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales/farmacología , Femenino , Humanos , Ipilimumab/farmacología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto Joven

RESUMEN

Breast cancer is the leading cause of women's death among all cancers. The main reason associated with this is the development of metastasis and therapy-resistant breast carcinoma (BC), which pose the main challenge of oncology nowadays. Evidence suggest that these tumors seem to have inhibitory mechanisms that may favor their progression and surveillance. Cancer cells can evade antitumor T cell responses by expressing some immune inhibitory molecules such as the cytotoxic T-lymphocyte antigen-4 (CTLA-4), whose clinical meaning has emerged in the last few years and is poorly understood in the BC context. This systematic literature review aims at identifying studies on CTLA-4 expression in BC, and address what is known about its clinical meaning. A literature search was performed in PubMed and LILACS databases, using the MESH terms "breast cancer"; "CTLA-4 Antigen/antagonists and inhibitors"; and "Lymphocytes, Tumor-Infiltrating/immunology", published in the last 10 years. In total, 12 studies were included in this review. Systematic review used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Despite the small number of eligible studies, the literature reports some associations between CTLA-4 expression in the tumor microenvironment and worse BC outcomes, regardless of its molecular subtype. CTLA-4 expression in BC is a putative marker of clinical significance and a rationale therapeutic target in the emerging field of immunotherapy.

Asunto(s)

Neoplasias de la Mama/inmunología , Antígeno CTLA-4/metabolismo , Inhibidores de Puntos de Control Inmunológico/farmacología , Recurrencia Local de Neoplasia/epidemiología , Microambiente Tumoral/inmunología , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Antígeno CTLA-4/análisis , Antígeno CTLA-4/antagonistas & inhibidores , Línea Celular Tumoral , Toma de Decisiones Clínicas , Supervivencia sin Enfermedad , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/prevención & control , Pronóstico , Escape del Tumor/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos

RESUMEN

BACKGROUND: Considering clinical benefits of new combination therapies for metastatic renal-cell carcinoma (mRCC), this study aims to calculate the number needed to treat (NTT) and the cost of preventing an event (COPE) for pembrolizumab plus axitinib (P + A), and nivolumab plus ipilimumab (N + I) as first-line treatments, from the Brazilian private perspective. METHODS: Overall survival (OS) and progression-free survival (PFS) data for intermediate- and poor-risk groups were obtained from KEYNOTE-426 and CHECKMATE-214 trials for P + A and N + I, respectively, versus sunitinib as mRCC first-line treatment. RESULTS: Considering a 12-month time horizon, 6 patients should be treated with P + A to prevent one death with sunitinib use, resulting in a COPE of 3,773,865 BRL. Using N + I, NNT for 12-month OS rate was 13 compared to sunitinib, with a COPE of 6,357,965 BRL. Regarding PFS data, NNT was also 6 when comparing P + A versus sunitinib, with an estimated COPE of 3,773,865 BRL. Estimated NNT was 20 comparing N + I and sunitinib, resulting in a COPE of 10,172,744 BRL. Cost differences between two treatment options, reached more than 6 million BRL for PFS, and 2 million BRL for OS. CONCLUSION: At the 12-month landmark, P + A suggests better economic scenario versus N + I as first-line mRCC treatment option for intermediate- and poor-risk groups, through an indirect comparison using sunitinib as a common comparator.

Asunto(s)

Antineoplásicos Inmunológicos/economía , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Neoplasias Renales/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/economía , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Axitinib/economía , Axitinib/uso terapéutico , Brasil , Carcinoma de Células Renales/patología , Análisis Costo-Beneficio , Femenino , Gastos en Salud/estadística & datos numéricos , Recursos en Salud/economía , Recursos en Salud/estadística & datos numéricos , Humanos , Ipilimumab/economía , Ipilimumab/uso terapéutico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Modelos Económicos , Nivolumab/economía , Nivolumab/uso terapéutico , Supervivencia sin Progresión , Índice de Severidad de la Enfermedad , Sunitinib/economía , Sunitinib/uso terapéutico , Adulto Joven

