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On April 3, 2023, the FDA granted accelerated approval to enfortumab vedotin-ejfv (EV) plus pembrolizumab for treatment of patients with locally advanced or metastatic urothelial carcinoma who are ineligible for cisplatin-containing chemotherapy. Substantial evidence of effectiveness was obtained from EV-103/KEYNOTE-869 (NCT03288545), a multicohort study. Across cohorts, a total of 121 patients received EV 1.25 mg/kg (maximum of 125 mg) intravenously on days 1 and 8 of a 21-day cycle plus pembrolizumab 200 mg intravenously on day 1 of each 21-day cycle until disease progression or unacceptable toxicity. The major efficacy outcome measures were objective response rate (ORR) and duration of response (DoR), determined by blinded independent central review using RECIST v1.1. The confirmed ORR in 121 patients was 68% (95% confidence interval, 59-76), including 12% with complete responses. The median DoR for the 82 responders was 22 months (range: 1+ to 46+). The safety profile of the combination comprised adverse reactions expected to occur with the corresponding monotherapies, but with overall increased frequency of adverse reactions, including skin toxicity, pneumonitis, and peripheral neuropathy. The article summarizes the data and the FDA thought process supporting accelerated approval of EV + pembrolizumab, as well as additional exploratory analyses conducted by the FDA.
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Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Protocolos de Quimioterapia Combinada Antineoplásica , Aprobación de Drogas , United States Food and Drug Administration , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Estados Unidos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano , Femenino , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales/uso terapéutico , Persona de Mediana Edad , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Cisplatino/uso terapéutico , Anciano de 80 o más Años , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Resultado del TratamientoRESUMEN
BACKGROUND: This pooled analysis of patient-level data from trials evaluated the clinical outcomes of patients with metastatic renal cell carcinoma with or without cytoreductive nephrectomy before a combination of immune checkpoint inhibitor and antiangiogenic therapy. METHODS: Data from 5 trials of immune checkpoint inhibitors plus antiangiogenic therapy were pooled. Only patients with stage 4 disease at initial diagnosis were included to ensure that nephrectomy was performed for cytoreductive purposes and not to previously treat an earlier stage of disease. The effect of cytoreductive nephrectomy before immune checkpoint inhibitor therapy on outcomes was evaluated using the Kaplan-Meier method and a Cox proportional hazards regression model, adjusted for age, sex, risk group, performance status, and the presence of sarcomatoid differentiation. RESULTS: A total of 981 patients were included. The estimated median progression-free survival with and without nephrectomy was 15 and 11 months, respectively; the adjusted hazard ratio was 0.71 (95% confidence interval = 0.59 to 0.85). The estimated median overall survival with and without nephrectomy was 46 and 28 months, respectively; the adjusted hazard ratio was 0.63 (95% confidence interval = 0.51 to 0.77). Objective response was 60% of patients with vs 46% of patients without cytoreductive nephrectomy. CONCLUSIONS: Patients with metastatic renal cell carcinoma who undergo cytoreductive nephrectomy before immune checkpoint inhibitor plus antiangiogenic therapy had improved outcomes compared with patients without cytoreductive nephrectomy. Selection factors for cytoreductive nephrectomy may be prognostic and could not be fully controlled for in this retrospective analysis. Prospective determination of and stratification by prior cytoreductive nephrectomy may be considered when designing clinical trials to assess the impact of this factor on prognosis.
