RESUMEN
BACKGROUND: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma. METHODS: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881. FINDINGS: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups. INTERPRETATION: Adjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting. FUNDING: Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.
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Melanoma , Neoplasias Cutáneas , Humanos , Adyuvantes Inmunológicos/uso terapéutico , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/genética , Melanoma/cirugía , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/cirugíaRESUMEN
WHAT IS THIS SUMMARY ABOUT?: In this article, we summarize results from the ongoing phase 3 CheckMate 76K clinical study published online in Nature Medicine in October 2023. The study goal was to learn whether nivolumab works as an adjuvant therapy (that is, helps to keep cancer from coming back when it is given after surgery) for stage 2 melanoma (skin cancer) that has not spread to other parts of the body. Nivolumab is an immunotherapy that activates a person's immune system so it can destroy cancer cells. In melanoma, staging describes the severity of the cancer. Melanoma staging ranges from 0 (very thin and confined to the upper layer of the skin) to 4 (spread to distant parts of the body), with earlier stages removed by surgery. The people in this study had stage 2 melanoma that had not spread to the lymph nodes or other organs in the body. HOW WAS THE STUDY DESIGNED?: People 12 years and older with stage 2 melanoma that had not spread and had been removed by surgery were included in CheckMate 76K. People were randomly assigned to receive either nivolumab (526 patients) or placebo (264 patients). A placebo resembles the test medicine but does not contain any active medicines. The researchers assessed whether people who received nivolumab lived longer without their cancer returning and/or spreading to other parts of their bodies (compared with placebo) and if nivolumab was well tolerated. WHAT WERE THE RESULTS?: Researchers found that people who received nivolumab were 58% less likely to have their cancer return and 53% less likely of having their cancer spread to distant parts of their body, compared with placebo. These reductions in risk with nivolumab were seen in different subgroups of people with a range of characteristics, and regardless of how deep the melanoma had gone into the skin. People taking nivolumab had more side effects than those taking placebo, but most were mild to moderate and manageable. WHAT DO THE RESULTS MEAN?: Results from CheckMate 76K support the benefit of using nivolumab as a treatment option for people with stage 2 melanoma post-surgery.
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Melanoma , Neoplasias Cutáneas , Humanos , Melanoma/patología , Nivolumab , Ipilimumab/uso terapéutico , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/cirugía , Neoplasias Cutáneas/etiología , Terapia Combinada , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
BACKGROUND: Mucinous ovarian carcinoma (MOC) is a rare ovarian cancer with limited evidence to support clinical care. AIMS: We undertook a clinician survey to better understand current practice in treating MOC in Australia and New Zealand, and to determine any features associated with variation in care. In addition, we aimed to understand future research priorities. METHODS: A RedCap survey was distributed to clinician members of the Australia New Zealand Gynaecological Oncology Group (ANZGOG). Questions included respondent demographics, three case studies and future research priorities. Clinicians were asked questions specific to their speciality. RESULTS: Respondents (n = 47) were commonly experienced gynae-oncology specialists, most often surgical (38%) or medical (30%) oncologists. There was good consensus for surgical approaches for stage I disease; however, variation in practice was noted for advanced or recurrent MOC. Variation was also observed for medical oncologists; in early-stage disease there was no clear consensus on whether to offer chemotherapy, or which regimen to recommend. For advanced and recurrent disease a wide range of chemotherapy options was considered, with a trend away from an ovarian-type toward gastrointestinal (GI)-type regimens in advanced MOC. This practice was reflected in future research priorities, with 'Is a GI chemotherapy regimen better than an ovarian regimen?' the most highly ranked option, followed by 'Should stage 1C patients receive chemotherapy?' CONCLUSIONS: Although the number of respondents limited the analyses, it was clear that chemotherapy selection was a key point of divergence for medical oncologists. Future research is needed to establish well-evidenced guidelines for clinical care of MOC.
