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BACKGROUND AND OBJECTIVE: Until recently, the standard first-line treatment for advanced urothelial carcinoma (UC) was platinum-based combination chemotherapy followed by avelumab maintenance therapy for patients without progressive disease (PD). For patients with advanced UC who experience PD or recurrence, standard-of-care treatment is pembrolizumab monotherapy based on the phase 3 KEYNOTE-045 study. This post hoc analysis of the KEYNOTE-045 study evaluated the efficacy of pembrolizumab compared with chemotherapy by the best response to prior platinum-based chemotherapy. METHODS: Patients with advanced UC that progressed or recurred after first-line platinum-based chemotherapy were randomly assigned 1:1 to receive either pembrolizumab 200 mg every 3 wk (Q3W) for ≤2 yr or investigator's choice of chemotherapy (paclitaxel [175 mg/m2], docetaxel [75 mg/m2], or vinflunine [320 mg/m2], each Q3W). Endpoints included overall survival (OS) from the initiation of the last treatment prior to death, objective response rate (ORR), and duration of response (DOR) as per Response Evaluation Criteria in Solid Tumors version 1.1 from the date of the first response. KEY FINDINGS AND LIMITATIONS: An objective response to pembrolizumab was observed in all groups in terms of a prior response to first-line platinum-based chemotherapy. Median OS, ORR, and median DOR were numerically greater with pembrolizumab than with chemotherapy across subgroups. Patients with PD as the best response to prior platinum-based chemotherapy had the poorest OS outcomes. Limitations include a lack of formal hypothesis testing. CONCLUSIONS AND CLINICAL IMPLICATIONS: When compared with chemotherapy, prolonged OS and durable responses to second-line pembrolizumab were observed independently of the response to or type of prior platinum-based chemotherapy. These findings further support pembrolizumab as second-line treatment for advanced UC.
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Circulating tumor DNA (ctDNA) is emerging as a potential biomarker in early-stage urothelial cancer, but its utility in metastatic disease remains unknown. In the phase 3 KEYNOTE-361 study, pembrolizumab with and without chemotherapy was compared with chemotherapy alone in patients with metastatic urothelial cancer. The study did not meet prespecified efficacy thresholds for statistical significance. To identify potential biomarkers of response, we retrospectively evaluated the association of pre- and posttreatment ctDNA with clinical outcomes in a subset of patients who received pembrolizumab (n = 130) or chemotherapy (n = 130) in KEYNOTE-361. Baseline ctDNA was associated with best overall response (BOR; P = 0.009), progression-free survival (P < 0.001) and overall survival (OS; P < 0.001) for pembrolizumab but not for chemotherapy (all; P > 0.05). Chemotherapy induced larger ctDNA decreases from baseline to treatment cycle 2 than pembrolizumab; however, change with pembrolizumab (n = 87) was more associated with BOR (P = 4.39 × 10-5) and OS (P = 7.07 × 10-5) than chemotherapy (n = 102; BOR: P = 1.01 × 10-4; OS: P = 0.018). Tumor tissue-informed versions of ctDNA change metrics were most associated with clinical outcomes but did not show a statistically significant independent value for explaining OS beyond radiographic change by RECIST v.1.1 when jointly modeled (pembrolizumab P = 0.364; chemotherapy P = 0.823). These results suggest distinct patterns in early ctDNA changes with immunotherapy and chemotherapy and differences in their association with long-term outcomes, which provide preliminary insights into the utility of liquid biopsies for treatment monitoring in metastatic urothelial cancer. Clinical trial registration: NCT02853305 .
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BACKGROUND: No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma. METHODS: We conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin-pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival. RESULTS: A total of 886 patients underwent randomization: 442 to the enfortumab vedotin-pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin-pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin-pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin-pembrolizumab group and in 69.5% of those in the chemotherapy group. CONCLUSIONS: Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.).