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Carcinoma de Células Renales , Procedimientos Quirúrgicos de Citorreducción , Inhibidores de Puntos de Control Inmunológico , Neoplasias Renales , Nefrectomía , United States Food and Drug Administration , Humanos , Nefrectomía/métodos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Renales/cirugía , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Neoplasias Renales/mortalidad , Estados Unidos/epidemiología , Masculino , Femenino , Carcinoma de Células Renales/cirugía , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Persona de Mediana Edad , Anciano , Inhibidores de la Angiogénesis/uso terapéutico , AdultoRESUMEN
PURPOSE: We performed a pooled analysis of multiple trials of poly(ADP-ribose) polymerase inhibitors (PARPi) in metastatic castration-resistant prostate cancer (mCRPC) to investigate the efficacy of PARPi in each individual homologous recombination repair (HRR) mutated (m) gene. PATIENTS AND METHODS: We pooled patient-level data from trials of PARPi in mCRPC that reported mutation status in individual HRR genes. Any HRR gene with available data across all the randomized trials of PARPi in first-line mCRPC was selected. The hazard ratios (HRs; 95% CI) for radiographic progression-free survival (rPFS; by blinded independent review) and overall survival (OS) of a PARPi plus an androgen receptor pathway inhibitor (ARPI) relative to placebo plus an ARPI in the pool of three randomized trials in first-line mCRPC were calculated using Kaplan-Meier estimates and a Cox proportional hazards model. RESULTS: In ATMm (N = 268), rPFS HR was 1.05 (0.74 to 1.49) and OS HR was 1.18 (0.82 to 1.71). In BRCA1m (N = 64), rPFS HR was 0.51 (0.23 to 1.1) and OS HR was 0.74 (0.34 to 1.61). In BRCA2m (N = 422), rPFS HR was 0.31 (0.23 to 0.42) and OS HR was 0.66 (0.49 to 0.89). In CDK12m (N = 164), rPFS HR was 0.50 (0.32 to 0.80) and OS HR was 0.63 (0.39 to 0.99). In CHEK2m (N = 172), rPFS HR was 1.06 (0.67 to 1.66) and OS HR was 1.53 (0.95 to 2.46). In PALB2m (N = 41) rPFS HR was 0.52 (0.23 to 1.17) and OS HR was 0.78 (0.34 to 1.8). CONCLUSION: In this pooled analysis, benefit from PARPi appeared greatest for patients with BRCA1m, BRCA2m, CDK12m, and PALB2m. Given limitations of this exploratory analysis, the apparent lack of benefit from PARPi in patients with CHEK2m or ATMm should be further explored in future clinical trials.
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Proteína BRCA2 , Mutación , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Neoplasias de la Próstata Resistentes a la Castración , Ensayos Clínicos Controlados Aleatorios como Asunto , Reparación del ADN por Recombinación , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Masculino , Reparación del ADN por Recombinación/genética , Proteína BRCA2/genética , Proteína BRCA1/genética , Estados Unidos , Quinasa de Punto de Control 2/genética , Quinasas Ciclina-Dependientes/genética , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Supervivencia sin Progresión , Antagonistas de Receptores Androgénicos/uso terapéutico , Anciano , Receptores Androgénicos/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
PURPOSE: A clinically meaningful attribute of some immune-oncology (IO) regimens is potential durable clinical benefit during a treatment-free interval. We characterize treatment-free survival (TFS) with and without ongoing toxicity in trials of frontline IO-VEGF tyrosine kinase inhibitor (TKI) combinations in patients with advanced renal cell carcinoma (aRCC). EXPERIMENTAL DESIGN: Individual patient data were pooled by treatment arm from randomized trials submitted to the FDA evaluating IO-TKI combination in treatment-naïve aRCC with at least 30 months of median follow-up. OS, TFS, TFS with and without toxicity, and time to all protocol therapy cessation were assessed. TFS was estimated by 30-month restricted mean times, defined as area between Kaplan-Meier curves for two time-to-event endpoints originating at randomization: time to all protocol therapy cessation and time to subsequent systemic therapy initiation or death. RESULTS: Three trials met criteria for analysis; 1,183 patients received IO-TKI versus 1,184 on control arms receiving TKI alone (sunitinib, SUN). IO-TKI and SUN groups spent 9% {2.7 months [95% confidence interval (CI), 1.8-3.5]} and 10% [2.9 months (95% CI, 2.1-3.8)] of the 30-month period alive and treatment-free, respectively. Mean TFS without grade ≥3 toxicity was 1.7 and 2.3 months in IO-TKI and SUN groups, respectively. CONCLUSIONS: In this post hoc partitioned survival analysis, TFS and TFS without toxicity appeared similar in the IO-TKI group compared with the SUN group. These findings may reflect contin-uation of TKI until progression per protocol design in all trials and discontinuation of IO after 2 years in two trials. See related commentary by Stadler and Karrison, p. 3098.
