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BACKGROUND: Phase 1-2 trials involving patients with resectable, macroscopic stage III melanoma have shown that neoadjuvant immunotherapy is more efficacious than adjuvant immunotherapy. METHODS: In this phase 3 trial, we randomly assigned patients with resectable, macroscopic stage III melanoma, in a 1:1 ratio, to receive two cycles of neoadjuvant ipilimumab plus nivolumab and then undergo surgery or to undergo surgery and then receive 12 cycles of adjuvant nivolumab. Only the patients in the neoadjuvant group who had a partial response or nonresponse received subsequent adjuvant treatment. The primary end point was event-free survival. RESULTS: A total of 423 patients underwent randomization. At a median follow-up of 9.9 months, the estimated 12-month event-free survival was 83.7% (99.9% confidence interval [CI], 73.8 to 94.8) in the neoadjuvant group and 57.2% (99.9% CI, 45.1 to 72.7) in the adjuvant group. The difference in restricted mean survival time was 8.00 months (99.9% CI, 4.94 to 11.05; P<0.001; hazard ratio for progression, recurrence, or death, 0.32; 99.9% CI, 0.15 to 0.66). In the neoadjuvant group, 59.0% of the patients had a major pathological response, 8.0% had a partial response, 26.4% had a nonresponse (>50% residual viable tumor), and 2.4% had progression; in 4.2%, surgery had not yet been performed or was omitted. The estimated 12-month recurrence-free survival was 95.1% among patients in the neoadjuvant group who had a major pathological response, 76.1% among those who had a partial response, and 57.0% among those who had a nonresponse. Adverse events of grade 3 or higher that were related to systemic treatment occurred in 29.7% of the patients in the neoadjuvant group and in 14.7% in the adjuvant group. CONCLUSIONS: Among patients with resectable, macroscopic stage III melanoma, neoadjuvant ipilimumab plus nivolumab followed by surgery and response-driven adjuvant therapy resulted in longer event-free survival than surgery followed by adjuvant nivolumab. (Funded by Bristol Myers Squibb and others; NADINA ClinicalTrials.gov number, NCT04949113.).
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BACKGROUND: Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1-2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma. METHODS: In this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti-cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×109 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival. RESULTS: A total of 168 patients (86% with disease refractory to anti-programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression. CONCLUSIONS: In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.).
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Imunoterapia Adotiva , Linfócitos do Interstício Tumoral , Melanoma , Humanos , Terapia Baseada em Transplante de Células e Tecidos , Ipilimumab/efeitos adversos , Melanoma/tratamento farmacológicoRESUMO
BACKGROUND: Immune checkpoint inhibitor treatment of patients with metastatic Merkel cell carcinoma (mMCC) has shown high response rates, ranging from 33% to 73%. The ideal duration of treatment, however, is currently unknown. The aim of this study was to evaluate if avelumab treatment for mMCC can be safely stopped after 1 year of treatment and a complete response (CR) confirmed by fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging. METHODS: Patients who received more than one dose of avelumab treatment for mMCC between November 2017 and February 2022 were included in this study. Treatment was discontinued in case of a FDG-PET/CT confirmed CR after 1 year (26 cycles) of avelumab or a CR and unacceptable toxicity earlier. The primary end point was recurrence-free survival (RFS). RESULTS: Sixty-five patients were included: 25 (38%) had a FDG-PET/CT-confirmed CR at discontinuation of avelumab. In those 25 patients, reasons for discontinuation of treatment were completion of 1 year of treatment in 13 (52%), toxicity in five (20%), and patient preference in seven (28%). Median duration of treatment in this group was 11 months (interquartile range, 6.1-11.7). Median follow-up was 27 months (interquartile range, 15.8-33.8). The 12-month RFS was 88% (95% CI, 0.74-1) and median RFS was not reached. Two patients (8%) had a recurrence at 4 and 7 months after discontinuation of treatment. CONCLUSIONS: Patients with mMCC who acquire a CR on PET/CT imaging appear to have durable responses after discontinuation of treatment after 1 year.