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Neoplasias Ováricas , Pautas de la Práctica en Medicina , Humanos , Femenino , Nueva Zelanda , Australia , Neoplasias Ováricas/terapia , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adenocarcinoma Mucinoso/terapia , Adenocarcinoma Mucinoso/patología , Adenocarcinoma Mucinoso/cirugía , Encuestas y Cuestionarios , Estadificación de Neoplasias , Oncólogos , Oncología Médica , GinecologíaRESUMEN
BACKGROUND: Many patients do not respond or eventually relapse on treatment with programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) checkpoint inhibitors due to secondary or acquired resistance; therefore, there is a need to investigate novel PD-1/PD-L1 inhibitors. METHODS: This open-label, non-randomised study investigated the safety and anti-tumour activity of BGB-A333, a PD-L1 inhibitor, alone and in combination with tislelizumab in patients with advanced solid tumours with progression during/after standard therapy. The primary objectives were to determine the recommended Phase 2 dose (RP2D), safety and tolerability for BGB-A333 alone and in combination with tislelizumab (Phase 1a/1b) and to determine the overall response rate (ORR) with BGB-A333 plus tislelizumab (Phase 2). RESULTS: Overall, 39 patients across Phase 1a (N = 15), 1b (N = 12) and 2 (N = 12) were enroled. In Phase 1a, an RP2D of 1350 mg was determined. In Phase 1a and 1b/2, serious treatment-emergent adverse events (TEAEs) were reported in five and eight patients, respectively. Two patients experienced TEAEs that led to death. In Phase 2, the ORR was 41.7% (n = 5/12; 95% confidence interval: 15.17%, 72.33%). CONCLUSIONS: TEAEs reported with BGB-A333 were consistent with other PD-L1 inhibitors. Encouraging preliminary anti-tumour activity was observed with BGB-A333 in combination with tislelizumab. CLINICAL TRIAL REGISTRATION: NCT03379259.
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Antígeno B7-H1 , Inhibidores de Puntos de Control Inmunológico , Humanos , Receptor de Muerte Celular Programada 1 , Recurrencia Local de Neoplasia/tratamiento farmacológico , Anticuerpos Monoclonales/efectos adversosRESUMEN
BACKGROUND: The aim of this study was to investigate the antitumour activity, safety, and tolerability of pamiparib plus tislelizumab in patients with previously treated advanced solid tumours. METHODS: In this study, patients were enrolled into eight arms by tumour type. All received pamiparib 40 mg orally twice daily plus tislelizumab 200 mg intravenously every 3 weeks. The primary endpoint was objective response rate (ORR), assessed by the investigator per Response Evaluation Criteria in Solid Tumours v1.1. Secondary endpoints included duration of response (DoR), safety, and tolerability. RESULTS: Overall, 180 patients were enrolled. In the overall population, the ORR was 20.0% (range: 0-47.4 across study arms), with median DoR of 17.1 months (95% confidence interval [CI]: 6.2, not estimable [NE]). The highest ORR was observed in the triple-negative breast cancer (TNBC) arm (patients with BRCA1/2 mutations and/or homologous recombination deficiency) (ORR: 47.4%; median DoR: 17.1 months [95% CI: 3.0, NE]). Treatment-emergent adverse events (TEAEs) of ≥Grade 3 occurred in 61.7% of patients. Serious TEAEs occurred in 50.0% of patients. CONCLUSIONS: Pamiparib plus tislelizumab showed a variable level of antitumour activity in patients with advanced solid tumours, with the highest ORR in TNBC and was associated with a manageable safety profile. CLINICAL TRIAL REGISTRATION: ClinicalTrial.gov: NCT02660034.
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Proteína BRCA1 , Neoplasias de la Mama Triple Negativas , Humanos , Proteína BRCA2 , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
OBJECTIVES: In ovarian cancer (OC), suboptimal muscle morphology (i.e., low muscle mass and density) is associated with poor clinical outcomes, yet little is known about the effect of interventions aimed at improving these measures. We investigated the effect of resistance exercise after first-line treatment on muscle mass and density, muscle strength and physical function, health-related quality of life (QoL), and pelvic-floor function in advanced-stage OC survivors. METHODS: Fifteen OC survivors participated in supervised resistance exercise twice weekly for 12 weeks (in-clinic or by telehealth). Assessments included muscle mass and density (dual-energy X-ray absorptiometry, peripheral quantitative computed tomography), muscle strength (1-repetition maximum [1RM] chest press, 5RM leg press, handgrip strength), physical function (400-m walk, timed up-and-go [TUG]), QoL (QLQ-C30 questionnaire), and self-reported pelvic floor function (Australian Pelvic Floor Questionnaire). RESULTS: The median age was 64 (range 33-72) years, 10 women underwent neoadjuvant chemotherapy and five underwent adjuvant chemotherapy. All participants completed the intervention (median attendance = 92%; range 79-100%). Post-intervention improvements were observed for whole-body lean mass (1.0 ± 1.4 kg, p = 0.015), appendicular lean mass (0.6 ± 0.9 kg, p = 0.013), muscle density (p = 0.011), upper and lower body strength (p ≤ 0.001), 400-m walk (p = 0.001), TUG (p = 0.005), and social and cognitive QoL domains (p = 0.002 and 0.007), with no change to pelvic floor symptoms (p > 0.05). CONCLUSION: In this study, supervised resistance exercise effectively improved muscle mass and density, muscle strength, and physical functioning without deleterious effects on the pelvic floor. Considering the prognostic value of these outcomes, larger studies are needed to confirm the benefits of resistance exercise in OC supportive care.