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Carcinoma de Células Renales , Neoplasias Renales , Inhibidores de Proteínas Quinasas , Humanos , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/mortalidad , Carcinoma de Células Renales/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/administración & dosificación , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/mortalidad , Neoplasias Renales/patología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Estimación de Kaplan-Meier , Adulto , Sunitinib/uso terapéutico , Sunitinib/administración & dosificación , Sunitinib/efectos adversosRESUMEN
PURPOSE: This article summarizes the US Food and Drug Administration (FDA) review of the data leading to approval of olaparib plus abiraterone for the treatment of patients with deleterious or suspected deleterious BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC), as determined by an FDA-approved companion diagnostic test. PATIENTS AND METHODS: Approval was based on the results from PROpel, a double-blind trial that randomly assigned 796 patients with mCRPC to abiraterone plus prednisone or prednisolone with either olaparib or placebo. The primary end point was radiographic progression-free survival (rPFS) per investigator assessment. RESULTS: There was a statistically significant improvement in rPFS for olaparib plus abiraterone versus placebo plus abiraterone, with a median rPFS of 25 versus 17 months and a hazard ratio (HR) of 0.66 (95% CI, 0.54 to 0.81) in the intention-to-treat population. In an exploratory analysis of the subgroup of 85 patients with BRCAm mCRPC, the HR for rPFS was 0.24 (95% CI, 0.12 to 0.45) and the HR for overall survival (OS) was 0.30 (95% CI, 0.15 to 0.59). In an exploratory analysis of the subgroup of 711 patients without an identified BRCA mutation, the HR for rPFS was 0.77 (95% CI, 0.63 to 0.96) and the HR for OS was 0.92 (95% CI, 0.74 to 1.14). Adding olaparib to abiraterone resulted in increased toxicity, including anemia requiring transfusion in 18% of patients. CONCLUSION: In patients with mCRPC, efficacy of the combination of olaparib plus abiraterone was primarily attributed to the treatment effect in the BRCAm subgroup, the indicated population for the approval. For patients without BRCAm, the FDA determined that the modest rPFS improvement, combined with clinically significant toxicities, did not demonstrate a favorable risk/benefit assessment.
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Androstenos , Ftalazinas , Piperazinas , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Estados Unidos , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Acetato de Abiraterona/uso terapéutico , United States Food and Drug Administration , Supervivencia sin Enfermedad , Prednisona , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: While frontline immuno-oncology/tyrosine kinase inhibitor (IO/TKI) combination therapy has established a benefit in metastatic renal cell carcinoma (mRCC), this may differ by International Metastatic RCC Database Consortium (IMDC) risk grouping. Looking at individual trials, we noted an apparently smaller magnitude of benefit for favorable-risk disease. OBJECTIVE: We aimed to assess treatment benefit by risk groupings, especially in favorable-risk, augmenting patient numbers via a pooled analysis. DESIGN, SETTING, AND PARTICIPANTS: We pooled four frontline mRCC trials of IO/TKI combinations including 3,098 patients (839 favorable-risk) with approvals from 2019 to 2021. INTERVENTION: All trials used IO/TKI combinations as the treatment option and sunitinib as the control. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We analyzed progression-free survival (PFS) and overall survival (OS) by IMDC groupings. To specifically address the favorable-risk group, we combined all others into an intermediate/poor-risk group. RESULTS AND LIMITATIONS: In this exploratory analysis adjusted for baseline covariates, IO/TKI combinations have yet to demonstrate an OS benefit in favorable-risk (hazard ratio [HR] 1.24; 95% confidence interval [CI]: 0.86, 1.78) despite demonstrating an OS benefit in the intermediate/poor-risk group (HR 0.64; 95% CI: 0.55, 0.75). In contrast, IO/TKI demonstrated a PFS benefit for both the favorable-risk (HR 0.63; 95% CI: 0.50, 0.79) and the intermediate/poor-risk (HR 0.52; 95% CI: 