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Anticorpos Monoclonais Humanizados , Carcinoma de Célula de Merkel , Neoplasias Cutâneas , Humanos , Carcinoma de Célula de Merkel/diagnóstico por imagem , Carcinoma de Célula de Merkel/tratamento farmacológico , Carcinoma de Célula de Merkel/induzido quimicamente , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/induzido quimicamente , Fluordesoxiglucose F18 , Anticorpos Monoclonais/efeitos adversosRESUMO
BACKGROUND: Ongoing research in the field of both localized, locally advanced and metastatic renal cell carcinoma has resulted in the availability of multiple treatment options. Hence, many questions are still unanswered and await further research. A nationwide collaborative registry allows to collect corresponding data. For this purpose, the Dutch PROspective Renal Cell Carcinoma cohort (PRO-RCC) has been founded, for the prospective collection of long-term clinical data, patient reported outcome measures (PROMs) and patient reported experience measures (PREMs). METHODS: PRO-RCC is designed as a multicenter cohort for all Dutch patients with renal cell carcinoma (RCC). Recruitment will start in the Netherlands in 2023. Importantly, participants may also consent to participation in a 'Trial within cohorts' studies (TwiCs). The TwiCs design provides a method to perform (randomized) interventional studies within the registry. The clinical data collection is embedded in the Netherlands Cancer Registry (NCR). Next to the standardly available data on RCC, additional clinical data will be collected. PROMS entail Health-Related Quality of Life (HRQoL), symptom monitoring with optional ecological momentary assessment (EMA) of pain and fatigue, and optional return to work- and/or nutrition questionnaires. PREMS entail satisfaction with care. Both PROMS and PREMS are collected through the PROFILES registry and are accessible for the patient and the treating physician. TRIAL REGISTRATION: Ethical board approval has been obtained (2021_218) and the study has been registered at ClinicalTrials.gov (NCT05326620). DISCUSSION: PRO-RCC is a nationwide long-term cohort for the collection of real-world clinical data, PROMS and PREMS. By facilitating an infrastructure for the collection of prospective data on RCC, PRO-RCC will contribute to observational research in a real-world study population and prove effectiveness in daily clinical practice. The infrastructure of this cohort also enables that interventional studies can be conducted with the TwiCs design, without the disadvantages of classic RCTs such as slow patient accrual and risk of dropping out after randomization.
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Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/terapia , Países Baixos/epidemiologia , Estudos Prospectivos , Qualidade de Vida , Neoplasias Renais/epidemiologia , Neoplasias Renais/terapiaRESUMO
OBJECTIVE: To analyse if exposure to sunitinib in the Immediate Surgery or Surgery After Sunitinib Malate in Treating Patients With Metastatic Kidney Cancer (SURTIME) trial, which investigated opposite sequences of cytoreductive nephrectomy (CN) and systemic therapy, is associated with the overall survival (OS) benefit observed in the deferred CN arm. PATIENTS AND METHODS: A post hoc analysis of SURTIME trial data. Variables analysed included number of patients receiving sunitinib, time from randomisation to start sunitinib, overall response rate by Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1, and duration of drug exposure and dose in the intention-to-treat population of the immediate and deferred arm. Descriptive methods and 95% confidence-intervals (CI) were used. RESULTS: In the deferred arm, 97.7% (95% CI 89.3-99.6%; n = 48) received sunitinib vs 80% (95% CI 66.9-88.7%, n = 40) in the immediate arm. Following immediate CN, 19.6% progressed 4 weeks after CN and the median time to start sunitinib was 39.5 vs 4.5 days in the deferred arm. At week 16, 46.0% had progressed at metastatic sites in the immediate CN arm vs 32.7% in the deferred arm. Sunitinib dose reductions, escalations and interruptions were not statistically significantly different between arms. Among patients who received sunitinib in the immediate or deferred arm the median total sunitinib treatment duration was 172.5 vs 248 days. Reduction of target lesions was more profound in the deferred arm. CONCLUSIONS: In comparison to the deferred CN approach, immediate CN impairs administration, onset, and duration of sunitinib. Starting with systemic therapy leads to early and more profound disease control and identification of progression prior to planned CN, which may have contributed to the observed OS benefit.
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Carcinoma de Células Renais , Neoplasias Renais , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/cirurgia , Procedimentos Cirúrgicos de Citorredução , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/cirurgia , Nefrectomia/métodos , Sunitinibe/uso terapêuticoRESUMO
OBJECTIVE: To evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib plus trametinib (BRAF and MEK inhibitor) to allow for radical surgical resection in patients with unresectable locally advanced melanoma. SUMMARY BACKGROUND DATA: Approximately 5% of stage III melanoma patients presents with unresectable locally advanced disease, making standard of care with resection followed by adjuvant systemic therapy impossible. Although neoadjuvant targeted therapy has shown promising results in resectable stage III melanoma, its potency to enable surgical resection in patients with primarily unresectable locally advanced stage III melanoma is still unclear. METHODS: In this prospective, single-arm, phase II trial, patients with unresectable BRAF-mutated locally advanced stage IIIC or oligometastatic stage IV melanoma were included. After 8âweeks of treatment with dabrafenib and trametinib, evaluation by positron emission tomography/computed tomography and physical examination were used to assess sufficient downsizing of the tumor to enable resection. The primary objective was the percentage of patients who achieved a radical (R0) resection. RESULTS: Between August 2014 and March 2019, 21 patients (20/21 stage IIIC American Joint Committee on Cancer staging manual 7th edition) were included. Planned inclusion of 25 patients was not reached due to slow accrual and changing treatment landscape. Despite this, the predefined endpoint was successfully met. In 18/21 (86%) patients a resection was performed, of which 17 were R0 resections. At a median follow-up of 50âmonths (interquartile range 37.7-57.1âmonths), median recurrence-free survival was 9.9âmonths (95% confidence interval 7.52-not reached) in patients undergoing surgery. CONCLUSIONS: This prospective, single-arm, open-label phase II trial, shows neoadjuvant dabrafenib plus trametinib as a potent cytoreductive treatment, allowing radical resection of metastases in 17/21 (81%) patients with prior unresectable locally advanced melanoma.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Procedimentos Cirúrgicos de Citorredução , Melanoma/tratamento farmacológico , Melanoma/cirurgia , Adulto , Idoso , Feminino , Humanos , Imidazóis/administração & dosagem , Imageamento por Ressonância Magnética , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Países Baixos , Oximas/administração & dosagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Estudos Prospectivos , Proteínas Proto-Oncogênicas B-raf , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagemRESUMO