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Neoplasias Ováricas , Entrenamiento de Fuerza , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Australia , Carcinoma Epitelial de Ovario , Fuerza de la Mano , Fuerza Muscular/fisiología , Neoplasias Ováricas/terapia , Calidad de Vida , Entrenamiento de Fuerza/métodosRESUMEN
OBJECTIVE: Our primary aim was to compare muscle morphology (skeletal muscle mass and density) between patients who underwent primary cytoreductive surgery versus interval cytoreductive surgery for advanced high-grade serous ovarian cancer. Secondarily, we explored the associations of muscle morphology with survival outcomes. METHODS: We retrospectively analysed computed tomography (CT) images for 88 ovarian cancer patients (aged 38-89 years) to calculate skeletal muscle index (cm2/m2) and skeletal muscle density (Hounsfield units (HU)). A skeletal muscle index of <38.5 cm2/m2 and skeletal muscle density of <33.7 HU were classified as low. Analyses included repeated measures analysis of covariance and multivariable Cox proportional hazards regression. RESULTS: At baseline, 44.3% of patients had low skeletal muscle index and 50.6% had low skeletal muscle density, with interval surgery patients having significantly lower mean skeletal muscle density than primary surgery patients (32.2±8.9 vs 37.3±8.6 HU, p=0.014). Although both groups had similar reductions in skeletal muscle index following treatment (p=0.49), primary surgery patients had a greater reduction in skeletal muscle density compared with interval surgery patients (-2.4 HU, 95% CI -4.3 to -0.5, p=0.016). Patients who experienced skeletal muscle density loss >2% during treatment (HR 5.16, 95% CI 1.33 to 20.02) and had low skeletal muscle density post-treatment (HR 58.87, 95% CI 3.70 to 935.68) had significantly worse overall survival. CONCLUSION: Low skeletal muscle index and skeletal muscle density were prevalent at ovarian cancer diagnosis. While both groups experienced muscle mass loss, greater reductions in skeletal muscle density occurred in patients undergoing primary surgery. In addition, skeletal muscle density loss during treatment and low skeletal muscle density post-treatment were associated with poorer overall survival. Supportive care involving resistance exercise targeting muscle hypertrophic drive, and nutrition counseling during and after ovarian cancer treatment may help preserve/enhance muscle mass and density.
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Procedimientos Quirúrgicos de Citorreducción , Neoplasias Ováricas , Humanos , Femenino , Estudios Retrospectivos , Procedimientos Quirúrgicos de Citorreducción/métodos , Músculo Esquelético/diagnóstico por imagen , Neoplasias Ováricas/diagnóstico por imagen , Neoplasias Ováricas/cirugía , Neoplasias Ováricas/etiologíaRESUMEN
BACKGROUND: The validity of circulating tumour DNA (ctDNA) as an indicator of disease progression compared to medical imaging in patients with metastatic melanoma requires detailed evaluation. METHODS: Here, we carried out a retrospective ctDNA analysis of 108 plasma samples collected at the time of disease progression. We also analysed a validation cohort of 66 metastatic melanoma patients monitored prospectively after response to systemic therapy. RESULTS: ctDNA was detected in 62% of patients at the time of disease progression. For 67 patients that responded to treatment, the mean ctDNA level at progressive disease was significantly higher than at the time of response (P < 0.0001). However, only 30 of these 67 (45%) patients had a statistically significant increase in ctDNA by Poisson test. A validation cohort of 66 metastatic melanoma patients monitored prospectively indicated a 56% detection rate of ctDNA at progression, with only two cases showing increased ctDNA prior to radiological progression. Finally, a correlation between ctDNA levels and metabolic tumour burden was only observed in treatment naïve patients but not at the time of progression in a subgroup of patients failing BRAF inhibition (N = 15). CONCLUSIONS: These results highlight the low efficacy of ctDNA to detect disease progression in melanoma when compared mainly to standard positron emission tomography imaging.
