RESUMO
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.
Assuntos
Carcinoma de Células Renais , Procedimentos Cirúrgicos de Citorredução , Inibidores de Checkpoint Imunológico , Neoplasias Renais , Nefrectomia , United States Food and Drug Administration , Humanos , Nefrectomia/métodos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/cirurgia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Renais/mortalidade , Estados Unidos/epidemiologia , Masculino , Feminino , Carcinoma de Células Renais/cirurgia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Pessoa de Meia-Idade , Idoso , Inibidores da Angiogênese/uso terapêutico , AdultoRESUMO
PURPOSE: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: The approval was based on the HRR gene-mutated (HRRm) population of TALAPRO-2, a randomized, double-blind trial that randomly assigned 1,035 patients with mCRPC to receive enzalutamide with either talazoparib or placebo. Two cohorts enrolled sequentially: an all-comer population (Cohort 1), followed by an HRRm-only population (Cohort 2). The independent primary end points were radiographic progression-free survival (rPFS) per blinded independent central review (BICR) in Cohort 1 (all-comers) and in the combined HRRm population (all HRRm patients from Cohorts 1 and 2). Overall survival (OS) was a key secondary end point. RESULTS: A statistically significant improvement in rPFS by BICR was demonstrated in both the all-comers cohort and the combined HRRm population, with hazard ratio (HR) of 0.63 (95% CI, 0.51 to 0.78; P < .0001) and 0.45 (95% CI, 0.33 to 0.61; P < .0001), respectively. In an exploratory analysis of the 155 patients with BRCA-mutated (BRCAm) mCRPC, rPFS HR was 0.20 (95% CI, 0.11 to 0.36). In the non-HRRm/unknown stratum of Cohort 1 (n = 636), the rPFS HR was 0.70 (95% CI, 0.54 to 0.89). OS was immature. CONCLUSION: Despite a statistically significant rPFS improvement in the all-comer cohort, FDA did not consider the magnitude of rPFS clinically meaningful in the context of the broad indication, combination treatment, and safety profile. Approval was therefore limited to patients with HRRm mCRPC, for whom there was a statistically significant and clinically meaningful improvement in rPFS and favorable OS results. This represents the first approval for the first-line treatment of patients with HRRm mCRPC.
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Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Aprovação de Drogas , Mutação , Nitrilas , Feniltioidantoína , Ftalazinas , Neoplasias de Próstata Resistentes à Castração , Reparo de DNA por Recombinação , United States Food and Drug Administration , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Nitrilas/uso terapêutico , Feniltioidantoína/uso terapêutico , Feniltioidantoína/análogos & derivados , Benzamidas/uso terapêutico , Estados Unidos , Ftalazinas/uso terapêutico , Ftalazinas/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Método Duplo-Cego , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Intervalo Livre de ProgressãoRESUMO
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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Anticorpos Monoclonais Humanizados , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Aprovação de Drogas , United States Food and Drug Administration , Humanos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Estados Unidos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso , Feminino , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Pessoa de Meia-Idade , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Cisplatino/uso terapêutico , Idoso de 80 Anos ou mais , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/patologia , Carcinoma de Células de Transição/tratamento farmacológico , Carcinoma de Células de Transição/patologia , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/patologia , Resultado do TratamentoRESUMO
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.
Assuntos
Proteína BRCA2 , Mutação , Inibidores de Poli(ADP-Ribose) Polimerases , Neoplasias de Próstata Resistentes à Castração , Ensaios Clínicos Controlados Aleatórios como Assunto , Reparo de DNA por Recombinação , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/patologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Masculino , Reparo de DNA por Recombinação/genética , Proteína BRCA2/genética , Proteína BRCA1/genética , Estados Unidos , Quinase do Ponto de Checagem 2/genética , Quinases Ciclina-Dependentes/genética , Quinases Ciclina-Dependentes/antagonistas & inibidores , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Intervalo Livre de Progressão , Antagonistas de Receptores de Andrógenos/uso terapêutico , Idoso , Receptores Androgênicos/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
PURPOSE: The US Food and Drug Administration (FDA) approved elacestrant for the treatment of postmenopausal women or adult men with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-), estrogen receptor 1 (ESR1)-mutated advanced or metastatic breast cancer with disease progression after at least one line of endocrine therapy (ET). PATIENTS AND METHODS: Approval was based on EMERALD (Study RAD1901-308), a randomized, open-label, active-controlled, multicenter trial in 478 patients with ER+, HER2- advanced or metastatic breast cancer, including 228 patients with ESR1 mutations. Patients were randomly assigned (1:1) to receive either elacestrant 345 mg orally once daily (n = 239) or investigator's choice of ET (n = 239). RESULTS: In the ESR1-mut subgroup, EMERALD demonstrated a statistically significant improvement in progression-free survival (PFS) by blinded independent central review assessment (n = 228; hazard ratio [HR], 0.55 [95% CI, 0.39 to 0.77]; P value = .0005). Although the overall survival (OS) end point was not met, there was no trend toward a potential OS detriment (HR, 0.90 [95% CI, 0.63 to 1.30]) in the ESR1-mut subgroup. PFS also reached statistical significance in the intention-to-treat population (ITT, N = 478; HR, 0.70 [95% CI, 0.55 to 0.88]; P value = .0018). However, improvement in PFS in the ITT population was primarily attributed to results from patients in the ESR1-mut subgroup. More patients who received elacestrant experienced nausea, vomiting, and dyslipidemia. CONCLUSION: The approval of elacestrant in ER+, HER2- advanced or metastatic breast cancer was restricted to patients with ESR1 mutations. Benefit-risk assessment in the ESR1-mut subgroup was favorable on the basis of a statistically significant improvement in PFS in the context of an acceptable safety profile including no evidence of a potential detriment in OS. By contrast, the benefit-risk assessment in patients without ESR1 mutations was not favorable. Elacestrant is the first oral estrogen receptor antagonist to receive FDA approval for patients with ESR1 mutations.