BACKGROUND: The outcome of patients with macroscopic stage III melanoma is poor. Neoadjuvant treatment with ipilimumab plus nivolumab at the standard dosing schedule induced pathological responses in a high proportion of patients in two small independent early-phase trials, and no patients with a pathological response have relapsed after a median follow up of 32 months. However, toxicity of the standard ipilimumab plus nivolumab dosing schedule was high, preventing its broader clinical use. The aim of the OpACIN-neo trial was to identify a dosing schedule of ipilimumab plus nivolumab that is less toxic but equally effective. METHODS: OpACIN-neo is a multicentre, open-label, phase 2, randomised, controlled trial. Eligible patients were aged at least 18 years, had a WHO performance status of 0-1, had resectable stage III melanoma involving lymph nodes only, and measurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1. Patients were enrolled from three medical centres in Australia, Sweden, and the Netherlands, and were randomly assigned (1:1:1), stratified by site, to one of three neoadjuvant dosing schedules: group A, two cycles of ipilimumab 3 mg/kg plus nivolumab 1 mg/kg once every 3 weeks intravenously; group B, two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg once every 3 weeks intravenously; or group C, two cycles of ipilimumab 3 mg/kg once every 3 weeks directly followed by two cycles of nivolumab 3 mg/kg once every 2 weeks intravenously. The investigators, site staff, and patients were aware of the treatment assignment during the study participation. Pathologists were masked to treatment allocation and all other data. The primary endpoints were the proportion of patients with grade 3-4 immune-related toxicity within the first 12 weeks and the proportion of patients achieving a radiological objective response and pathological response at 6 weeks. Analyses were done in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT02977052, and is ongoing with an additional extension cohort and to complete survival analysis. FINDINGS: Between Nov 24, 2016 and June 28, 2018, 105 patients were screened for eligibility, of whom 89 (85%) eligible patients were enrolled and randomly assigned to one of the three groups. Three patients were excluded after randomisation because they were found to be ineligible, and 86 received at least one dose of study drug; 30 patients in group A, 30 in group B, and 26 in group C (accrual to this group was closed early upon advice of the Data Safety Monitoring Board on June 4, 2018 because of severe adverse events). Within the first 12 weeks, grade 3-4 immune-related adverse events were observed in 12 (40%) of 30 patients in group A, six (20%) of 30 in group B, and 13 (50%) of 26 in group C. The difference in grade 3-4 toxicity between group B and A was -20% (95% CI -46 to 6; p=0·158) and between group C and group A was 10% (-20 to 40; p=0·591). The most common grade 3-4 adverse events were elevated liver enzymes in group A (six [20%)]) and colitis in group C (five [19%]); in group B, none of the grade 3-4 adverse events were seen in more than one patient. One patient (in group A) died 9·5 months after the start of treatment due to the consequences of late-onset immune-related encephalitis, which was possibly treatment-related. 19 (63% [95% CI 44-80]) of 30 patients in group A, 17 (57% [37-75]) of 30 in group B, and nine (35% [17-56]) of 26 in group C achieved a radiological objective response, while pathological responses occurred in 24 (80% [61-92]) patients in group A, 23 (77% [58-90]) in group B, and 17 (65% [44-83]) in group C. INTERPRETATION: OpACIN-neo identified a tolerable neoadjuvant dosing schedule (group B: two cycles of ipilimumab 1 mg/kg plus nivolumab 3 mg/kg) that induces a pathological response in a high proportion of patients and might be suitable for broader clinical use. When more mature data confirm these early observations, this schedule should be tested in randomised phase 3 studies versus adjuvant therapies, which are the current standard-of-care systemic therapy for patients with stage III melanoma. FUNDING: Bristol-Myers Squibb.
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Antineoplásicos Imunológicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ipilimumab/administração & dosagem , Melanoma/tratamento farmacológico , Terapia Neoadjuvante , Nivolumabe/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Cutâneas/patologia , Adulto JovemRESUMO
INTRODUCTION: Severe immune-related adverse events (irAEs) due to immune checkpoint inhibitors (ICIs) can lead to admission to the intensive care unit (ICU). In this retrospective study, we determined the incidence, treatment patterns and survival outcomes of this patient population at a comprehensive cancer center. METHODS: All patients admitted to the ICU due to irAEs from ICI treatment between January 2015 and July 2022 were included. Descriptive statistics were reported on patient characteristics and treatment patterns during hospital admission. Overall survival (OS) from the time of ICU discharge to death was estimated using the Kaplan-Meier method. RESULTS: Over the study period, 5561 patients received at least one ICI administration, of which 32 patients (0.6%) were admitted to the ICU due to irAEs. Twenty patients were treated with anti-PD-1 plus anti-CTLA-4 treatment, whereas 12 patients were treated with ICI monotherapy. The type of irAEs were de novo diabetes-related ketoacidosis (n = 8), immune-related gastrointestinal toxicity (n = 8), myocarditis or myositis (n = 10), nephritis (n = 3), pneumonitis (n = 2), and myelitis (n = 1). The median duration of ICU admission was 3 days (interquartile range: 2-6 days). Three patients died during ICU admission. The median OS of the patients who were discharged from the ICU was 18 months (95% confidence interval, 5.0-NA). CONCLUSION: The incidence of irAEs leading to ICU admission in patients treated with ICI was low in this study. ICU mortality due to irAEs was low and a subset of this patient population even had long-term survival.
