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PURPOSE: The majority of patients with metastatic prostate cancer who receive androgen-deprivation therapy and androgen receptor (AR) signaling inhibitors (ARSI) progress. Activation of the glucocorticoid receptor (GR) is associated with ARSI resistance. This single-arm phase I trial assessed safety and pharmacokinetic (PK) feasibility of a combined AR antagonist (enzalutamide) and selective GR modulator (relacorilant) in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This was a phase I trial (NCT03674814) of relacorilant and enzalutamide in patients with refractory mCRPC enrolled using a 6+3 design. The enzalutamide dose was kept constant at 120 mg/d with escalating doses of relacorilant based on safety and PK measures in cohorts of ≥6 patients. The primary objective was safety and establishment of pharmacologically active doses. Secondary objectives were related to antitumor activity. RESULTS: Thirty-five patients with mCRPC were enrolled. Twenty-three were accrued across three dose cohorts in the dose-escalation phase, and 12 enrolled at the recommended phase II dose. The combination was generally well tolerated, safe, and achieved desirable enzalutamide PK. RP2D of 120 + 150 mg/d, respectively, was established. Median time on study was 2.2 months with four patients remaining on study for longer than 11 months. Four of 12 evaluable patients had a prostate-specific antigen (PSA) partial response. CONCLUSIONS: This is the first prospective trial combining an AR antagonist and a nonsteroidal selective GR modulator. The combination was safe and well tolerated with PSA response and prolonged disease control observed in a limited subset of patients. Further prospective trials are justified to evaluate efficacy and identify predictive biomarkers of response.
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Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Nitrilos , Feniltiohidantoína , Neoplasias de la Próstata Resistentes a la Castración , Receptores de Glucocorticoides , Humanos , Masculino , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/efectos adversos , Feniltiohidantoína/uso terapéutico , Feniltiohidantoína/farmacocinética , Benzamidas/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Nitrilos/administración & dosificación , Anciano , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Anciano de 80 o más Años , Metástasis de la Neoplasia , Antagonistas de Receptores Androgénicos/uso terapéutico , Antagonistas de Receptores Androgénicos/administración & dosificación , Antagonistas de Receptores Androgénicos/farmacocinética , Antagonistas de Receptores Androgénicos/efectos adversos , Receptores Androgénicos/metabolismo , Resultado del TratamientoRESUMEN
BACKGROUND AND OBJECTIVE: In comparison to chemotherapy, enfortumab vedotin (EV) prolonged overall survival in patients with previously treated advanced urothelial carcinoma in EV-301. The objective of the present study was to assess patient experiences of EV versus chemotherapy using patient-reported outcome (PRO) analysis of health-related quality of life (HRQoL). METHODS: For patients in the phase 3 EV-301 trial randomized to EV or chemotherapy we assessed responses to the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline, weekly for the first 12 wk, and then every 12 wk until discontinuation. We analyzed the QLQ-C30 change from baseline to week 12, the confirmed improvement rate, and the time to improvement or deterioration. KEY FINDINGS AND LIMITATIONS: Baseline PRO compliance rates were 91% for the EV arm (n = 301) and 89% for the chemotherapy arm (n = 307); the corresponding average rates from baseline to week 12 were 70% and 67%. Patients receiving EV versus chemotherapy had reduced pain (difference in change from baseline to week 12: -5.7, 95% confidence interval [CI] -10.8 to -0.7; p = 0.027) and worsening appetite loss (7.3, 95% CI 0.90-13.69; p = 0.026). Larger proportions of patients in the EV arm reported HRQoL improvement from baseline than in the chemotherapy arm; the odds of a confirmed improvement across ten QLQ-C30 function/symptom scales were 1.67 to 2.76 times higher for EV than for chemotherapy. Patients in the EV arm had a shorter time to first confirmed improvement in global health status (GHS)/QoL, fatigue, pain, and physical, role, emotional, and social functioning (all p < 0.05). EV delayed the time to first confirmed deterioration in GHS/QoL (p = 0.027), but worsening appetite loss occurred earlier (p = 0.009) in comparison to chemotherapy. CONCLUSIONS AND CLINICAL IMPLICATIONS: HRQoL with EV was maintained, and deterioration in HRQoL was delayed with EV in comparison to chemotherapy. Better results with EV were reported for some scales, with the greatest difference observed for pain. These findings reinforce the EV safety and efficacy outcomes and benefits observed in EV-301. PATIENT SUMMARY: Patients with previously treated advanced cancer of the urinary tract receiving the drug enfortumab vedotin maintained their HRQoL in comparison to patients treated with chemotherapy. The EV-301 trial is registered on ClinicalTrials.gov as NCT03474107 and on EudraCT as 2017-003344-21.