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Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Imagen por Resonancia Magnética/métodos , Melanoma/patología , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Carga Tumoral/genética , Biomarcadores de Tumor/sangre , ADN Tumoral Circulante/sangre , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Melanoma/sangre , Melanoma/diagnóstico por imagen , Melanoma/genética , Persona de Mediana Edad , Estudios Prospectivos , Estudios RetrospectivosRESUMEN
Despite improvements made with checkpoint inhibitor (CPI) therapy, a need for new approaches to improve outcomes for patients with unresectable or metastatic melanoma remains. EVX-01, a personalized neoepitope vaccine, combined with pembrolizumab treatment, holds the potential to fulfill this need. Here we present the rationale and novel design behind the KEYNOTE - D36 trial: an open label, single arm, phase II trial aiming to establish the clinical proof of concept and evaluate the safety of EVX-01 in combination with pembrolizumab in CPI naive patients with unresectable or metastatic melanoma. The primary objective is to evaluate if EVX-01 improves best overall response after initial stable disease or partial response to pembrolizumab treatment, in patients with advanced melanoma. The novel end points ensure a decisive readout which may prove helpful before making major investments in phase III trials with limited phase I data. Clinical Trial Registration: NCT05309421 (ClinicalTrials.gov).
Drugs targeting the immune system have improved the outcomes for patients with advanced melanoma. However, a significant proportion of patients do not benefit and there is a need for better therapeutic agents to be used alone or in combination with immune modulating agents. This article summarizes the rationale and design of a new trial with a personalized vaccine (EVX-01) that may improve outcomes for patients with advanced melanoma (unresectable stage III or IV melanoma). The EVX-01 vaccine aims to stimulate the patient's immune system to generate T cells that target specific molecules that can only be found on the surface of the individual patients' cancer cells (i.e. neoepitopes), resulting in cancer cell death. The trial will investigate if the personalized EVX-01 vaccine together with checkpoint inhibitor therapy works better for patients with advanced melanoma, than checkpoint inhibitor therapy alone.
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Melanoma , Vacunas , Humanos , Melanoma/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunoterapia , Vacunas/uso terapéuticoRESUMEN
BACKGROUND: Physical symptoms, anxiety, depression, fear of recurrence, sexual dysfunction, and social withdrawal are common in women after treatment for ovarian cancer. Most patients would like and need help dealing with these symptoms. The traditional model of follow-up care is unstructured and largely focused on diagnosing recurrent disease, and most oncologists lack skills to identify and manage psychosocial issues. No high quality prospective clinical trials have been conducted to determine the optimal follow-up regimen or the cost effectiveness of ovarian cancer surveillance strategies. PRIMARY OBJECTIVES: To assess emotional wellbeing, acceptability, safety, and cost effectiveness of nurse led follow-up via telehealth for women with ovarian cancer following completion of primary treatment. STUDY HYPOTHESIS: We hypothesize that compared with routine clinic based follow-up, nurse led follow-up via telehealth, including serum CA125 monitoring and completion of a patient reported outcome instrument, the Measure of Ovarian Symptoms and Treatment concerns-Surveillance (MOST-S26), will improve emotional wellbeing in women with ovarian cancer; be feasible, safe, acceptable, and not delay the time to diagnosis of recurrent disease; will result in greater patient satisfaction; will identify more patients with psychological distress, lead to better care, and improved psychological outcomes; and be cost-effective. TRIAL DESIGN: Phase II multicenter randomized trial comparing 3 monthly nurse led telehealth consultations that include serum CA125 monitoring and completion of the MOST-S26, with routine clinic based follow-up. The allocation ratio will be 1:1. MAJOR INCLUSION/EXCLUSION CRITERIA: Eligible patients will be women with high grade epithelial ovarian cancer who have normalized serum CA125 (to <35 kU/L) at completion of first line chemotherapy. PRIMARY ENDPOINTS: Emotional wellbeing at 12 months. SAMPLE SIZE: 150 patients. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: July 2023. Results expected in 2025, 24 months after the last participant is enrolled. TRIAL REGISTRATION: ACTRN12620000332921.