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Inibidores de Checkpoint Imunológico , Unidades de Terapia Intensiva , Neoplasias , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Masculino , Feminino , Unidades de Terapia Intensiva/estatística & dados numéricos , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Neoplasias/tratamento farmacológico , Neoplasias/mortalidade , Adulto , Incidência , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/mortalidade , Idoso de 80 Anos ou mais , Antígeno CTLA-4/antagonistas & inibidoresRESUMO
OBJECTIVE: ILP has shown to achieve high response rates in patients with melanoma ITM. Possibly there is a synergistic mechanism of action of ILP and anti-PD1. The aim of this trial was to investigate the safety and efficacy of adding a single dose of systemic anti-PD1 to isolated limb perfusion (ILP) for patients with melanoma in-transit metastases (ITM). METHODS: In this placebo controlled double-blind phase Ib/II trial, patients with melanoma ITM were randomized 1:1 to either a single systemic dose of nivolumab or placebo one day prior to ILP. The primary endpoint was complete response (CR) rate at three months, and safety in terms of incidence and severity of adverse events (AEs). RESULTS: A total of 20 patients were included. AEs of any grade occurred in 90% of patients in the nivolumab arm and in 80% in the placebo arm within three months after ILP. Grade 3 AEs were reported in 40% and 30% respectively, most commonly related to wound infection, wound dehiscence, or skin necrosis. There were no grade 4 or 5 AEs reported. The CR rate was 75% in the nivolumab arm and 60% in the placebo arm. The 1-year local progression-free rate was 86% in the nivolumab arm and 67% in the placebo arm. The 1-year OS was 100% in both arms. CONCLUSION: For patients with melanoma ITM, the addition of a single systemic dose of nivolumab the day before ILP is considered safe and feasible with promising efficacy. Accrual will continue in a phase 2 trial.
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Quimioterapia do Câncer por Perfusão Regional , Melanoma , Nivolumabe , Neoplasias Cutâneas , Humanos , Melanoma/tratamento farmacológico , Melanoma/secundário , Melanoma/patologia , Nivolumabe/administração & dosagem , Nivolumabe/uso terapêutico , Método Duplo-Cego , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Quimioterapia do Câncer por Perfusão Regional/métodos , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/administração & dosagem , Adulto , Extremidades , Idoso de 80 Anos ou maisRESUMO
PURPOSE: The development of resistance limits the clinical benefit of BRAF and MEK inhibitors (BRAFi/MEKi) in BRAFV600-mutated melanoma. It has been shown that short-term treatment (14 days) with vorinostat was able to initiate apoptosis of resistant tumor cells. We aimed to assess the antitumor activity of sequential treatment with vorinostat following BRAFi/MEKi in patients with BRAFV600-mutated melanoma who progressed after initial response to BRAFi/MEKi. PATIENTS AND METHODS: Patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma were treated with vorinostat 360 mg once daily for 14 days followed by BRAFi/MEKi. The primary endpoint was an objective response rate of progressive lesions of at least 30% according to Response Evaluation Criteria in Solid Tumors 1.1. Secondary endpoints included progression-free survival, overall survival, safety, pharmacokinetics of vorinostat, and translational molecular analyses using ctDNA and tumor biopsies. RESULTS: Of the 26 patients with progressive BRAFi/MEKi-resistant BRAFV600-mutated melanoma receiving treatment with vorinostat, 22 patients were evaluable for response. The objective response rate was 9%, with one complete response for 31.2 months and one partial response for 14.9 months. Median progression-free survival and overall survival were 1.4 and 5.4 months, respectively. Common adverse events were fatigue (23%) and nausea (19%). ctDNA analysis showed emerging secondary mutations in NRAS and MEK in eight patients at the time of BRAFi/MEKi resistance. Elimination of these mutations by vorinostat treatment was observed in three patients. CONCLUSIONS: Intermittent treatment with vorinostat in patients with BRAFi/MEKi-resistant BRAFV600-mutated melanoma is well tolerated. Although the primary endpoint of this study was not met, durable antitumor responses were observed in a minority of patients (9%).