Assuntos
Neoplasias da Mama , Tetra-Hidronaftalenos , Adulto , Estados Unidos , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio/genética , United States Food and Drug Administration , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
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.
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Inibidores de Proteínas Quinases , Humanos , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/patologia , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estimativa de Kaplan-Meier , Adulto , Sunitinibe/uso terapêutico , Sunitinibe/administração & dosagem , Sunitinibe/efeitos adversosRESUMO
In 2020, Novartis Pharmaceuticals Corporation and the U.S. Food and Drug Administration (FDA) started a 4-year scientific collaboration to approach complex new data modalities and advanced analytics. The scientific question was to find novel radio-genomics-based prognostic and predictive factors for HR+/HER- metastatic breast cancer under a Research Collaboration Agreement. This collaboration has been providing valuable insights to help successfully implement future scientific projects, particularly using artificial intelligence and machine learning. This tutorial aims to provide tangible guidelines for a multi-omics project that includes multidisciplinary expert teams, spanning across different institutions. We cover key ideas, such as "maintaining effective communication" and "following good data science practices," followed by the four steps of exploratory projects, namely (1) plan, (2) design, (3) develop, and (4) disseminate. We break each step into smaller concepts with strategies for implementation and provide illustrations from our collaboration to further give the readers actionable guidance.
Assuntos
Inteligência Artificial , Multiômica , Humanos , Aprendizado de Máquina , GenômicaRESUMO
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.
Assuntos
Androstenos , Ftalazinas , Piperazinas , Neoplasias de Próstata Resistentes à Castração , Masculino , Estados Unidos , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/genética , Acetato de Abiraterona/uso terapêutico , United States Food and Drug Administration , Intervalo Livre de Doença , Prednisona , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
SUMMARY: Cancer drug development remained robust in 2023. Highlights of U.S. drug approvals this year include new immunotherapies and targeted drug development in adult and pediatric patients as well as patients with rare diseases.
Assuntos
Antineoplásicos , Neoplasias , Humanos , Criança , Estados Unidos , Linfócitos T , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Aprovação de Drogas , Imunoterapia , United States Food and Drug AdministrationRESUMO
Anticancer agents can impair ovarian function, resulting in premature menopause and associated long-term health effects. Ovarian toxicity is not usually adequately assessed in trials of anticancer agents, leaving an important information gap for patients facing therapy choices. This American Society of Clinical Oncology (ASCO) statement provides information about the incorporation of ovarian toxicity measures in trial design. ASCO recommends: (1) measurement of ovarian toxicity in relevant clinical trials of anticancer agents that enrol post-pubertal, pre-menopausal patients; (2) collection of ovarian function measures at baseline and at 12-24 months after anticancer agent cessation, as a minimum, and later in line with the trial schedule; and (3) assessment of both clinical measures and biomarkers of ovarian function. ASCO recognises that routine measurement of ovarian toxicity and function in cancer clinical trials will add additional complexity and burden to trial resources but asserts that this issue is of such importance to patients that it cannot continue to be overlooked.