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Neoplasias Ováricas , Telemedicina , Carcinoma Epitelial de Ovario , Femenino , Estudios de Seguimiento , Humanos , Rol de la Enfermera , Neoplasias Ováricas/tratamiento farmacológico , Medición de Resultados Informados por el Paciente , Estudios ProspectivosRESUMEN
BACKGROUND: State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin-paclitaxel or carboplatin-gemcitabine) or the most active non-bevacizumab regimen: carboplatin-pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin-pegylated liposomal doxorubicin combined with bevacizumab. METHODS: This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251. FINDINGS: Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin-pegylated liposomal doxorubicin-bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin-gemcitabine-bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3-21·7) in the experimental group and 11·3 months (8·0-18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7-14·2) in the experimental group versus 11·6 months (11·0-12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68-0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (<1%; large intestine perforation) and two patients in the standard group (1%; one case each of osmotic demyelination syndrome and intracranial haemorrhage). INTERPRETATION: Carboplatin-pegylated liposomal doxorubicin-bevacizumab is a new standard treatment option for platinum-eligible recurrent ovarian cancer. FUNDING: F Hoffmann-La Roche.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Bevacizumab/administración & dosificación , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Australia/epidemiología , Austria/epidemiología , Bevacizumab/efectos adversos , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Doxorrubicina/administración & dosificación , Doxorrubicina/análogos & derivados , Neoplasias de las Trompas Uterinas/patología , Femenino , Francia/epidemiología , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/patología , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Platino (Metal)/administración & dosificación , Platino (Metal)/efectos adversos , Polietilenglicoles/administración & dosificaciónRESUMEN
BACKGROUND: Circulating tumour cells (CTCs) can be assessed through a minimally invasive blood sample with potential utility as a predictive, prognostic and pharmacodynamic biomarker. The large heterogeneity of melanoma CTCs has hindered their detection and clinical application. METHODS: Here we compared two microfluidic devices for the recovery of circulating melanoma cells. The presence of CTCs in 43 blood samples from patients with metastatic melanoma was evaluated using a combination of immunocytochemistry and transcript analyses of five genes by RT-PCR and 19 genes by droplet digital PCR (ddPCR), whereby a CTC score was calculated. Circulating tumour DNA (ctDNA) from the same patient blood sample, was assessed by ddPCR targeting tumour-specific mutations. RESULTS: Our analysis revealed an extraordinary heterogeneity amongst melanoma CTCs, with multiple non-overlapping subpopulations. CTC detection using our multimarker approach was associated with shorter overall and progression-free survival. Finally, we found that CTC scores correlated with plasma ctDNA concentrations and had similar pharmacodynamic changes upon treatment initiation. CONCLUSIONS: Despite the high phenotypic and molecular heterogeneity of melanoma CTCs, multimarker derived CTC scores could serve as viable tools for prognostication and treatment response monitoring in patients with metastatic melanoma.
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Melanoma/patología , Células Neoplásicas Circulantes/patología , Estudios de Casos y Controles , Línea Celular Tumoral , Femenino , Humanos , Masculino , PronósticoRESUMEN
BACKGROUND: PD-1 inhibitors are routinely used for the treatment of advanced melanoma. This study sought to determine whether PD-L1 expression on circulating tumor cells (CTCs) can serve as a predictive biomarker of clinical benefit and response to treatment with the PD-1 inhibitor pembrolizumab. METHODS: Blood samples were collected from patients with metastatic melanoma receiving pembrolizumab, prior to treatment and 6-12 weeks after initiation of therapy. Multiparametric flow cytometry was used to identify CTCs and evaluate the expression of PD-L1. RESULTS: CTCs were detected in 25 of 40 patients (63%). Patients with detectable PD-L1+ CTCs (14/25, 64%) had significantly longer progression-free survival (PFS) compared with patients with PD-L1- CTCs (26.6 months vs. 5.5 months; p = .018). The 12-month PFS rates were 76% versus 22% in the PD-L1+ versus PD-L1- CTCs groups (p = .012), respectively. A multivariate linear regression analysis confirmed that PD-L1+ CTC is an independent predictive biomarker of PFS (hazard ratio, 0.229; 95% confidence interval, 0.052-1.012; p = .026). CONCLUSION: Our results reveal the potential of CTCs as a noninvasive real-time biopsy to evaluate PD-L1 expression in patients with melanoma. PD-L1 expression on CTCs may be predictive of response to pembrolizumab and longer PFS. IMPLICATIONS FOR PRACTICE: The present data suggest that PD-L1 expression on circulating tumor cells may predict response to pembrolizumab in advanced melanoma. This needs further validation in a larger trial and, if proven, might be a useful liquid biopsy tool that could be used to stratify patients into groups more likely to respond to immunotherapy, hence leading to health cost savings.