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Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores de Histona Desacetilases , Melanoma , Mutação , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf , Vorinostat , Humanos , Melanoma/tratamento farmacológico , Melanoma/genética , Melanoma/patologia , Melanoma/mortalidade , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Vorinostat/administração & dosagem , Vorinostat/farmacologia , Feminino , Masculino , Pessoa de Meia-Idade , Idoso , Adulto , Inibidores de Histona Desacetilases/administração & dosagem , Inibidores de Histona Desacetilases/uso terapêutico , Inibidores de Histona Desacetilases/efeitos adversos , Inibidores de Histona Desacetilases/farmacologia , Inibidores de Histona Desacetilases/farmacocinética , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudo de Prova de Conceito , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Idoso de 80 Anos ou maisRESUMO
INTRODUCTION: Treatment with the immune checkpoint inhibitor anti-programmed cell death protein-1 (PD-1) often causes immune-related adverse events (irAEs). Since irAEs resemble autoimmune diseases, autoantibodies might play a role and could potentially be used to identify patients at risk. Therefore, we investigated the association between autoantibody-positivity and toxicity as well as clinical response in patients with melanoma treated with anti-PD-1. MATERIALS AND METHODS: This two-center, retrospective study included 143 patients with melanoma treated with anti-PD-1. Toxicities grade ≥2 and recurrences/responses were captured until 6 months after treatment initiation. Autoantibody measurements were performed at baseline and 3 months after treatment initiation, including IgM-rheumatoid factor (RF), antinuclear antibodies (ANA), extractable nuclear antigen, anti-cyclic citrullinated peptide antibodies (anti-CCP2) and anti-thyroid antibodies. RESULTS: 169 irAEs were experienced by 86/143 patients (137 grades 1-2, 32 grades 3-4), the most common being thyroiditis (n=25), dermatitis (n=24), and sicca problems (n=19). Patients with autoantibodies at baseline experienced more irAEs (p=0.001), predominantly associated with anti-thyroid antibodies and thyroid dysfunction. No association was observed between any irAE and anti-CCP2, RF or ANA. In women, baseline and on-treatment anti-thyroid antibody-positivity as well as seroconversion during treatment was associated with thyroid dysfunction. In men, this association was only observed on-treatment. The presence of autoantibodies was not associated with melanoma recurrence (p=0.776) or response (p=0.597). CONCLUSION: The presence of autoantibodies prior to anti-PD-1 therapy is associated with irAEs in patients with melanoma. Both baseline positivity and seroconversion of anti-thyroid antibodies were strongly associated with thyroid dysfunction. This association was stronger in women, with all women who were baseline positive developing thyroid dysfunction.
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Autoanticorpos , Inibidores de Checkpoint Imunológico , Melanoma , Soroconversão , Humanos , Melanoma/tratamento farmacológico , Melanoma/imunologia , Feminino , Masculino , Autoanticorpos/sangue , Autoanticorpos/imunologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Idoso , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Adulto , Idoso de 80 Anos ou mais , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologiaRESUMO
Background: Upfront cytoreductive nephrectomy (CN) is no longer the standard of care for patients with metastastic renal cell carcinoma (mRCC) with intermediate or poor prognosis according to the International mRCC Database Consortium categories. Objective: To investigate indications for CN following first-line ipilimumab-nivolumab, and assess management and outcomes for patients achieving no evidence of disease (NED) after CN. Design setting and participants: This was a retrospective cohort study among 125 patients with synchronous mRCC who received ipilimumab-nivolumab treatment between March 2019 and June 2022 at four European centres. At one of the four centres, nivolumab was stopped following NED. Outcome measurements and statistical analysis: We measured complete response of metastases (mCR) according to Response Evaluation Criteria in Solid Tumours 1.1; near-complete response of mestastases (mnCR) was defined as a >80% reduction in cumulative metastatic volume. Treatment-free survival (TFS), disease-free survival (DFS), progression-free survival (PFS), and cancer-specific survival (CSS) were determined. Results and limitations: At median follow-up of 25 mo, 23/125 patients (18%) had undergone deferred CN. Of 26 patients (21%) with mCR or mnCR, 19 (73%) underwent CN to achieve NED, of whom 11 (58%) discontinued nivolumab, with median TFS of 21 mo. For patients who continued (n = 8, 42%) versus discontinued nivolumab following NED, 2-yr DFS was 83% versus 60% (p = 0.675) and 3-yr CSS was 100% versus 70% (p = 0.325). Four patients underwent CN because of a dissociated response of the primary tumour and were still alive at median follow-up of 5 mo. Conclusions: CN can result in NED, durable DFS, and substantial time off systemic therapy. More collaborative data are required to ascertain the benefits of treatment discontinuation versus oncologic safety. Patient summary: In our study using real-world data, 18% of patients treated with immunotherapy underwent deferred kidney surgery. The majority were free of disease after 3 years. Half of the patients who stopped immunotherapy after surgery have been off therapy for 21 months or longer. Larger studies are needed to investigate the effect of kidney surgery and discontinuation of immunotherapy on survival.