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Anticuerpos Monoclonales , Antineoplásicos , Carcinoma de Células Transicionales , Neoplasias Urológicas , Humanos , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Carcinoma de Células Transicionales/secundario , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Neoplasias de la Vejiga Urinaria , Gemcitabina/administración & dosificación , Gemcitabina/efectos adversos , Gemcitabina/uso terapéutico , Carboplatino/administración & dosificación , Carboplatino/efectos adversos , Carboplatino/uso terapéutico , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Antineoplásicos/uso terapéutico , Análisis de Supervivencia , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Neoplasias Urológicas/secundarioRESUMEN
PURPOSE: Patients with locally advanced or metastatic urothelial cancer (la/mUC) who are ineligible for cisplatin-based therapy have limited first-line (1L) treatment options and significant need for improved therapies. Enfortumab vedotin (EV) and pembrolizumab (Pembro) individually have shown a survival benefit in urothelial cancer in second-line + la/mUC settings. Here, we present data from the pivotal trial of EV plus Pembro (EV + Pembro) in the 1L setting. PATIENTS AND METHODS: In Cohort K of the EV-103 phase Ib/II study, cisplatin-ineligible patients with previously untreated la/mUC were randomly assigned 1:1 to receive EV as monotherapy or in combination with Pembro. The primary end point was confirmed objective response rate (cORR) per blinded independent central review. Secondary end points included duration of response (DOR) and safety. There were no formal statistical comparisons between treatment arms. RESULTS: The cORR was 64.5% (95% CI, 52.7 to 75.1) and 45.2% (95% CI, 33.5 to 57.3) for patients treated with EV + Pembro (N = 76) and EV monotherapy (N = 73), respectively. The median DOR was not reached for the combination and was 13.2 months for monotherapy; 65.4% and 56.3% of patients who responded to the combination and monotherapy, respectively, maintained a response at 12 months. The most common grade 3 or higher treatment-related adverse events (TRAEs) in patients treated with the combination were maculopapular rash (17.1%), fatigue (9.2%), and neutropenia (9.2%). EV TRAEs of special interest (any grade) in the combination arm included skin reactions (67.1%) and peripheral neuropathy (60.5%). CONCLUSION: EV + Pembro showed a high cORR with durable responses as 1L treatment in cisplatin-ineligible patients with la/mUC. Patients who received EV monotherapy had a response and safety profile consistent with previous studies. Adverse events for EV + Pembro were manageable, with no new safety signals observed.
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Carcinoma de Células Transicionales , Cisplatino , Humanos , Cisplatino/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéuticoRESUMEN
PURPOSE: In an exploratory analysis, we investigated the association between programmed death ligand 1 (PD-L1), tumor mutational burden (TMB), T-cell-inflamed gene expression profile (TcellinfGEP), and stromal signature with outcomes of pembrolizumab in urothelial carcinoma (UC). PATIENTS AND METHODS: Patients with advanced UC received first-line pembrolizumab 200 mg every 3 weeks in the single-arm phase II KEYNOTE-052 trial (NCT02335424) and salvage pembrolizumab 200 mg every 3 weeks or chemotherapy (paclitaxel/docetaxel/vinflunine) in the randomized phase III KEYNOTE-045 trial (NCT02256436). The association of each biomarker (continuous variable) with objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) was evaluated using logistic regression (ORR) and Cox PH (PFS, OS), adjusted for ECOG PS; nominal P values were calculated without multiplicity adjustment (one-sided, pembrolizumab; two-sided, chemotherapy). Significance was prespecified at α = 0.05. RESULTS: In KEYNOTE-052, PD-L1, TMB, and TcellinfGEP were significantly associated with improved outcomes; stromal signature was significantly associated with worse outcomes. In KEYNOTE-045, although findings for TMB and TcellinfGEP with pembrolizumab were consistent with those of KEYNOTE-052, PD-L1 was not significantly associated with improved outcomes, nor was stromal signature associated with worse outcomes with pembrolizumab; chemotherapy was not associated with outcomes in a consistent manner for any of the biomarkers. Hazard ratio (HR) estimates at prespecified cutoffs showed an advantage for pembrolizumab versus chemotherapy regardless of PD-L1 or TMB, with a trend toward lower HRs in the combined positive score ≥10 and the TMB ≥175 mutation/exome subgroup. For TcellinfGEP, PFS and OS HRs were lower in the TcellinfGEP-nonlow subgroup regardless of treatment. CONCLUSIONS: Multiple biomarkers characterizing the tumor microenvironment may help predict response to pembrolizumab monotherapy in UC, and potential clinical utility of these biomarkers may be context-dependent.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/genética , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/genética , Femenino , Humanos , Masculino , Microambiente Tumoral , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/genéticaRESUMEN