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Melanoma , Células Neoplásicas Circulantes , Anticuerpos Monoclonales Humanizados , Antígeno B7-H1 , Humanos , Melanoma/tratamiento farmacológico , Proyectos PilotoRESUMEN
BACKGROUND: Rationale exists for combined treatment with immune checkpoint inhibitors and poly (ADP-ribose) polymerase (PARP) inhibitors in a variety of solid tumours. This study aimed to investigate the safety and antitumour effects of pamiparib, an oral PARP 1/2 inhibitor, combined with tislelizumab, a humanised anti-PD-1 monoclonal antibody, in patients with advanced solid tumours and to determine the optimum doses for further evaluation. METHODS: We did a multicentre, open-label, phase 1a/b study at five academic sites or community oncology centres in Australia. We recruited adults (aged ≥18 years) with advanced solid tumours who had received one or more previous lines of therapy, with an Eastern Cooperative Oncology Group performance score of 1 or less, and a life expectancy of 12 weeks or more. Patients were enrolled into one of five dose-escalation cohorts, with dose-escalation done in a 3â+â3 design. Cohorts 1-3 received intravenous tislelizumab 2 mg/kg every 3 weeks plus 20, 40, or 60 mg oral pamiparib twice daily, respectively; cohorts 4 and 5 received 200 mg intravenous tislelizumab every 3 weeks plus 40 or 60 mg oral pamiparib twice daily, respectively. The primary endpoints of the phase 1a dose-escalation part of the study were safety and tolerability, including the occurrence of dose-limiting toxicities and determination of the maximum tolerated dose and recommended phase 2 dose. All primary endpoints were analysed in the safety analysis set, which included all patients who received at least one dose of tislelizumab or pamiparib, with the exception of the occurrence of dose-limiting toxicities, which was analysed in the dose-limiting toxicity analysis set, which included all patients who received at least 90% of the first scheduled tislelizumab dose and at least 75% of scheduled pamiparib doses, or who had a dose-limiting toxicity event during cycle 1. Reported here are results of the phase 1a dose-escalation stage of the trial. This trial is registered with ClinicalTrials.gov, number NCT02660034, and is ongoing. FINDINGS: Between Jan 22, 2016, and May 16, 2017, we enrolled 49 patients (median age 63 years [IQR 55-67]), all of whom received at least one dose of pamiparib or tiselzumab. Four patients had dose-limiting toxicities (intractable grade 2 nausea [n=1] and grade 3 rash [n=1] in cohort 4, and grade 2 nausea and vomiting [n=1] and grade 4 immune-mediated hepatitis [n=1] in cohort 5). The recommended phase 2 dose was tislelizumab 200 mg every 3 weeks plus pamiparib 40 mg twice daily (the dose given in cohort 4). The most common treatment-emergent adverse events were nausea (in 31 [63%] of 49 patients), fatigue (26 [53%]), diarrhoea (17 [35%]), and vomiting (15 [31%]). 23 (47%) of 49 patients had immune-related adverse events, of whom nine (39%) had asymptomatic grade 3-4 hepatic immune-related adverse events, which were reversible with corticosteroid treatment. The most common adverse event of grade 3 or worse severity was anaemia (in six [12%] patients) and no grade 5 adverse events were reported. Hepatitis or autoimmune hepatitis was the only serious adverse event to occur in two or more patients (in four [8%] patients). At a median follow-up of 8·3 months (IQR 4·8-12·8), ten (20%) of 49 patients achieved an objective response according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, including two complete responses and eight partial responses. INTERPRETATION: Pamiparib with tislelizumab was generally well tolerated and associated with antitumour responses and clinical benefit in patients with advanced solid tumours supporting further investigation of the combination of pamiparib with tislelizumab. FUNDING: BeiGene.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Fluorenos/administración & dosificación , Neoplasias/tratamiento farmacológico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estudios de Cohortes , Relación Dosis-Respuesta a Droga , Fatiga/inducido químicamente , Fatiga/patología , Femenino , Fluorenos/efectos adversos , Humanos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Náusea/inducido químicamente , Náusea/patología , Estadificación de Neoplasias , Neoplasias/clasificación , Neoplasias/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Supervivencia sin Progresión , Resultado del TratamientoRESUMEN