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Anticuerpos Monoclonales , Carcinoma de Células Transicionales , Medición de Resultados Informados por el Paciente , Calidad de Vida , Humanos , Masculino , Femenino , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/patología , Anticuerpos Monoclonales/uso terapéutico , Anciano , Persona de Mediana Edad , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Antineoplásicos/uso terapéutico , Antineoplásicos/efectos adversosRESUMEN
INTRODUCTION: Many patients with muscle-invasive bladder cancer are poor candidates for radical cystectomy or trimodality therapy with maximal transurethral resection of bladder tumor (TURBT) and chemoradiotherapy with cisplatin or mitomycin C. Given the benefit of chemotherapy in bladder-preserving therapy, less-intense concurrent chemotherapy regimens are needed. This study reports on efficacy and toxicity for patients treated with trimodality therapy using single-agent concurrent capecitabine. MATERIALS AND METHODS: Patients deemed ineligible for radical cystectomy or standard chemoradiotherapy by a multidisciplinary tumor board and patients who refused cystectomy were included. Following TURBT, patients received twice-daily capecitabine (goal dose 825 mg/m2) concurrent with radiotherapy to the bladder +/- pelvis depending on nodal staging and patient risk factors. Toxicity was evaluated prospectively in weekly on-treatment visits and follow-up visits by the treating physicians. Descriptive statistics are provided. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival were estimated using the Kaplan-Meier method. RESULTS: Twenty-seven consecutive patients met criteria for inclusion from 2013 to 2023. The median age was 79 with 9 patients staged cT3-4a and 7 staged cN1-3. The rate of complete response in the bladder and pelvis was 93%. Overall, progression-free, cancer-specific, distant metastasis-free, and bladder recurrence-free survival at 2 years were estimated as 81%, 65%, 91%, 75%, and 92%, respectively. There were 2 bladder recurrences, both noninvasive. There were 7 grade 3 acute hematologic or metabolic events but no other grade 3+ toxicities. CONCLUSION: Maximal TURBT followed by radiotherapy with concurrent capecitabine offers a high rate of bladder control and low rates of acute and late toxicity.
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Neoplasias de la Vejiga Urinaria , Vejiga Urinaria , Humanos , Anciano , Capecitabina/efectos adversos , Terapia Combinada , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Cisplatino/uso terapéutico , Cistectomía , Invasividad NeoplásicaRESUMEN
PURPOSE: Locally advanced/metastatic urothelial cancer (la/mUC) affects patients' quality of life (QOL) and functioning. We describe the impact of first-line (1L) enfortumab vedotin (EV) alone or with pembrolizumab (P) on QOL/functioning/symptoms in patients with la/mUC who were cisplatin-ineligible from EV-103 Cohort K. METHODS: In this phase Ib/II trial, patients were randomly assigned 1:1 to EV + P or EV monotherapy (mono). Exploratory patient-reported outcomes (PROs) were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core Questionnaire (EORTC QLQ-C30) and Brief Pain Inventory Short Form (BPI-SF) at baseline, once per week for cycles 1-3, and then in every cycle through the end of treatment. Changes in scores from baseline to week 24, reported as least squares mean (standard error), were assessed by mixed models for repeated measures. There were no formal statistical comparisons between treatment arms. RESULTS: Of 149 patients treated, 65 (EV + P) and 63 (EV mono) comprised the PRO analysis set. For EV + P, EORTC QLQ-C30 QOL was maintained through week 24 with improvements in emotional functioning, pain, and insomnia. Clinically meaningful improvements were seen in EORTC QLQ-C30 pain after EV + P at weeks 12 (-14.41 [3.14]) and 24 (-14.99 [3.56]) and BPI-SF worst pain at week 24 (-2.07 [0.37]). For EV mono, EORTC QLQ-C30 QOL remained stable with clinically meaningful improvements in EORTC QLQ-C30 pain (-12.55 [4.27]), insomnia (-14.46 [4.69]), and constipation (-10.09 [4.35]) at week 24. There were small-to-moderate improvements in BPI-SF worst pain at week 24. CONCLUSION: EV + P in patients with la/mUC who were cisplatin-ineligible was associated with preservation or improvement of QOL/functioning/symptoms. Improvement in pain was seen in both PRO instruments and treatment arms. These data complement clinical outcomes of 1L EV + P.