BACKGROUND: PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma. METHODS: KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m2] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m2] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305. FINDINGS: Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7-36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5-8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4-7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65-0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5-19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3-16·7) in the chemotherapy group (0·86, 0·72-1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1-17·9] with pembrolizumab vs 14·3 months [12·3-16·7] with chemotherapy; HR 0·92, 95% CI 0·77-1·11) and the population with CPS of at least 10 (16·1 months [13·6-19·9] with pembrolizumab vs 15·2 months [11·6-23·3] with chemotherapy; 1·01, 0·77-1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group. INTERPRETATION: The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma. FUNDING: Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Urotelio/efectos de los fármacos , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carboplatino/uso terapéutico , Carcinoma/inmunología , Carcinoma/mortalidad , Carcinoma/patología , Cisplatino/uso terapéutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Progresión de la Enfermedad , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Masculino , Persona de Mediana Edad , Supervivencia sin Progresión , Factores de Tiempo , Neoplasias de la Vejiga Urinaria/inmunología , Neoplasias de la Vejiga Urinaria/mortalidad , Neoplasias de la Vejiga Urinaria/patología , Urotelio/inmunología , Urotelio/patología , GemcitabinaRESUMEN
BACKGROUND: Merkel cell carcinoma (MCC) is an aggressive skin cancer associated with poor survival. Programmed cell death-1 (PD-1) pathway inhibitors have shown high rates of durable tumor regression compared with chemotherapy for MCC. The current study was undertaken to assess baseline and on-treatment factors associated with MCC regression and 3-year survival, and to explore the effects of salvage therapies in patients experiencing initial non-response or tumor progression after response or stable disease following first-line pembrolizumab therapy on Cancer Immunotherapy Trials Network-09/KEYNOTE-017. METHODS: In this multicenter phase II trial, 50 patients with advanced unresectable MCC received pembrolizumab 2 mg/kg every 3 weeks for ≤2 years. Patients were followed for a median of 31.8 months. RESULTS: Overall response rate to pembrolizumab was 58% (complete response 30%+partial response 28%; 95% CI 43.2 to 71.8). Among 29 responders, the median response duration was not reached (NR) at 3 years (range 1.0+ to 51.8+ months). Median progression-free survival (PFS) was 16.8 months (95% CI 4.6 to 43.4) and the 3-year PFS was 39.1%. Median OS was NR; the 3-year OS was 59.4% for all patients and 89.5% for responders. Baseline Eastern Cooperative Oncology Group performance status of 0, greater per cent tumor reduction, completion of 2 years of treatment and low neutrophil-to-lymphocyte ratio were associated with response and longer survival. Among patients with initial disease progression or those who developed progression after response or stable disease, some had extended survival with subsequent treatments including chemotherapies and immunotherapies. CONCLUSIONS: This study represents the longest available follow-up from any first-line anti-programmed death-(ligand) 1 (anti-PD-(L)1) therapy in MCC, confirming durable PFS and OS in a proportion of patients. After initial tumor progression or relapse following response, some patients receiving salvage therapies survived. Improving the management of anti-PD-(L)1-refractory MCC remains a challenge and a high priority. TRIAL REGISTRATION NUMBER: NCT02267603.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Células de Merkel/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Terapia Recuperativa , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Carcinoma de Células de Merkel/inmunología , Carcinoma de Células de Merkel/mortalidad , Carcinoma de Células de Merkel/patología , Progresión de la Enfermedad , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Supervivencia sin Progresión , Terapia Recuperativa/efectos adversos , Terapia Recuperativa/mortalidad , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/mortalidad , Neoplasias Cutáneas/patología , Factores de TiempoRESUMEN
INTRODUCTION: Pembrolizumab has been approved in the United States (US) for the first-line treatment of patients with advanced or metastatic urothelial carcinoma, who are ineligible for cisplatin-containing chemotherapy and with tumors expressing programmed death-ligand 1 (PD-L1) (Combined Positive Score ≥ 10), or ineligible for any platinum-containing chemotherapy regardless of PD-L1 status. Long-term KEYNOTE-052 data continue to demonstrate pembrolizumab's meaningful, durable, and well-tolerated antitumor activity. This study evaluates the cost-effectiveness of pembrolizumab versus carboplatin plus gemcitabine as first-line treatment for cisplatin-ineligible patients who have PD-L1-positive tumors from a US third-party healthcare payer's perspective. PATIENTS AND METHODS: A partitioned survival model containing 3 health states (progression-free, progressed, and death) was developed. A simulated treatment comparison and a network meta-analysis were conducted to estimate the comparative efficacy of pembrolizumab versus carboplatin-based chemotherapy. Overall survival, progression-free survival, time on treatment, adverse events, and utilities were modeled using the final analyses of the KEYNOTE-052 trial and 4 studies for carboplatin plus gemcitabine. Cost data were estimated using US standard sources and real-world data. Deterministic, probabilistic, and scenario analyses were conducted to assess the robustness of the results. RESULTS: Over 20 years, pembrolizumab resulted in a mean gain of 2.58 life-years, 2.01 quality-adjusted life-years, and additional costs of $158,561, leading to an incremental cost-effectiveness ratio of $78,925/quality-adjusted life-year compared with carboplatin plus gemcitabine. CONCLUSION: This study suggests that pembrolizumab is cost-effective compared with carboplatin plus gemcitabine as a first-line therapy for patients with advanced or metastatic urothelial carcinoma who are PD-L1-positive.