0.45, 0.60) group. For objective response rate, a smaller difference was observed between the combination and sunitinib arms in favorable-risk (68.2% vs 49.9%) versus intermediate/poor-risk (59.9% vs 36.5%) groups, while the difference in complete response rate was larger for favorable-risk (15.3% vs 6.0%) versus intermediate/poor-risk (9.1% vs 3.4%) groups. CONCLUSIONS: The frontline IO/TKI combination therapy benefit was shown to be greater in the intermediate/poor-risk group than in the favorable-risk group. The OS benefit observed with IO/TKI for mRCC has yet to be demonstrated for favorable-risk patients; longer follow-up is needed. PATIENT SUMMARY: Patients with intermediate/poor-risk metastatic renal cell carcinoma derive an overall survival benefit from immuno-oncology/tyrosine kinase inhibitor combinations, while data for favorable-risk remain immature.
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Antineoplásicos , Carcinoma de Células Renales , Neoplasias Renales , Estados Unidos , Humanos , Carcinoma de Células Renales/patología , Sunitinib/uso terapéutico , Antineoplásicos/efectos adversos , Neoplasias Renales/patología , United States Food and Drug Administration , Supervivencia sin Enfermedad , Inhibidores de Proteínas Quinasas/efectos adversos , Estudios RetrospectivosRESUMEN
BACKGROUND: Despite recent drug development for non-muscle invasive bladder cancer (NMIBC), few therapies have been approved by the US Food and Drug Administration (FDA), and there remains an unmet clinical need. Bacillus Calmette-Guerin (BCG) supply issues underscore the importance of developing safe and effective drugs for NMIBC. OBJECTIVE: On November 18-19, 2021, the FDA held a public virtual workshop to discuss NMIBC research needs and potential trial designs for future development of effective therapies. METHODS: Representatives from various disciplines including urologists, oncologists, pathologists, statisticians, basic and translational scientists, and the patient advocacy community participated. The workshop format included invited lectures, panel discussions, and opportunity for audience discussion and comment. RESULTS: In a pre-workshop survey, 92% of urologists surveyed considered the development of alternatives to BCG as a high drug development priority for BCG-naïve high-risk patients. Key topics discussed included definitions of disease states; trial design for BCG-naïve NMIBC, BCG-unresponsive carcinoma in situ, and BCG-unresponsive papillary carcinoma; strengths and limitations of single-arm trial designs; assessing patient-reported outcomes; and considerations for assessing avoidance of cystectomy as an efficacy measure. CONCLUSIONS: The workshop discussed several important opportunities for trial design refinement in NMIBC. FDA encourages sponsors to meet with the appropriate review division to discuss trial design proposals for NMIBC early in drug development.
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On August 13, 2021, the FDA approved belzutifan (WELIREG, Merck), a first-in-class hypoxia-inducible factor (HIF) inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. The FDA granted approval based on the clinically meaningful effects on overall response rate (ORR) observed in patients enrolled in Study MK-6482-004. All 61 patients had VHL-associated RCC; some also had CNS hemangioblastomas and/or pNET. For VHL disease-associated RCC, ORR was 49% [95% confidence interval (CI), 36-62], median duration of response (DoR) was not reached, 56% of responders had DoR ≥12 months, and median time to response was 8 months. Twenty-four patients had measurable CNS hemangioblastomas with an ORR of 63% (95% CI, 41-81), and 12 patients had measurable pNET with an ORR of 83% (95% CI, 52-98). For these tumors, median DoR was not reached, with 73% and 50% of patients having response durations ≥12 months for CNS hemangioblastomas and pNET, respectively. The most common adverse reactions, including laboratory abnormalities, reported in ≥20% were anemia, fatigue, increased creatinine, headache, dizziness, increased glucose, and nausea. Belzutifan can render some hormonal contraceptives ineffective and can cause embryo-fetal harm during pregnancy. This article summarizes the data and the FDA thought process supporting traditional approval of belzutifan for this indication.