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Antineoplásicos , Neoplasias , Feminino , Humanos , Estados Unidos , Neoplasias/terapia , Antineoplásicos/efeitos adversos , Ovário , OncologiaRESUMO
On December 10, 2021, the FDA expanded the indications for ribociclib to include male patients for the treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer. Ribociclib is now indicated in combination with an aromatase inhibitor (AI) as initial endocrine-based therapy in adult patients, or with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy (ET), in postmenopausal women or in men. The efficacy of ribociclib + AI for male patients was primarily based on previous favorable benefit-risk assessments of ribociclib from MONALEESA-2 and MONALEESA-7 trials, and supported by COMPLEEMENT-1, an open-label, single-arm, multicenter clinical trial, in which 39 male patients (n = 3,246 total patients) received ribociclib + letrozole + goserelin/leuprolide. The overall response rate (ORR) based on confirmed responses in male patients with measurable disease at baseline was 46.9% [95% confidence interval (CI), 29.1-65.3], consistent with an ORR of 43.6% (95% CI, 41.5-45.8) in the overall population. Overall, adverse reactions occurring in male patients were similar to those occurring in female patients treated with ribociclib + ET. The efficacy of ribociclib + fulvestrant for male patients was primarily based on the previous findings of a favorable benefit-risk assessment from the MONALEESA-3 trial, supported by FDA review of clinical data of a limited number of male patients treated in clinical practice receiving ribociclib + fulvestrant. The known mechanism of action, biologic rationale, and clinical information available adequately demonstrate that the efficacy and safety of ribociclib + AI/fulvestrant are similar in male and female patients. This article summarizes the FDA's decision-making and data supporting the approval of ribociclib in male patients with breast cancer, and discusses regulatory insights.
Assuntos
Neoplasias da Mama , Receptores de Estrogênio , Adulto , Feminino , Humanos , Masculino , Letrozol , Fulvestranto/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Aminopiridinas , Inibidores da Aromatase/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Receptor ErbB-2/uso terapêuticoRESUMO
PURPOSE: The Standardized Definitions for Efficacy End Points (STEEP) criteria, established in 2007 and updated in 2021 (STEEP 2.0), provide standardized definitions of adjuvant breast cancer (BC) end points. STEEP 2.0 identified a need to separately address end points for neoadjuvant clinical trials. The multidisciplinary NeoSTEEP working group of experts was convened to critically evaluate and align neoadjuvant BC trial end points. METHODS: The NeoSTEEP working group concentrated on neoadjuvant systemic therapy end points in clinical trials with efficacy outcomes-both pathologic and time-to-event survival end points-particularly for registrational intent. Special considerations for subtypes and therapeutic approaches, imaging, nodal staging at surgery, bilateral and multifocal diseases, correlative tissue collection, and US Food and Drug Administration regulatory considerations were contemplated. RESULTS: The working group recommends a preferred definition of pathologic complete response (pCR) as the absence of residual invasive cancer in the complete resected breast specimen and all sampled regional lymph nodes (ypT0/Tis ypN0 per AJCC staging). Residual cancer burden should be a secondary end point to facilitate future assessment of its utility. Alternative end points are needed for hormone receptor-positive disease. Time-to-event survival end point definitions should pay particular attention to the measurement starting point. Trials should include end points originating at random assignment (event-free survival and overall survival) to capture presurgery progression and deaths as events. Secondary end points adapted from STEEP 2.0, which are defined from starting at curative-intent surgery, may also be appropriate. Specification and standardization of biopsy protocols, imaging, and pathologic nodal evaluation are also crucial. CONCLUSION: End points in addition to pCR should be selected on the basis of clinical and biologic aspects of the tumor and the therapeutic agent investigated. Consistent prespecified definitions and interventions are paramount for clinically meaningful trial results and cross-trial comparison.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Terapia Neoadjuvante/métodos , Projetos de Pesquisa , Intervalo Livre de ProgressãoRESUMO
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 Renais , Neoplasias Renais , Estados Unidos , Humanos , Carcinoma de Células Renais/patologia , Sunitinibe/uso terapêutico , Antineoplásicos/efeitos adversos , Neoplasias Renais/patologia , United States Food and Drug Administration , Intervalo Livre de Doença , Inibidores de Proteínas Quinases/efeitos adversos , Estudos RetrospectivosRESUMO
On November 14, 2022, the FDA granted accelerated approval to mirvetuximab soravtansine-gynx for treatment of adult patients with folate receptor-α (FRα)-positive, platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received one to three prior systemic therapies. The VENTANA FOLR1 (FOLR-2.1) RxDx Assay was approved as a companion diagnostic device to select patients for this indication. Approval was based on Study 0417 (SORAYA, NCT04296890), a single-arm, multicenter trial. In 104 patients with measurable disease who received mirvetuximab soravtansine-gynx, the overall response rate was 31.7% [95% confidence interval (CI), 22.9-41.6] with a median duration of response of 6.9 months (95% CI, 5.6-9.7). Ocular toxicity was included as a Boxed Warning in the U.S. Prescribing Information (USPI) to alert providers of the risks of developing severe ocular toxicity including vision impairment and corneal disorders. Pneumonitis and peripheral neuropathy were additional important safety risks included as Warnings and Precautions in the USPI. This is the first approval of a targeted therapy for FRα-positive, platinum-resistant ovarian cancer and the first antibody-drug conjugate approved for ovarian cancer. This article summarizes the favorable benefit-risk assessment leading to FDA's approval of mirvetuximab soravtansine-gynx.