OBJECTIVE: There is a need to develop and validate biomarkers for treatment response and survival in tubo-ovarian high-grade serous carcinoma (HGSC). The chemotherapy response score (CRS) stratifies patients into complete/near-complete (CRS3), partial (CRS2), and no/minimal (CRS1) response after neoadjuvant chemotherapy (NACT). Our aim was to review current evidence to determine whether the CRS is prognostic in women with tubo-ovarian HGSC treated with NACT. METHODS: We established an international collaboration to conduct a systematic review and meta-analysis, pooling individual patient data from 16 sites in 11 countries. Patients had stage IIIC/IV HGSC, 3-4 NACT cycles and >6-months follow-up. Random effects models were used to derive combined odds ratios in the pooled population to investigate associations between CRS and progression free and overall survival (PFS and OS). RESULTS: 877 patients were included from published and unpublished studies. Median PFS and OS were 15â¯months (IQR 5-65) and 28â¯months (IQR 7-92) respectively. CRS3 was seen in 249 patients (28%). The pooled hazard ratios (HR) for PFS and OS for CRS3 versus CRS1/CRS2 were 0·55 (95% CI, 0·45-0·66; Pâ¯<â¯0·001) and 0·65 (95% CI 0·50-0·85, Pâ¯=â¯0·002) respectively; no heterogeneity was identified (PFS: Qâ¯=â¯6·42, Pâ¯=â¯0·698, I2â¯=â¯0·0%; OS: Qâ¯=â¯6·89, Pâ¯=â¯0·648, I2â¯=â¯0·0%). CRS was significantly associated with PFS and OS in multivariate models adjusting for age and stage. Of 306 patients with known germline BRCA1/2 status, those with BRCA1/2 mutations (nâ¯=â¯80) were more likely to achieve CRS3 (Pâ¯=â¯0·027). CONCLUSIONS: CRS3 was significantly associated with improved PFS and OS compared to CRS1/2. This validation of CRS in a real-world setting demonstrates it to be a robust and reproducible biomarker with potential to be incorporated into therapeutic decision-making and clinical trial design.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/uso terapéutico , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Neoplasias Quísticas, Mucinosas y Serosas/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Antineoplásicos , Biomarcadores de Tumor/análisis , Supervivencia sin Enfermedad , Neoplasias de las Trompas Uterinas/mortalidad , Neoplasias de las Trompas Uterinas/patología , Femenino , Humanos , Terapia Neoadyuvante , Neoplasias Quísticas, Mucinosas y Serosas/mortalidad , Neoplasias Quísticas, Mucinosas y Serosas/patología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/patología , Resultado del TratamientoRESUMEN
BACKGROUND: Circulating tumour DNA (ctDNA) may serve as a measure of tumour burden and a useful tool for non-invasive monitoring of cancer. However, ctDNA is not always detectable in patients at time of diagnosis of metastatic disease. Therefore, there is a need to understand the correlation between ctDNA levels and the patients' overall metabolic tumour burden (MTB). METHODS: Thirty-two treatment naïve metastatic melanoma patients were included in the study. MTB and metabolic tumour volume (MTV) was measured by 18F-fluoro-D-glucose positron emission tomography/computed tomography (FDG PET/CT). Plasma ctDNA was quantified using droplet digital PCR (ddPCR). RESULTS: CtDNA was detected in 23 of 32 patients. Overall, a significant correlation was observed between ctDNA levels and MTB (p < 0.001). CtDNA was not detectable in patients with an MTB of ≤10, defining this value as the lower limit of tumour burden that can be detected through ctDNA analysis by ddPCR. CONCLUSIONS: We showed that ctDNA levels measured by ddPCR correlate with MTB in treatment naïve metastatic melanoma patients and observed a limit in tumour size for which ctDNA cannot be detected in blood. Nevertheless, our findings support the use of ctDNA as a non-invasive complementary modality to functional imaging for monitoring tumour burden.