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Antineoplásicos , Carcinoma de Células Renales , Neoplasias del Sistema Nervioso Central , Hemangioblastoma , Neoplasias Renales , Tumores Neuroectodérmicos Primitivos , Enfermedad de von Hippel-Lindau , Adulto , Humanos , Embarazo , Femenino , Enfermedad de von Hippel-Lindau/complicaciones , Enfermedad de von Hippel-Lindau/tratamiento farmacológico , Enfermedad de von Hippel-Lindau/patología , Hemangioblastoma/complicaciones , Hemangioblastoma/patología , Carcinoma de Células Renales/complicaciones , Tumores Neuroectodérmicos Primitivos/complicacionesRESUMEN
The role of adjuvant therapy in renal cell carcinoma and urothelial carcinoma is rapidly evolving. To date, the U.S. Food and Drug Administration has approved sunitinib and pembrolizumab in the adjuvant setting for renal cell carcinoma and nivolumab for urothelial carcinoma based on disease-free survival benefit. The U.S. Food and Drug Administration held a joint workshop with the National Cancer Institute and the Society of Urologic Oncology in 2017 to harmonize design elements, including eligibility and radiologic assessments across adjuvant trials in renal cell carcinoma and urothelial carcinoma. Considerations from the discussion at these workshops led the U.S. Food and Drug Administration to draft guidances to help inform subsequent adjuvant trial design for renal cell carcinoma and urothelial carcinoma. Patient-centered decision-making is crucial when determining therapeutic choices in the adjuvant setting; utility functions can be used to help quantify each patient's goals, values, and risk/benefit trade-offs to ensure that the decision regarding adjuvant therapy is informed by their preferences and the evolving outcomes data.
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Carcinoma de Células Renales , Carcinoma de Células Transicionales , Neoplasias Renales , Neoplasias de la Vejiga Urinaria , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Carcinoma de Células Transicionales/tratamiento farmacológico , Quimioterapia Adyuvante , Humanos , Riñón/patología , Neoplasias Renales/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
Importance: Immune checkpoint inhibitors (ICIs) and radiation therapy (RT) are widely used to treat various cancers, but little data are available to guide clinicians on ICI use sequentially with RT. Objective: To assess whether there is an increased risk of serious adverse events (AEs) associated with RT given within 90 days prior to an ICI. Design, Setting, and Participants: Individual patient data were pooled from 68 prospective trials of ICIs submitted in initial or supplemental licensing applications in the US Food and Drug Administration (FDA) databases through December 2019. Two cohorts were generated: (1) patients who received RT within the 90 days prior to beginning ICI therapy and (2) those who did not receive RT within the 90 days prior to beginning ICI therapy, and AE frequencies were determined. A 1:1 propensity score-matched analysis was performed. Interventions: All patients received an ICI (atezolizumab, avelumab, cemiplimab, durvalumab, ipilimumab, nivolumab, or pembrolizumab); 1733 received RT within the 90 days prior to starting ICI therapy, and 13â¯956 did not. Main Outcomes and Measures: The primary outcome was frequency and severity of AEs. Incidence of AEs was compared descriptively between participants who did vs did not receive RT in the propensity score-matched set. Because all analyses are exploratory (ie, not preplanned and no alpha allocated), assessment for statistical significance of the differences between groups was not considered appropriate. Results: A total of 25â¯469 patients were identified; 8634 were excluded because they lacked comparators who had received RT (n = 976), did not receive an ICI (n = 4949), received RT outside of the target window (n = 2338), or had missing data in 1 or more variables used in the propensity analysis (n = 371), leaving 16â¯835 patients included in the analysis. The majority were younger than 65 years (9447 [56.1%]), male (10â¯459 [62.1%]), and White (13â¯422 [79.7%]). Patients receiving RT had generally similar rates of AEs overall to those patients who did not receive RT. The average absolute difference in rates across the AEs was 1.2%, and the difference ranged from 0% for neurologic AEs to 8% for fatigue. No difference in grade 3 to 4 AEs was observed between the 2 groups (absolute difference ranged from 0.01% to 2%). These findings persisted after propensity score matching. Conclusions and Relevance: In this pooled analysis, administration of an ICI within 90 days following RT did not appear to be associated with an increased risk of serious AEs. Thus, it would appear to be safe to administer an ICI within 90 days of receiving RT. These findings should be confirmed in future prospective trials.