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Antineoplásicos Inmunológicos , Carcinoma de Células Transicionales , Neoplasias Pulmonares , Neoplasias de la Vejiga Urinaria , Anticuerpos Monoclonales Humanizados , Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1 , Carboplatino/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Cisplatino/uso terapéutico , Análisis Costo-Beneficio , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Metaanálisis en Red , Estados Unidos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
PURPOSE: Combination therapy with reduced-dose programmed death 1 inhibitor plus standard-dose cytotoxic T-lymphocyte-associated antigen 4 inhibitor demonstrated efficacy, but substantial toxicity, in melanoma. We present long-term results of part 1B of KEYNOTE-029, which assessed safety and efficacy of standard-dose pembrolizumab plus reduced-dose ipilimumab in advanced melanoma. PATIENTS AND METHODS: Part 1B was an expansion cohort of the open-label, phase Ib portion of KEYNOTE-029. Eligible patients had advanced melanoma and no previous immune checkpoint inhibitor therapy. Patients received pembrolizumab 2 mg/kg (amended to 200 mg) every 3 weeks plus ipilimumab 1 mg/kg every 3 weeks (four cycles), then pembrolizumab alone for up to 2 years. Primary end point was safety; secondary end points included objective response rate (ORR), progression-free survival (PFS), duration of response (DOR), and overall survival (OS). RESULTS: A total of 153 patients received at least one dose of pembrolizumab plus ipilimumab. At a median follow-up of 36.8 months, 71.9% had received four doses of ipilimumab and 30.7% had completed 2 years of pembrolizumab; 26.1% completed both treatments. Treatment-related adverse events occurred in 96.1% (47.1% grade 3/4; no deaths), leading to discontinuation of one or both study drugs in 35.9%. ORR was 62.1% with 42 (27.5%) complete and 53 (34.6%) partial responses. Median DOR was not reached; 36-month ongoing response rate was 84.2%. Median PFS and OS were not reached; 36-month rates were 59.1% and 73.4%, respectively. CONCLUSIONS: Standard-dose pembrolizumab plus reduced-dose ipilimumab demonstrated robust antitumor activity, durable response, and favorable long-term survival with manageable toxicity.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Antígeno CTLA-4/genética , Ipilimumab/administración & dosificación , Melanoma/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Antígeno CTLA-4/antagonistas & inhibidores , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Masculino , Melanoma/genética , Melanoma/patología , Persona de Mediana Edad , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Supervivencia sin ProgresiónRESUMEN
Importance: The optimal sequencing of immune checkpoint inhibitors and targeted therapy for BRAF V600E/K-mutant melanoma is not well established. Objective: To assess the association of BRAF wild-type (WT) or BRAF V600E/K-mutant status and BRAF inhibitor (BRAFi) with or without MEK inhibitor (MEKi) therapy with response to pembrolizumab. Design, Setting, and Participants: This study is a post hoc subgroup analysis of pooled data from 3 multinational, multisite studies: KEYNOTE-001 (data cutoff September 1, 2017), KEYNOTE-002 (data cutoff May 30, 2018), and KEYNOTE-006 (data cutoff December 4, 2017). Patients included in this analysis were adults with advanced melanoma and known BRAF V600E/K tumor status who had received pembrolizumab. Interventions: Patients received pembrolizumab in dosages of 2 mg/kg every 3 weeks, 10 mg/kg every 2 weeks, or 10 mg/kg every 3 weeks. Main Outcomes and Measures: End points were objective response rate (ORR) and progression-free survival (PFS) assessed by Response Evaluation Criteria in Solid Tumors, version 1.1, and overall survival (OS). Objective response rates, 4-year PFS, and OS rates were compared in the following patient subgroups: BRAF WT vs BRAF V600E/K-mutant melanoma and BRAF V600E/K-mutant melanoma with vs without previous treatment with BRAFi with or without MEKi therapy. Results: The overall study population (N = 1558) included 944 men (60.6%) and 614 women (39.4%). The mean (SD) age was 60.0 years (14.0). The ORR was 38.3% (596/1558), 4-year PFS rate was 22.0%, and 4-year OS rate was 36.9%. For patients with BRAF WT (n = 1124) and BRAF V600E/K-mutant melanoma (n = 434), ORR was 39.8% (n = 447) and 34.3% (n = 149), 4-year PFS rate was 22.9% and 19.8%, and 4-year OS rate was 37.5% and 35.1%, respectively. Patients with BRAF V600E/K-mutant melanoma who had (n = 271) vs had not (n = 163) previously received BRAFi with or without MEKi therapy had baseline characteristics with worse prognosis; ORR was 28.4% (n = 77) and 44.2% (n = 72), 4-year PFS rate was 15.2% and 27.8%, and 4-year OS rate was 26.9% and 49.3%, respectively. Conclusions and Relevance: Results of this subgroup analysis support the use of pembrolizumab for treatment of advanced melanoma regardless of BRAF V600E/K mutation status or receipt of prior BRAFi with or without MEKi therapy.