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PURPOSE: The combination of talimogene laherparepvec (T-VEC) and pembrolizumab previously demonstrated an acceptable safety profile and an encouraging complete response rate (CRR) in patients with advanced melanoma in a phase Ib study. We report the efficacy and safety from a phase III, randomized, double-blind, multicenter, international study of T-VEC plus pembrolizumab (T-VEC-pembrolizumab) versus placebo plus pembrolizumab (placebo-pembrolizumab) in patients with advanced melanoma. METHODS: Patients with stage IIIB-IVM1c unresectable melanoma, naïve to antiprogrammed cell death protein-1, were randomly assigned 1:1 to T-VEC-pembrolizumab or placebo-pembrolizumab. T-VEC was administered at ≤ 4 × 106 plaque-forming unit (PFU) followed by ≤ 4 × 108 PFU 3 weeks later and once every 2 weeks until dose 5 and once every 3 weeks thereafter. Pembrolizumab was administered intravenously 200 mg once every 3 weeks. The dual primary end points were progression-free survival (PFS) per modified RECIST 1.1 by blinded independent central review and overall survival (OS). Secondary end points included objective response rate per mRECIST, CRR, and safety. Here, we report the primary analysis for PFS, the second preplanned interim analysis for OS, and the final analysis. RESULTS: Overall, 692 patients were randomly assigned (346 T-VEC-pembrolizumab and 346 placebo-pembrolizumab). T-VEC-pembrolizumab did not significantly improve PFS (hazard ratio, 0.86; 95% CI, 0.71 to 1.04; P = .13) or OS (hazard ratio, 0.96; 95% CI, 0.76 to 1.22; P = .74) compared with placebo-pembrolizumab. The objective response rate was 48.6% for T-VEC-pembrolizumab (CRR 17.9%) and 41.3% for placebo-pembrolizumab (CRR 11.6%); the durable response rate was 42.2% and 34.1% for the arms, respectively. Grade ≥ 3 treatment-related adverse events occurred in 20.7% of patients in the T-VEC-pembrolizumab arm and in 19.5% of patients in the placebo-pembrolizumab arm. CONCLUSION: T-VEC-pembrolizumab did not significantly improve PFS or OS compared with placebo-pembrolizumab. Safety results of the T-VEC-pembrolizumab combination were consistent with the safety profiles of each agent alone.
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Herpesvirus Humano 1 , Melanoma , Terapia Viral Oncolítica , Humanos , Melanoma/tratamento farmacológico , Terapia Viral Oncolítica/métodos , Método Duplo-CegoRESUMO
BACKGROUND: Continuous combination of MAPK pathway inhibition (MAPKi) and anti-programmed death-(ligand) 1 (PD-(L)1) showed high response rates, but only limited improvement in progression-free survival (PFS) at the cost of a high frequency of treatment-related adverse events (TRAE) in patients with BRAFV600-mutated melanoma. Short-term MAPKi induces T-cell infiltration in patients and is synergistic with anti-programmed death-1 (PD-1) in a preclinical melanoma mouse model. The aim of this phase 2b trial was to identify an optimal regimen of short-term MAPKi with dabrafenib plus trametinib in combination with pembrolizumab. METHODS: Patients with treatment-naïve BRAFV600E/K-mutant advanced melanoma started pembrolizumab 200 mg every 3 weeks. In week 6, patients were randomized to continue pembrolizumab only (cohort 1), or to receive, in addition, intermittent dabrafenib 150 mg two times per day plus trametinib 2 mg one time per day for two cycles of 1 week (cohort 2), two cycles of 2 weeks (cohort 3), or continuously for 6 weeks (cohort 4). All cohorts continued pembrolizumab for up to 2 years. Primary endpoints were safety and treatment-adherence. Secondary endpoints were objective response rate (ORR) at week 6, 12, 18 and PFS. RESULTS: Between June 2016 and August 2018, 33 patients with advanced melanoma have been included and 32 were randomized. Grade 3-4 TRAE were observed in 12%, 12%, 50%, and 63% of patients in cohort 1, 2, 3, and 4, respectively. All planned targeted therapy was given in 88%, 63%, and 38% of patients in cohort 2, 3, and 4. ORR at week 6, 12, and 18 were 38%, 63%, and 63% in cohort 1; 25%, 63%, and 75% in cohort 2; 25%, 50%, and 75% in cohort 3; and 0%, 63%, and 50% in cohort 4. After a median follow-up of 43.5 months, median PFS was 10.6 months for pembrolizumab monotherapy and not reached for patients treated with pembrolizumab and intermittent dabrafenib and trametinib (p=0.17). The 2-year and 3-year landmark PFS were both 25% for cohort 1, both 63% for cohort 2, 50% and 38% for cohort 3 and 75% and 60% for cohort 4. CONCLUSIONS: The combination of pembrolizumab plus intermittent dabrafenib and trametinib seems more feasible and tolerable than continuous triple therapy. The efficacy is promising and appears to be favorable over pembrolizumab monotherapy. TRIAL REGISTRATION NUMBER: NCT02625337.