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Inmunoterapia , Neoplasias , Humanos , Inmunoterapia/efectos adversos , Ipilimumab/efectos adversos , Masculino , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Nivolumab/efectos adversos , Estados Unidos/epidemiología , United States Food and Drug AdministrationRESUMEN
The success of the use of novel therapies in the treatment of advanced urothelial carcinoma has contributed to growing interest in evaluating these therapies at earlier stages of the disease. However, trials evaluating these therapies in the neoadjuvant setting must have clearly defined study elements and appropriately selected end points to ensure the applicability of the trial and enable interpretation of the study results. To advance the development of rational trial design, a public workshop jointly sponsored by the US Food and Drug Administration and the Bladder Cancer Advocacy Network convened in August 2019. Clinicians, clinical trialists, radiologists, biostatisticians, patients, advocates and other stakeholders discussed key elements and end points when designing trials of neoadjuvant therapy for muscle-invasive bladder cancer (MIBC), identifying opportunities to refine eligibility, design and end points for neoadjuvant trials in MIBC. Although pathological complete response (pCR) is already being used as a co-primary end point, both individual-level and trial-level surrogacy for time-to-event end points, such as event-free survival or overall survival, remain incompletely characterized in MIBC. Additionally, use of pCR is limited by heterogeneity in pathological evaluation and the fact that the magnitude of pCR improvement that might translate into a meaningful clinical benefit remains unclear. Given existing knowledge gaps, capture of highly granular patient-related, tumour-related and treatment-related characteristics in the current generation of neoadjuvant MIBC trials will be critical to informing the design of future trials.
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Carcinoma de Células Transicionales/terapia , Ensayos Clínicos como Asunto/métodos , Terapia Neoadyuvante , Neoplasias de la Vejiga Urinaria/terapia , Carcinoma de Células Transicionales/patología , Humanos , Estados Unidos , United States Food and Drug Administration , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
On March 10, 2021, the FDA granted regular approval to tivozanib for treatment of patients with relapsed or refractory (R/R) advanced renal cell carcinoma (RCC) following two or more prior systemic therapies. Approval was based on the TIVO-3 study, a randomized trial of tivozanib versus sorafenib in patients with R/R advanced RCC. In TIVO-3, patients were randomized to receive either tivozanib 1.34 mg orally once daily for 21 consecutive days of every 28-day cycle or sorafenib 400 mg orally twice daily continuously. The primary endpoint was progression-free survival (PFS) per RECIST v1.1. Tivozanib demonstrated efficacy compared with sorafenib with an improvement in PFS [HR, 0.73; 95% confidence interval (CI), 0.56-0.95; P = 0.016]. The estimated median PFS was 5.6 months and 3.9 months in the tivozanib and sorafenib arms, respectively. There was no evidence of a detrimental effect on overall survival: HR, 0.97 (95% CI, 0.75-1.24). The most common grade 3 to 4 adverse reaction on the tivozanib arm was hypertension (24%). Compared with sorafenib, tivozanib was associated with lower rates of grade 3 to 4 diarrhea, rash, and palmar-plantar erythrodysesthesia. Patients receiving tivozanib in TIVO-3 had lower rates of dose reduction, interruption, or permanent discontinuation than those receiving sorafenib.