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Melanoma/tratamiento farmacológico , Quinasas de Proteína Quinasa Activadas por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Anciano , Método Doble Ciego , Femenino , Humanos , Masculino , Melanoma/genética , Melanoma/mortalidad , Persona de Mediana Edad , Mutación , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
PURPOSE: The phase II single-arm KEYNOTE-052 study evaluated the efficacy and safety of first-line pembrolizumab for patients with locally advanced or metastatic cisplatin-ineligible urothelial carcinoma (UC). PATIENTS AND METHODS: Three hundred seventy patients received pembrolizumab 200 mg intravenously every 3 weeks for up to 24 months. Positive tumor programmed death ligand 1 (PD-L1) expression was defined as combined positive score (CPS) ≥ 10. Response was assessed by independent central review every 9 weeks per RECIST v1.1. The primary end point was objective response rate (ORR). RESULTS: At data cutoff (September 26, 2018), the minimum follow-up was 2 years since the last patient enrolled. ORR was 28.6% (95% CI, 24.1% to 33.5%); 33 patients (8.9%) and 73 patients (19.7%) achieved complete and partial response, respectively. The median duration of response was 30.1 months (95% CI, 18.1 months to not reached [NR]); responses lasted ≥ 12 and ≥ 24 months in 67% and 52% of patients, respectively. Forty patients with complete or partial response completed 2 years of study treatment, and 32 had ongoing response at completion. Median overall survival (OS) was 11.3 months (95% CI, 9.7 to 13.1 months), and 12- and 24-month OS rates were 46.9% and 31.2%, respectively. In patients with CPS ≥ 10, ORR was 47.3% (95% CI, 37.7% to 57.0%) and median OS was 18.5 months (95% CI, 12.2 to 28.5 months). In patients with lymph node-only disease, ORR was 49.0% (95% CI, 34.8% to 63.4%), and median OS was 27.0 months (12.4 months to NR). There were no new safety signals. CONCLUSION: First-line pembrolizumab confers meaningful and durable clinical response in cisplatin-ineligible patients with advanced UC and is associated with prolonged OS, particularly with PD-L1 CPS ≥ 10 and lymph node-only disease.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Neoplasias Urológicas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/administración & dosificación , Antineoplásicos Inmunológicos/efectos adversos , Antígeno B7-H1/biosíntesis , Antígeno B7-H1/inmunología , Cisplatino/administración & dosificación , Humanos , Persona de Mediana Edad , Resultado del Tratamiento , Neoplasias Urológicas/inmunologíaRESUMEN
PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer often caused by the Merkel cell polyomavirus. Clinical trials of programmed cell death-1 pathway inhibitors for advanced MCC (aMCC) demonstrate increased progression-free survival (PFS) compared with historical chemotherapy data. However, response durability and overall survival (OS) data are limited. PATIENTS AND METHODS: In this multicenter phase II trial (Cancer Immunotherapy Trials Network-09/Keynote-017), 50 adults naïve to systemic therapy for aMCC received pembrolizumab (2 mg/kg every 3 weeks) for up to 2 years. Radiographic responses were assessed centrally per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. RESULTS: Among 50 patients, the median age was 70.5 years, and 64% had Merkel cell polyomavirus-positive tumors. The objective response rate (ORR) to pembrolizumab was 56% (complete response [24%] plus partial response [32%]; 95% CI, 41.3% to 70.0%), with ORRs of 59% in virus-positive and 53% in virus-negative tumors. Median follow-up time was 14.9 months (range, 0.4 to 36.4+ months). Among 28 responders, median response duration was not reached (range, 5.9 to 34.5+ months). The 24-month PFS rate was 48.3%, and median PFS time was 16.8 months (95% CI, 4.6 months to not estimable). The 24-month OS rate was 68.7%, and median OS time