RESUMEN

From a complete literature review, we were able to present in this paper what is most current in the treatment with immunotherapy for advanced non-small cell lung cancer (NSCLC). Especially the use of immunotherapy, particularly inhibitors of PD-1 (programmed cell death protein 1), PDL-1 (programmed cell death protein ligand 1), and CTLA-4 (cytotoxic T-lymphocyte antigen 4). Since 2015, these drugs have transformed the treatment of advanced NSCLC lacking driver mutations, evolving from second-line therapy to first-line, with excellent results. The arrival of new checkpoint inhibitors such as cemiplimab and the use of checkpoint inhibitors earlier in the therapy of advanced and metastatic cancers has been making the future prospects for treating NSCLC lacking driver mutations more favorable and optimistic. In addition, for those patients who have low PDL-1 positivity tumors, the combination of cytotoxic chemotherapy, VEGF inhibitor, and immunotherapy have shown an important improvement in global survival and progression free survival regardless the PDL-1 status. We also explored the effectiveness of adding radiotherapy to immunotherapy and the most current results about this combination. One concern that cannot be overlooked is the safety profile of immune checkpoint inhibitors (ICI) and the most common toxicities are described throughout this paper as well as tumor resistance to ICI.

RESUMEN

Objective: To perform an analysis over time of the number needed to treat (NNT) and the cost of preventing an event (COPE) for nivolumab + ipilimumab (NIVO+IPI) and pembrolizumab + axitinib (PEMBRO+AXI) as first-line treatments for advanced renal cell carcinoma patients with intermediate or poor-risk, under the Brazilian private healthcare system perspective. Methods: The NNT for overall survival (OS) and progression-free survival (PFS) from 12-month to maximum available follow-up from CheckMate 214 and KEYNOTE-426 studies were used to estimate the COPE. Treatment costs were estimated considering the labeled dosing and median PFS as a proxy for treatment duration. Results: The OS NNT for NIVO+IPI decreased from 12 to 8 and for PEMBRO+AXI increased slightly from 7 to 8 at 12 and 42 months, respectively. For PFS, NNT for NIVO+IPI decreased from 15 to 6, and for PEMBRO+AXI increased from 7 to 10 at 12 and 30 months. The estimated treatment cost is R$ 638,620 for an estimated median of 11.2 months of NIVO+IPI treatment and R$ 966,818 for 13.8 months of PEMBRO+AXI treatment. COPE for OS at 12 and 42 months was R$ 7,663,440 and R$ 5,108,960 with NIVO+IPI and R$ 6,047,417 and R$ 7,734,547 with PEMBRO+AXI. For PFS, COPE at 12 and 30 months was R$ 9,579,300 and R$ 3,831,720 with NIVO+IPI and R$ 6,047,417 and R$ 9,668,184 with PEMBRO+AXI. Conclusions: Treatment with NIVO+IPI results in lower COPE than PEMBRO+AXI from month 18 onwards, driven by lower treatment costs and improved NNT over time with NIVO+IPI

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Objetivo: Analisar ao longo do tempo o número necessário a tratar (NNT) e o custo para prevenir um evento (COPE) para nivolumabe + ipilimumabe (NIVO+IPI) e pembrolizumabe + axitinibe (PEMBRO+AXI) na primeira linha de tratamento do carcinoma de células renais avançado com risco intermediário ou alto na perspectiva do sistema suplementar de saúde brasileiro. Métodos: O NNT para sobrevida global (SG) e sobrevida livre de progressão (SLP) para 12 meses até o máximo de tempo de seguimento disponível dos estudos CheckMate 214 e KEYNOTE-426 foi usado para estimar o COPE. Custos de tratamento foram estimados considerando a dosagem em bula e a mediana de SLP como aproximação para duração de tratamento. Resultados: O NNT de SG para NIVO+IPI reduziu de 12 para 8 e para PEMBRO+AXI subiu de 7 para 8 em 12 e 42 meses, respectivamente. Para SLP, NIVO+IPI teve redução de 15 para 6 e para PEMBRO+AXI aumentou de 7 para 10 em 12 e 30 meses. O custo estimado é de R$ 638.620 para mediana de 11,2 meses de tratamento com NIVO+IPI e de R$ 966.818 para 13,8 meses com PEMBRO+AXI. O COPE para SG foi de R$ 7.663.440 e R$ 5.108.960 com NIVO+IPI e de R$ 6.047.417 e R$ 7.734.547 com PEMBRO+AXI para 12 e 42 meses. Para SLP, foi de R$ 9.579.300 e R$ 3.831.720 com NIVO+IPI e de R$ 6.047.417 e R$ 9.668.184 com PEMBRO+AXI em 12 e 30 meses. Conclusões: O tratamento com NIVO+IPI resulta em menor COPE, em comparação com PEMBRO+AXI, a partir de 18 meses de seguimento, justificado por menor custo de tratamento e melhora do NNT ao longo do tempo com NIVO+IPI