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Carcinoma de Células Renales/tratamiento farmacológico , Aprobación de Drogas , Neoplasias Renales/tratamiento farmacológico , Compuestos de Fenilurea/uso terapéutico , Quinolinas/uso terapéutico , Administración Oral , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Renales/mortalidad , Femenino , Humanos , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Compuestos de Fenilurea/administración & dosificación , Compuestos de Fenilurea/efectos adversos , Quinolinas/administración & dosificación , Quinolinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Sorafenib/administración & dosificación , Sorafenib/uso terapéutico , Tasa de Supervivencia , Resultado del TratamientoRESUMEN
BACKGROUND: Little is known about the benefit-risk profile of second-generation androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. We aimed to examine the efficacy and safety of second-generation androgen receptor inhibitors in men aged 80 years or older with non-metastatic castration-resistant prostate cancer. METHODS: We searched for all randomised controlled clinical trials evaluating second-generation androgen receptor inhibitors in patients with non-metastatic castration-resistant prostate cancer submitted to the US Food and Drug Administration before Aug 15, 2020, and pooled data from three trials that met the selection criteria. All three trials enrolled patients who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, castration-resistant prostate cancer, prostate-specific antigen (PSA) 2·0 µg/L or greater, PSA doubling time of 10 months or less, and no evidence of distant metastatic disease on conventional imaging per the investigator's assessment at the time of screening. All patients had histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation or small-cell features. All patients who were randomly assigned to androgen receptor inhibitor or placebo groups in these trials were considered assessable and were included in this pooled analysis. We evaluated the effect of age on metastasis-free survival and overall survival across age groups (<80 years vs ≥80 years) in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study treatment. FINDINGS: Between Oct 14, 2013, and March 9, 2018, 4117 patients were assigned to androgen receptor inhibitor (apalutamide, enzalutamide, or daralutamide; n=2694) or placebo (n=1423) across three randomised trials. The median follow-up duration for metastasis-free survival was 18 months (IQR 11-26) and for overall survival was 44 months (32-55). In patients aged 80 years or older (n=1023), the estimated median metastasis-free survival was 40 months (95% CI 36-41) in the androgen receptor inhibitor groups and 22 months (18-29) in the placebo groups (adjusted hazard ratio [HR] 0·37 [95% CI 0·28-0·47]), and the median overall survival was 54 months (50-61) versus 49 months (43-58), respectively (adjusted HR 0·79 [0·64-0·98]). In patients younger than 80 years of age (n=3094), the estimated median metastasis-free survival was 41 months (95% CI 36-not estimable [NE]) in the androgen receptor inhibitor groups and 16 months (15-18) in the placebo groups (adjusted HR 0·31 [95% CI 0·27-0·35]), and the median overall survival was 74 months (74-NE) versus 61 months (56-NE), respectively (adjusted HR 0·69 [0·60-0·80]). In patients aged 80 years or older, grade 3 or worse adverse events were reported in 371 (55%) of 672 patients in the androgen receptor inhibitor groups and 140 (41%) of 344 patients in the placebo groups, compared with 878 (44%) of 2015 patients in the androgen receptor inhibitor groups and 321 (30%) of 1073 patients in the placebo groups among patients younger than 80 years. The most common grade 3-4 adverse events were hypertension (168 [8%] of 2015 patients aged <80 years and 51 [8%] of 672 patients aged ≥80 years in the androgen receptor inhibitor groups vs 53 [5%] of 1073 patients aged <80 years and 22 [6%] of 344 patients aged ≥80 years in the placebo groups) and fracture (61 [3%] and 36 [5%] in the androgen receptor inhibitor groups vs 15 [1%] and 11 [3%] in the placebo groups). INTERPRETATION: The findings of this pooled analysis support the use of androgen receptor inhibitors in older men with non-metastatic castration-resistant prostate cancer. Incorporating geriatric assessment tools in the care of older adults with non-metastatic castration-resistant prostate cancer might help clinicians to offer individualised treatment to each patient. FUNDING: None.