was not reached. Although tumor viral status did not correlate with ORR, PFS, or OS, there was a trend toward improved PFS and OS in patients with programmed death ligand-1-positive tumors. Grade 3 or greater treatment-related adverse events occurred in 14 (28%) of 50 patients and led to treatment discontinuation in seven (14%) of 50 patients, including one treatment-related death. CONCLUSION: Here, we present the longest observation to date of patients with aMCC receiving first-line anti-programmed cell death-1 therapy. Pembrolizumab demonstrated durable tumor control, a generally manageable safety profile, and favorable OS compared with historical data from patients treated with first-line chemotherapy.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Carcinoma de Células de Merkel/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Carcinoma de Células de Merkel/patología , Femenino , Estudios de Seguimiento , Humanos , Hipotiroidismo/inducido químicamente , Masculino , Persona de Mediana Edad , Neumonía/inducido químicamente , Supervivencia sin Progresión , Inducción de Remisión , Criterios de Evaluación de Respuesta en Tumores Sólidos , Neoplasias Cutáneas/patologíaRESUMEN
Purpose: Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC.Experimental Design: The phase Ib KEYNOTE-029 study (ClinicalTrials.gov, NCT02089685) included independent pembrolizumab plus reduced-dose ipilimumab and pembrolizumab plus PEG-IFN cohorts. Pembrolizumab 2 mg/kg every 3 weeks (Q3W) plus 4 doses of ipilimumab 1 mg/kg Q3W was tolerable if ≤6 of 18 patients experienced a dose-limiting toxicity (DLT). The target DLT rate for pembrolizumab 2 mg/kg Q3W plus PEG-IFN was 30%, with a maximum of 14 patients per dose level. Response was assessed per RECIST v1.1 by central review.Results: The ipilimumab cohort enrolled 22 patients, including 19 evaluable for DLTs. Six patients experienced ≥1 DLT. Grade 3 to 4 treatment-related adverse events occurred in 13 (59%) patients. Responses occurred in 5 of 12 (42%) patients with melanoma and 3 of 10 (30%) patients with RCC. In the PEG-IFN cohort, DLTs occurred in 2 of 14 (14%) patients treated at dose level 1 (PEG-IFN 1 µg/kg/week) and 2 of 3 (67%) patients treated at dose level 2 (PEG-IFN 2 µg/kg/week). Grade 3 to 4 treatment-related adverse events occurred in 10 of 17 (59%) patients. Responses occurred in 1 of 5 (20%) patients with melanoma and 2 of 12 (17%) patients with RCC.Conclusions: Pembrolizumab 2 mg/kg Q3W plus ipilimumab 1 mg/kg Q3W was tolerable and provided promising antitumor activity in patients with advanced melanoma or RCC. The maximum tolerated dose of pembrolizumab plus PEG-IFN had limited antitumor activity in this population. Clin Cancer Res; 24(8); 1805-15. ©2018 AACR.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Células Renales/tratamiento farmacológico , Melanoma/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/mortalidad , Femenino , Humanos , Interferón alfa-2/administración & dosificación , Interferón-alfa/administración & dosificación , Ipilimumab/administración & dosificación , Masculino , Melanoma/diagnóstico , Melanoma/genética , Melanoma/mortalidad , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia , Estadificación de Neoplasias , Polietilenglicoles/administración & dosificación , Proteínas Recombinantes/administración & dosificación , Resultado del Tratamiento , Adulto JovenRESUMEN
Continuous BRAF inhibition of BRAF mutant melanomas triggers a series of cell state changes that lead to therapy resistance and escape from immune control before establishing acquired resistance genetically. We used genome-wide transcriptomics and single-cell phenotyping to explore the response kinetics to BRAF inhibition for a panel of patient-derived BRAFV600 -mutant melanoma cell lines. A subset of plastic cell lines, which followed a trajectory covering multiple known cell state transitions, provided models for more detailed biophysical investigations. Markov modeling revealed that the cell state transitions were reversible and mediated by both Lamarckian induction and nongenetic Darwinian selection of drug-tolerant states. Single-cell functional proteomics revealed activation of certain signaling networks shortly after BRAF inhibition, and before the appearance of drug-resistant phenotypes. Drug targeting those networks, in combination with BRAF inhibition, halted the adaptive transition and led to prolonged growth inhibition in multiple patient-derived cell lines.