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Melanoma , Proteínas Proto-Oncogênicas B-raf , Melanoma/tratamento farmacológico , Melanoma/genética , Mutação , Proteínas Proto-Oncogênicas B-raf/genética , Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , IdosoRESUMO
Following CARMENA and SURTIME, patients with metastatic renal cell carcinoma (mRCC) and International Metastatic RCC Database Consortium (IMDC) intermediate and poor risk receive systemic therapy with the primary tumour (primary) in place, with the option of deferred cytoreductive nephrectomy (CN) in responding patients. We retrospectively analysed the safety and efficacy of first-line nivolumab/ipilimumab in 71 primary mRCC patients (42.3% IMDC poor risk; 43.6% with more than three metastatic sites). The baseline mean primary diameter was 9.3 cm and median follow-up was 11.5 mo. Of 69 patients with at least one follow-up computed tomography scan, 23 (33.3 %) had a partial response (PR) of the primary after a median of 4.8 mo, which was associated with a 91.3% overall response rate at metastatic sites (MSs) and absence of progressive disease, irrespective of the IMDC risk. The complete response (CR) rate at MSs (n = 7 [10.1%]) is similar to the CR rate in CheckMate 214. Thirteen deferred CNs were performed (18.8%) after a median of 13 mo, rendering four patients disease free. Only 4.3% of primaries progressed; grade 3-4 immune-related adverse events occurred in 31.9%. Irrespective of the IMDC risk, patients with a PR in the primary had a 1-yr overall survival rate of 89% versus 67% in those without (p = 0.012). PATIENT SUMMARY: Patients with metastatic kidney cancer receiving immunotherapy with nivolumab and ipilimumab had superior response at metastatic sites and better survival irrespective of International Metastatic RCC Database Consortium (IMDC) risk.
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As a subset of advanced melanoma patients derive long-term benefit from anti-PD-1 therapy, early identification of non-responsiveness would enable an early switch to next line therapies. This study assessed if an early increase in S100B or lactate dehydrogenase (LDH) could be predictive for non-responsiveness to anti-PD-1. We retrospectively analysed advanced melanoma patients treated with anti-PD-1 monotherapy. Serum S100B and LDH levels were measured at baseline and before every infusion. Non-response was defined as progression or death at 6 months. Marker cut-offs were defined based on > 95% specificity and feasibility in clinical practice. For validation an independent cohort was analysed. In total, 313 patients were included (166 patients in training cohort, 147 patients in validation cohort). Increase of > 50% in LDH or > 100% in S100B above upper limit of normal at week 6 compared to baseline was determined as criterion to positively test for non-responsiveness. In the validation cohort, obtained specificity of the combination test was > 95% with a positive predictive value of 82%; obtained sensitivity was lower (21%), with a negative predictive value of 55%. Early increase in S100B or LDH is a strong parameter for non-responsiveness to anti-PD-1 in advanced melanoma. Prospective confirmation is needed before clinical implementation.
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Melanoma , Neoplasias Cutâneas , Anticorpos/uso terapêutico , Biomarcadores Tumorais , Humanos , L-Lactato Desidrogenase , Melanoma/diagnóstico , Melanoma/tratamento farmacológico , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Estudos Prospectivos , Estudos Retrospectivos , Subunidade beta da Proteína Ligante de Cálcio S100 , Neoplasias Cutâneas/diagnósticoRESUMO
INTRODUCTION: With the introduction of tyrosine kinase inhibitors and systemic antibodies, including immune checkpoint inhibitors, the survival of advanced-stage cancer patients has improved for many tumor types. These patients are increasingly referred for radiotherapy, but it is unclear whether radiotherapy combined with these drugs is safe. No international guidelines exist on whether or how to combine these drugs with radiotherapy. Therefore, we investigated the current clinical practice in the Netherlands regarding hypofractionated radiotherapy in patients using targeted drugs and immunotherapy. MATERIALS AND METHODS: We sent a survey to all 21 Dutch radiotherapy institutes. Dedicated radiation oncologists, medical oncologists and pulmonologists were asked to fill out the survey. The questions explored their familiarity with the combination of targeted drugs and immunotherapy with radiotherapy, the encountered clinical difficulties and factors influencing treatment decisions. RESULTS: The survey was filled out by 54 respondents from 19 different institutes. The median annual number of patients per radiation oncologist referred for radiotherapy when using targeted drugs or immunotherapy was 10 and 15, respectively. Despite this high number, only 11% of the radiation oncologists stated that they had sufficient information (resources) for adequate treatment decision making. Among all physicians, 44% stated that there was insufficient knowledge within their institute regarding this topic. Only 17% stated that there was a multidisciplinary protocol available. The application of radiotherapy treatment adaptations (technique, dose, fractionation, field size) varied widely. Generally, there seemed to be no consensus regarding the expected toxicity of combined drug-radiotherapy treatments and the expected risk of tumor flare upon temporary drug discontinuation. CONCLUSION: There is no consensus amongst involved medical specialties on expected toxicity. Consequently, it is necessary to perform clinical studies examining the safety of combined drug-radiotherapy treatments, to add radiotherapy to phase I-III clinical trials for new drugs and to incorporate outcomes into multidisciplinary, evidence-based guidelines.