Asunto(s)
Antagonistas de Receptores Androgénicos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antagonistas de Receptores Androgénicos/efectos adversos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Masculino , Metástasis de la Neoplasia , Supervivencia sin Progresión , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Neoplasias de la Próstata Resistentes a la Castración/patología , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Tasa de Supervivencia , Estados Unidos/epidemiología , United States Food and Drug AdministrationRESUMEN
Despite recent treatment advances, kidney and bladder cancer cases have continued to rise in both incidence and mortality over the last few decades. Not every demographic subgroup of patients diagnosed with these cancers has an equivalent outcome. Women diagnosed with bladder cancer have worse overall survival than men diagnosed with bladder cancer. Older adults with muscle-invasive bladder cancer have worse cancer-specific outcomes than do younger patients. Black patients diagnosed with kidney and bladder cancers appear to have worse overall survival than White patients diagnosed with these cancers. Although these differences in outcomes are likely multifactorial, in many cases they may be based on modifiable approaches to screening, diagnosing, and treating patients. We explore various causes of these differences in outcomes between patients and address patient engagement strategies and avenues to effect change. In 2021, equity in cancer and cancer care delivery has a more prominent place in the hierarchy of the continuum of medicine. Continued focus on this topic is critical, with clear accountabilities established and barriers to best care for patients eliminated.
Asunto(s)
Neoplasias Renales , Neoplasias de la Vejiga Urinaria , Negro o Afroamericano , Ensayos Clínicos como Asunto , Femenino , Humanos , Incidencia , Neoplasias Renales/diagnóstico , Neoplasias Renales/epidemiología , Neoplasias Renales/terapia , Masculino , Resultado del Tratamiento , Neoplasias de la Vejiga Urinaria/diagnóstico , Neoplasias de la Vejiga Urinaria/epidemiología , Neoplasias de la Vejiga Urinaria/terapia , Población BlancaRESUMEN
The U.S. Food and Drug Administration (FDA) granted accelerated approval to rucaparib in May 2020 for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer (mCRPC) who have been treated with androgen receptor-directed therapy and a taxane. This approval was based on data from the ongoing multicenter, open-label single-arm trial TRITON2. The primary endpoint, confirmed objective response rate, in the 62 patients who met the above criteria, was 44% (95% confidence interval [CI]: 31%-57%). The median duration of response was not estimable (95% CI: 6.4 to not estimable). Fifty-six percent of patients had a response duration of >6 months and 15% >12 months. The safety profile of rucaparib was generally consistent with that of the class of poly-(ADP-ribose) polymerase enzyme inhibitors and other trials of rucaparib in the treatment of ovarian cancer. Deaths due to adverse events (AEs) occurred in 1.7% of patients, and 8% discontinued rucaparib because of an AE. Grade 3-4 AEs occurred in 59% of patients. No patients with prostate cancer developed myelodysplastic syndrome or acute myeloid leukemia. The trial TRITON3 in patients with mCRPC is ongoing and is planned to verify the clinical benefit of rucaparib in mCRPC. This article summarizes the FDA thought process and data supporting this accelerated approval. IMPLICATIONS FOR PRACTICE: The accelerated approval of rucaparib for the treatment of adult patients with deleterious BRCA mutation (germline and/or somatic)-associated metastatic castrate-resistant prostate cancer who have been treated with androgen receptor-directed therapy and a taxane represents the first approved therapy for this selected patient population. This approval was based on a single-arm trial demonstrating a confirmed objective response rate greater than that of available therapy with a favorable duration of response and an acceptable toxicity profile. The ongoing trial TRITON3 is verifying the clinical benefit of this drug.