Asunto(s)

Carcinoma de Células Renales , Costos de la Atención en Salud , Costos y Análisis de Costo , Nivolumab , Axitinib

RESUMEN

Despite the success and ongoing promise of monoclonal antibody-targeted immune checkpoint inhibitor immunotherapy of advanced malignancies, in particular, antibodies directed against CTLA-4 and PD-1/PD-L1, the development of immune-related adverse events (irAEs) remains a constraint of this type of therapy. Although rarely fatal, the occurrence of irAEs may necessitate discontinuation of immunotherapy, as well as administration of corticosteroids or other immunosuppressive therapies that may not only compromise efficacy but also predispose for development of opportunistic infection. Clearly, retention of efficacy of immune checkpoint-targeted therapies with concurrent attenuation of immune-mediated toxicity represents a formidable challenge. In this context, the current brief review examines mechanistic relationships between these events, as well as recent insights into immunopathogenesis, and strategies which may contribute to resolving this issue. These sections are preceded by brief overviews of the discovery and functions of CTLA-4 and PD-1, as well as the chronology of the development of immunotherapeutic monoclonal antibodies which target these immune checkpoint inhibitors.

Asunto(s)

Antineoplásicos Inmunológicos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Inmunoterapia/efectos adversos , Neoplasias/terapia , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/inmunología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/uso terapéutico , Oncología Médica/métodos , Oncología Médica/tendencias , Neoplasias/epidemiología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología

RESUMEN

As the indications and clinical use of immune checkpoint inhibitors increase, it is expected that we will face some of their less frequently reported complications. Primary adrenal insufficiency is one of them, and given its unspecific symptoms and potentially serious consequences, it is important to have a high degree of clinical suspicion. We present 3 cases and a review of the literature concerning its main clinical characteristics, diagnostics, and management.

RESUMEN

INTRODUCTION: The useof immunotherapy in Mexico has been used since 2012 with ipilimumab and since 2015 with nivolumab and pembrolizumab, so it is a matter of necessity to know the experience of these drugs. MATERIAL AND METHODS: An observational, descriptive, cross-sectional, and retrospective study was performed in Médica Sur Hospital, where with dossiers from 2012 to June 2018 patients with metastatic cancer who received immunotherapy with ipilimumab, nivolumab, and pembrolizumab for six months were evaluated, searching as principal outcomes the adverse effects of those drugs and as secondary outcomes the response to treatment. RESULTS: Seventy subjects fulfilled the inclusion criteria for the study, and 42 (60%) were women with an average age of 60.73 ±13.64 years (16-82 years). The pathologies that received immunotherapy were the following: melanoma and lung cancer. The most frequent clinical and laboratory adverse effects were as follows: fatigue - 32 (45.71%), asthaenia - 30 (42%), nausea - 8 (11.4%), diarrhoea - 8 (11.4%), and rash - 7 (10%). The worst adverse effects were respiratory and endocrinological: pneumonitis - 10 (14.28%), hypothyroidism - 4 (5.71%), hyperglycaemia - 1 (1.4%), and hypophysitis - 2 (2.9%). With respect to treatment response: complete response - 8 (11.4%), partial response - 11 (15.71%), stable disease - 33 (47.14%), and disease progression - 19 (27.14%). CONCLUSIONS: The most common adverse effects did not condition the suspension of treatment or increase in intra-hospital stay, but there were some adverse effects that actually had an impact on evolution, hospital stay, and mortality.