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BRAF + MEK inhibition is preferentially applied as first-line therapy in BRAF V600-mutated melanoma patients with unfavourable prognostic features, due to the ability of targeted therapy (TT) to induce rapid symptom control, decrease tumour burden and normalize lactate dehydrogenase (LDH) levels. In addition, short-term TT transiently increases tumour antigen presentation and tumour influx of T cells. Therefore, it might be favourable to switch TT to checkpoint inhibition (CPI) before progression (PD). We retrospectively analysed melanoma patients treated first line with TT (TT1) and who subsequently switched to CPI during response to TT (sDR group) or at progression upon TT (sPD group). We identified 74 patients (n = 37 sDR group and n = 37 sPD group). ORR to CPI was 27.0% in the sDR group versus 24.3% in the sPD group (p = .790). Median was PFS 2.5 months versus 1.2 months (p = .145), and median OS was 30.6 versus 14.1 months (p = .007). After adjusting for baseline differences and known prognostic factors, hazard ratios (HRs) favouring sDR were 0.89 for PFS upon CPI (p = .956) and 0.48 for OS (p = .055). Thus, patients switching to CPI during ongoing clinical benefit from TT do not have an inferior outcome. Due to baseline imbalances and small patient population, a favourable trend for the sDR group can be hypothesized only.
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Progressão da Doença , Inibidores de Checkpoint Imunológico/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Terapia de Alvo Molecular , Mutação/genética , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
In clinical trials, dabrafenib plus trametinib improved overall survival (OS) compared with single-agent BRAF inhibitors (BRAFi) in patients with BRAF V600-mutant unresectable or metastatic melanoma. We investigated dabrafenib plus trametinib therapy in a compassionate-use setting [Named Patient Program (NPP); DESCRIBE II]. A retrospective chart review of patients with BRAF V600-mutated unresectable stage III/IV melanoma receiving dabrafenib plus trametinib as compassionate use was conducted. Treatment patterns and duration, clinical outcomes, and tolerability were evaluated. Of 271 patients, 92.6% had stage IV melanoma, including 36.5% with brain metastases. Overall, 162 patients (59.8%) were BRAFi naive and 171 (63.1%) received first-line dabrafenib plus trametinib. Among BRAFi-naive patients, the overall response rate (ORR) was 67.3%, median OS (mOS) was 20.0 months, and median progression-free survival (mPFS) was 7.5 months. In BRAFi-naive patients with known brain metastases (n = 62), ORR was 61.3%, mOS was 15.5 months, and mPFS was 6.2 months. Eighty-four patients received BRAFi monotherapy for >30 days and switched to dabrafenib plus trametinib prior to progression. Of these 84 patients, 63 had known disease status at the time of switch, and 22 improved with the combination therapy. No new safety signals were identified, and dabrafenib plus trametinib was well tolerated. Dabrafenib plus trametinib showed substantial clinical activity in NPP patients with BRAF V600-mutated unresectable or metastatic melanoma. Analysis of treatment patterns demonstrated the effectiveness of the combination in patients with brain metastases and across lines of therapy with a well tolerated and manageable safety profile.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Imidazóis/administração & dosagem , Melanoma/tratamento farmacológico , Oximas/administração & dosagem , Piridonas/administração & dosagem , Pirimidinonas/administração & dosagem , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Ensaios de Uso Compassivo , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Melanoma/genética , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas B-raf/genética , Estudos Retrospectivos , Neoplasias Cutâneas/genética , Resultado do Tratamento , Melanoma Maligno CutâneoRESUMO
Approximately, 50% of patients with uveal melanoma develop distant metastasis for which no standard therapy is established. In contrast to cutaneous melanoma, the anti-CTLA-4 antibody ipilimumab showed no clinical activity in uveal melanoma. Liver directed therapies improve local control, but fail to show overall survival (OS) benefit. Preclinical experiments demonstrated that radiofrequency ablation (RFA) induced durable responses in combination with anti-CTLA-4. The aim of this phase Ib/II study was to assess safety and efficacy of RFA plus ipilimumab in uveal melanoma. Patients underwent RFA of one liver lesion and subsequently received four courses ipilimumab 0.3, 3 or 10 mg/kg every 3 weeks in a 3 + 3 design. Primary endpoints were safety in terms of dose limiting toxicities per cohort to define the recommended phase II dose (RP2D) in the phase Ib part and confirmed the objective response rate and disease control rate (DCR) of non-RFA lesions in the phase II part. Secondary endpoints were progression-free survival (PFS) and OS. Ipilimumab 10 mg/kg + RFA was initially defined as the RP2D. However, after 19 patients, the study was amended to adjust the RP2D to ipilimumab 3 mg/kg + RFA, because 47% of patients treated with 10 mg/kg had developed grade 3 colitis. In the 3 mg/kg cohort, also 19 patients have been treated. Immunotherapy-related grade ≥3 adverse events were observed in 53% of patients in the 10 mg/kg cohort versus 32% in the 3 mg/kg cohort. No confirmed objective responses were observed; the confirmed DCR was 5% in the 10 mg/kg cohort and 11% in the 3 mg/kg cohort. Median PFS was 3 months and comparable for both cohorts, median OS was 14.2 months for the 10 mg/kg cohort versus 9.7 months for the 3 mg/kg cohort. Combining RFA with ipilimumab 3 mg/kg was well tolerated, but showed very limited clinical activity in uveal melanoma.