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ADN Tumoral Circulante/análisis , Melanoma/patología , Carga Tumoral , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Melanoma/genética , Melanoma/metabolismo , Melanoma/mortalidad , Persona de Mediana Edad , Tomografía Computarizada por Tomografía de Emisión de Positrones , Modelos de Riesgos Proporcionales , Estudios RetrospectivosRESUMEN
OBJECTIVE: Our objective was to validate the prognostic role of the chemotherapy response score (CRS), which has been proposed for measuring tumor response to neoadjuvant chemotherapy in patients with high-grade serous tubo-ovarian carcinoma, in predicting progression-free survival (PFS) and overall survival (OS). METHODS: A retrospective cohort study was conducted of patients with advanced high-grade serous tubo-ovarian carcinoma diagnosed between January 1, 2010, and December 31, 2014, and treated with neoadjuvant chemotherapy. Treatment-related tumor regression was determined according to the 3-tier CRS, and results were compared with standard clinicopathological variables. Survival analysis was performed using Cox proportional hazards models and the log-rank test. RESULTS: Seventy-one patients were eligible for analysis. Median OS was 25.5 months. Fifty-eight patients (82%) had disease recurrence and 32 (45%) had died at study census. Of the 71 patients, 19, 29, and 23 patients had a CRS of 1, 2, and 3, respectively. On univariate analysis, the CRS significantly predicted PFS (hazard ratio [HR], 3.77; 95% confidence interval [CI], 1.83-7.78; P = 0.000) and OS (HR, 2.81; 95% CI, 1.16-6.79; P = 0.022). In a multivariate model, the CRS was significantly associated with PFS (HR, 2.81; 95% CI, 1.16-6.79; P = 0.022) but not with OS (HR, 2.39; 95% CI, 0.47-3.08; P = 0.079). Patients with CRS of 1 and 2 combined were twice as likely to progress during the study period compared with patients with a CRS of 3 (HR, 2.0; 95% CI, 1.06-3.78; P = 0.032; median PFS, 16 vs 26 months). No significant association was observed for OS (CRS 1/2 vs 3; HR, 1.57; 95% CI, 0.68-3.65; P = 0.291). CONCLUSIONS: In this study, the CRS showed independent prognostic significance for PFS but not for OS.
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Cistadenocarcinoma Seroso/tratamiento farmacológico , Neoplasias de las Trompas Uterinas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/administración & dosificación , Quimioterapia Adyuvante , Estudios de Cohortes , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/cirugía , Procedimientos Quirúrgicos de Citorreducción , Neoplasias de las Trompas Uterinas/patología , Neoplasias de las Trompas Uterinas/cirugía , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/cirugía , Paclitaxel/administración & dosificación , Estudios RetrospectivosRESUMEN
BACKGROUND: Pleural malignant mesothelioma (MM) is a deadly tumour predominantly associated with asbestos exposure. A reliable diagnostic and prognostic marker for MM will significantly enhance clinical care and is an area of intense research. Soluble mesothelin is the most studied and an FDA-approved biomarker for MM. A recent report showed promising results using fibulin-3 as a new diagnostic marker. The aim of this study was to compare the utility of fibulin-3 versus mesothelin, singly or in combination. METHODS: Fibulin-3 and soluble mesothelin were determined by ELISA in the plasma and pleural fluid of 153 patients presenting with a pleural effusion including 82 with MM, 36 with non-MM malignant effusions and 35 with benign effusions. Biomarker concentrations were determined in the plasma of an additional 49 cases with benign asbestos-related disease. RESULTS: Mesothelin provides better diagnostic accuracy than fibulin-3 for MM whether measured in plasma or pleural effusion: area under the curve (AUC) for plasma was 0.822 (95% CI 0.76 to 0.87) compared with 0.671 (0.61 to 0.73), respectively, and for pleural fluid AUC was 0.815 (0.74 to 0.87) compared with 0.588 (0.51 to 0.67), respectively. Effusion fibulin-3 was an independent significant prognostic factor for survival in MM patients; HR 2.08 (1.14 to 3.82), p=0.017. MM patients with effusion fibulin-3 levels below the median survived significantly longer than those with levels above the median (14.1 vs 7.9â months, p=0.012). Mesothelin and neutrophil to lymphocyte ratio were not significant prognostic markers. CONCLUSIONS: Soluble mesothelin is a superior diagnostic biomarker for MM compared with fibulin-3, whereas fibulin-3 provides superior prognostic information compared with mesothelin.