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Resistencia a Antineoplásicos , Melanoma/genética , Melanoma/metabolismo , Transducción de Señal , Análisis de la Célula Individual , Adaptación Fisiológica , Antineoplásicos/farmacología , Línea Celular Tumoral , Perfilación de la Expresión Génica , Humanos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Cadenas de Markov , Melanoma/tratamiento farmacológico , Melanoma/patología , FN-kappa B/metabolismo , Fenotipo , Proteoma , Proteómica/métodos , Proteínas Proto-Oncogénicas B-raf/genéticaRESUMEN
The combination of targeted therapy with BRAF and MEK inhibitors has become the standard of care in patients with BRAF (V600E) mutant melanoma, but responses are not durable. In addition, the impressive clinical benefits with anti-PD-1 and anti-PD-L1 antibodies (Ab) in patients with heavily pretreated metastatic melanoma and the synergistic effect of dabrafenib, trametinib and anti-PD-1 compared with single therapy alone groups support the idea that combining dabrafenib, trametinib and immunotherapy based on PD-1 blockade could be an interesting approach in the treatment of metastatic melanoma. With our mouse model of syngeneic BRAF (V600E) driven melanoma (SM1), we tested whether the addition of an immunostimulatory Ab targeting CD137 (4-1BB) and/or CD134 (OX40) would enhance the antitumor effect of dabrafenib, trametinib and anti-PD-1 or anti-PD-L1 therapy. In vitro studies showed that the combination group of dabrafenib, trametinib and anti-PD-1 increases CD8(+) tumor infiltrating lymphocytes (TILs), as well as CD4(+) T cells and tumor-associated macrophages (TAMs). An upregulation of PD-L1 was observed in the combination of dabrafenib, trametinib and anti-PD-1 therapy. Combination of dabrafenib, trametinib and anti-PD-1, with either anti-CD137 or anti-CD134, showed a superior antitumor effect, but the five-agent combination was not superior to the four-agent combinations. In conclusion, the combination of dabrafenib, trametinib, anti-PD1 or anti-PD-L1 therapy results in robust antitumor activity, which is further improved by adding the immune-stimulating Ab anti-CD137 or anti-CD134. Our findings support the testing of these combinations in patients with BRAF (V600E) mutant metastatic melanoma.
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The programmed cell death protein 1 (PD-1) limits effector T-cell functions in peripheral tissues, and its inhibition leads to clinical benefit in different cancers. To better understand how PD-1 blockade therapy modulates the tumor-host interactions, we evaluated three syngeneic murine tumor models, the BRAFV600E-driven YUMM1.1 and YUMM2.1 melanomas, and the carcinogen-induced murine colon adenocarcinoma MC38. The YUMM cell lines were established from mice with melanocyte-specific BRAFV600E mutation and PTEN loss (BRAFV600E/PTEN-/-). Anti-PD-1 or anti-PD-L1 therapy engendered strong antitumor activity against MC38 and YUMM2.1, but not YUMM1.1. PD-L1 expression did not differ between the three models at baseline or upon interferon stimulation. Whereas mutational load was high in MC38, it was lower in both YUMM models. In YUMM2.1, the antitumor activity of PD-1 blockade had a critical requirement for both CD4 and CD8 T cells, as well as CD28 and CD80/86 costimulation, with an increase in CD11c+CD11b+MHC-IIhigh dendritic cells and tumor-associated macrophages in the tumors after PD-1 blockade. Compared with YUMM1.1, YUMM2.1 exhibited a more inflammatory profile by RNA sequencing analysis, with an increase in expression of chemokine-trafficking genes that are related to immune cell recruitment and T-cell priming. In conclusion, response to PD-1 blockade therapy in tumor models requires CD4 and CD8 T cells and costimulation that is mediated by dendritic cells and macrophages. Cancer Immunol Res; 4(10); 845-57. ©2016 AACR.