RESUMEN

INTRODUCTION: Ipilimumab has been approved in patients with advanced melanoma by different regulatory bodies worldwide, but its use in clinical practice is not fully consistent among oncologists. We have surveyed a representative sample of Spanish medical oncologists on issues related to the use of ipilimumab. MATERIALS AND METHODS: The survey was based on the Delphi method, where experts respond anonymously to two rounds of a questionnaire. Questionnaire consisted of 42 statements divided among the following eight categories: Pathology and Diagnosis; Patterns of Response; Parameters affecting Treatment Selection; Patient Profile; Sequencing of Treatment; Definition of Long-Term Survivors; Quality of Life; Concept of Immuno-oncology. The experts were asked to rate each statement on a scale of 1-9, where 1 meant "completely disagree" and 9 meant "completely agree". RESULTS: Thirty-three oncologists responded to both rounds of the survey (62.3 % of total surveyed). On issues related to pathology and diagnosis, patterns of response, and immuno-oncology, the specialists reached a high level of consensus. There was also a high level of agreement, albeit without consensus on assessment of BRAF mutations before deciding on treatment with ipilimumab. However, there was a lower level of agreement on sequencing treatment with BRAF inhibitors and ipilimumab, on predictive factors, on the use of corticosteroids, and on patient quality of life. CONCLUSIONS: The disparity in many of these topics suggests that oncologists need more information on certain aspects of ipilimumab treatment. We need to define generally accepted algorithms of treatment, especially with regard to issues that were shown to be controversial or unclear.

Asunto(s)

Anticuerpos Monoclonales/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/secundario , Médicos/psicología , Pautas de la Práctica en Medicina/normas , Calidad de Vida , Humanos , Ipilimumab , España , Encuestas y Cuestionarios

RESUMEN

PURPOSE: Ipilimumab is a human monoclonal antibody against cytotoxic T-lymphocyte antigen 4 available as an immunotherapy mainly for advanced melanoma. It induces an activation of T cells, resulting in an immune-mediated anti-tumor response and also immune-related adverse events, including hypophysitis. The aim of this review is to identify and discuss features concerning ipilimumab-induced hypophysitis (IIH). DESIGN: A MEDLINE research of all years of publication of IIH was conducted. We gathered information regarding clinical, radiologic and laboratory features of 71 cases recorded in the literature. RESULTS: In our review, IIH was more frequent among older and male patients. Fatigue and headache were the most frequent initial clinical manifestations of IIH and enlargement of the pituitary gland at MRI was present in the majority of patients. Those who received more than 3 cycles of ipilimumab had more fatigue (p = 0.04) and arthritis (p = 0.04). Adrenal insufficiency was more prevalent in men (p = 0.007). Glucocorticoid therapy and hormone replacement were required in most patients and pituitary function recovery was uncommon. Low prolactin at diagnosis tended to predict permanent pituitary dysfunction (p = 0.07). CONCLUSION: Hypopituitarism as a consequence of IIH, if not promptly recognized, can lead to potentially fatal events, such as adrenal insufficiency. IIH can be easily managed with glucocorticoids and hormonal replacement; therefore, physicians should be familiar with the key aspects of this condition. More studies to develop screening protocols and therapeutic intervention algorithms should be performed to decrease morbidity related to IIH.

Asunto(s)

Anticuerpos Monoclonales/efectos adversos , Hipopituitarismo/inducido químicamente , Factores Inmunológicos/efectos adversos , Melanoma/tratamiento farmacológico , Enfermedades de la Hipófisis/inducido químicamente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Ipilimumab , Masculino , Persona de Mediana Edad

RESUMEN

Over the last 4 years, various drugs have been approved for the treatment of metastatic cutaneous melanoma. Ipilimumab, an anti-CTLA-4 inhibitor that stimulates antitumor immunity, was the first agent to improve overall survival both in first line and in previously treated patients. Ipilimumab results in long term disease control in approximately 20% of the patients. Vemurafenib was the first BRAF inhibitor (BRAFi) approved and also resulted in improved overall survival compared with dacarbazine in patients with BRAF mutated metastatic melanoma. More recently, another BRAFi, dabrafenib, and a MEK inhibitor, trametinib, were approved either alone or in combination as they each showed significant antitumor activity relative to dacarbazine and the combination appeared superior to dabrafenib monotherapy. The major feature of such tumor targeted therapy is its high response rate (40-70%) and the rapidity of the responses, resulting in prompt clinical improvement. However, unlike immunotherapy, targeted therapy does not result in long-term treatment free survival. In this paper, we discuss how best to integrate the currently available treatment options including high-dose interleukin-2 (HD IL-2), systemic chemotherapy, ipilimumab and tumor targeted therapy in various clinical scenarios.