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Imunoconjugados , Neoplasias Ovarianas , Adulto , Humanos , Feminino , Neuropatia Óptica Tóxica/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Imunoconjugados/efeitos adversos , Receptor 1 de FolatoRESUMO
Oncology clinical trials terms and definitions have become increasingly complex, which has led to shortcomings among research staff and healthcare providers in informing clinical trial participants with the study results and consenting procedures in simple language. Understanding oncology clinical trial terms is of critical importance to assist patients and caregivers in making cancer treatment decisions, including enrollment into clinical trials. The U.S. Food and Drug Administration's (FDA) Oncology Center of Excellence (OCE) organized a physician and patient advocate-led focus group, with the primary goal of publishing a patient-centric public glossary of select cancer clinical trial terms for healthcare providers, patients, and caregivers. This commentary reports the results of the focus group sessions that gave FDA OCE valuable insights into how patients perceive clinical trial terms and how oncology clinical trial definitions can be improved to effectively communicate information to the patients to make better informed decisions about their treatment options.
Assuntos
Neoplasias , Médicos , Humanos , Neoplasias/tratamento farmacológico , Oncologia , Idioma , Tomada de DecisõesRESUMO
PURPOSE: The US Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd) for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry 1 + or immunohistochemistry 2+/in situ hybridization-) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. PATIENTS AND METHODS: Approval was based on DESTINY-Breast04, a phase III, randomized, open-label, multicenter trial in patients with unresectable or metastatic HER2-low breast cancer, determined at a central laboratory. A total of 557 patients were randomly assigned (2:1) to receive either T-DXd 5.4 mg/kg intravenously once every 3 weeks (n = 373) or physicians' choice of chemotherapy (n = 184). RESULTS: The study met its primary efficacy end point of progression-free survival (PFS) by blinded independent central review assessment in the hormone receptor-positive (HR+) cohort (N = 494) with an estimated hazard ratio (HR) of 0.51(95% CI, 0.40 to 0.64; P < .0001). Key secondary end points were also met, including PFS in the intent-to-treat population with an HR of 0.50 (95% CI, 0.40 to 0.63; P < .0001), overall survival (OS) in the HR+ cohort with an HR of 0.64 (95% CI, 0.48 to 0.86; P = .0028) and OS in the intent-to-treat with an HR of 0.64 (95% CI, 0.49 to 0.84; P = .0010). The safety profile of T-DXd was consistent with previously approved indications, and no new safety signals were observed in this study population. CONCLUSION: The approval of T-DXd in HER2-low metastatic breast cancer was based on statistically significant and clinically meaningful PFS and OS improvements observed in the DESTINY-Breast04 trial and represents the first approved therapy specifically for the treatment of HER2-low metastatic breast cancer.
Assuntos
Neoplasias da Mama , Estados Unidos , Adulto , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , United States Food and Drug Administration , Anticorpos Monoclonais Humanizados/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Trastuzumab , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Importance: Single-arm trials have allowed for transformative therapies to be made available to patients expeditiously. However, using single-arm trials to support drug approval presents several challenges that must be carefully considered. Observations: Between January 1, 2002, and December 31, 2021, the US Food and Drug Administration granted 176 new malignant hematology and oncology indications based on single-arm trials, including 116 accelerated approvals (AAs) and 60 traditional approvals. Overall, 87 approvals (49%) were for new molecular entities or original biologics and 89 (51%) were supplemental indications. Response rate (RR) was the most common end point used to support approval in these single-arm trials (173 of 176 [98%]). Of the 116 AAs based on single-arm trials, 45 (38%) fulfilled their postmarketing requirement to verify clinical benefit, 61 (52%) are pending verification of benefit, and 10 (9%) were withdrawn from the market as of December 31, 2021. Most (56 of 61 [92%]) AAs based on single-arm trials pending verification of benefit occurred during the previous 5 years and have ongoing confirmatory trials as of December 2021. Conclusions and Relevance: Single-arm trials have been a common development strategy to support regulatory approval as early-stage expansion cohorts with promising durable RRs have become more prevalent. In the appropriate context, single-arm trials using durable RRs can allow patients expedited access to novel therapies and will continue to serve a role in advancing drug development in oncology. However, single-arm trials have a smaller noncomparative safety data set, inability to use time-to-event end points, and other limitations that require careful consideration within the context of the disease and available therapies. The randomized clinical trial remains the preferred approach in clinical investigation.