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Anticuerpos Monoclonales/uso terapéutico , Antineoplásicos/uso terapéutico , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Melanoma/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Animales , Anticuerpos Monoclonales Humanizados , Línea Celular Tumoral , Células Dendríticas/inmunología , Interferón gamma/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Macrófagos/inmunología , Melanoma/genética , Melanoma/inmunología , Ratones Endogámicos C57BL , Mutación , Proteínas Proto-Oncogénicas B-raf/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: Approximately 75% of objective responses to anti-programmed death 1 (PD-1) therapy in patients with melanoma are durable, lasting for years, but delayed relapses have been noted long after initial objective tumor regression despite continuous therapy. Mechanisms of immune escape in this context are unknown. METHODS: We analyzed biopsy samples from paired baseline and relapsing lesions in four patients with metastatic melanoma who had had an initial objective tumor regression in response to anti-PD-1 therapy (pembrolizumab) followed by disease progression months to years later. RESULTS: Whole-exome sequencing detected clonal selection and outgrowth of the acquired resistant tumors and, in two of the four patients, revealed resistance-associated loss-of-function mutations in the genes encoding interferon-receptor-associated Janus kinase 1 (JAK1) or Janus kinase 2 (JAK2), concurrent with deletion of the wild-type allele. A truncating mutation in the gene encoding the antigen-presenting protein beta-2-microglobulin (B2M) was identified in a third patient. JAK1 and JAK2 truncating mutations resulted in a lack of response to interferon gamma, including insensitivity to its antiproliferative effects on cancer cells. The B2M truncating mutation led to loss of surface expression of major histocompatibility complex class I. CONCLUSIONS: In this study, acquired resistance to PD-1 blockade immunotherapy in patients with melanoma was associated with defects in the pathways involved in interferon-receptor signaling and in antigen presentation. (Funded by the National Institutes of Health and others.).
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Resistencia a Antineoplásicos/genética , Inmunoterapia , Janus Quinasa 1/genética , Janus Quinasa 2/genética , Melanoma/genética , Mutación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Microglobulina beta-2/genética , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Biopsia , Exoma , Regulación Neoplásica de la Expresión Génica , Genes MHC Clase I , Humanos , Interferón gamma/uso terapéutico , Melanoma/tratamiento farmacológico , Melanoma/secundario , Receptor de Muerte Celular Programada 1/metabolismo , Recurrencia , Análisis de Secuencia de ADN , Transducción de SeñalRESUMEN
Spranger and colleagues reported recently in Nature an inverse relationship between melanoma intrinsic ß-catenin signaling and intratumoral T cell infiltration, providing an explanation for potential mechanisms of T cell exclusion. Further insights are needed into the mechanisms leading to a lack of T cell infiltration of cancers and primary immune resistance.
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Melanoma/inmunología , Melanoma/fisiopatología , Transducción de Señal , Linfocitos T/inmunología , Microambiente Tumoral/inmunología , beta Catenina/inmunología , Animales , HumanosRESUMEN
Immune-regulatory mechanisms are used by cancer to hide from the immune system. Advances and in-depth understanding of the biology of melanoma and its interaction with the immune system have led to the development of some of antagonistic antibodies to the programmed death 1 pathway (PD-1) and one of its ligands, programmed death ligand 1 (PD-L1), which are demonstrating high clinical benefit rates and tolerability. Blocking the immune-regulatory checkpoints that limit T-cell responses to melanoma upon PD-1/PD-L1 modulation has provided clinically validated targets for cancer immunotherapy. Combinations with other anti-melanoma agents may result in additional benefits. Nivolumab, pembrolizumab (formerly known as MK-3475 and lambrolizumab), and pidilizumab are anti-PD-1 antibodies in clinical development for melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancers, lymphoma, and several other cancers. Long-term survivors already have been reported with these therapies. In this review, we discuss the current state of anti-PD-1 agents, the evidence in the literature to support the combination of anti-PD-1 antibodies with other anti-cancer agents and discuss the future directions for rational design of clinical trials that keep on increasing the number of long-term survivors.