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Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales , Carcinoma de Células Transicionales , Trastornos del Inicio y del Mantenimiento del Sueño , Humanos , Cisplatino , Dolor , Medición de Resultados Informados por el Paciente , Calidad de Vida/psicologíaRESUMEN
Great strides have been made in the past decade to lower barriers to clinical pharmacogenomics implementation. Nevertheless, PGx consultation prior to prescribing therapeutics is not yet mainstream. This review addresses the current climate surrounding PGx implementation, focusing primarily on strategies for implementation at academic institutions, particularly at The University of Chicago, and provides an up-to-date guide of resources supporting the development of PGx programs. Remaining challenges and recent strategies for overcoming these challenges to implementation are discussed.
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Farmacogenética , Medicina de Precisión , HumanosRESUMEN
BACKGROUND: IMvigor130 demonstrated statistically significant investigator-assessed progression-free survival benefit with first-line atezolizumab plus platinum-based chemotherapy (group A) versus placebo plus platinum-based chemotherapy (group C) in patients with locally advanced or metastatic urothelial carcinoma. Overall survival was not improved in interim analyses. Here we report the final overall analysis for group A versus group C. METHODS: In this global, partially blinded, randomised, controlled, phase 3 study, patients (aged ≥18 years) with previously untreated locally advanced or metastatic urothelial cancer and who had an Eastern Cooperative Oncology Group performance status of 0-2 were enrolled at 221 hospitals and oncology centres in 35 countries. Patients were randomly assigned (1:1:1), with a permuted block method (block size of six) and an interactive voice and web response system, stratified by PD-L1 status, Bajorin risk factor score, and investigator's choice of platinum-based chemotherapy, to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Sponsors, investigators, and patients were masked to assignment to atezolizumab or placebo (ie, group A and group C) and atezolizumab monotherapy (group B) was open label. For groups A and C, all patients received gemcitabine (1000 mg/m2 intravenously; day 1 and day 8 of each 21-day cycle), plus investigator's choice of carboplatin (area under curve 4·5 mg/mL per min or 5 mg/mL per min; intravenously) or cisplatin (70 mg/m2 intravenously), plus either atezolizumab (1200 mg intravenously) or placebo on day 1 of each cycle. Co-primary endpoints of the study were investigator-assessed progression-free survival and overall survival for group A versus group C in the intention-to-treat (ITT) population (ie, all randomised patients), and overall survival for group B versus group C, tested hierarchically. Final overall survival and updated safety outcomes (safety population; all patients who received any amount of any study treatment component) for group A versus group C are reported here. The final prespecified boundary for significance of the overall survival analysis was one-sided p=0·021. The trial is registered with ClinicalTrials.gov, NCT02807636, and is active but no longer recruiting. FINDINGS: Between July 15, 2016, and July 20, 2018, 1213 patients were enrolled and randomly assigned to treatment, of whom 851 were assigned to group A (n=451) and group C (n=400). 338 (75%) patients in group A and 298 (75%) in group C were male, 113 (25%) in group A and 102 (25%) in group C were female, and 346 (77%) in group A and 304 (76%) in group C were White. At data cutoff (Aug 31, 2022), after a median follow up of 13·4 months (IQR 6·2-30·8), median overall survival was 16·1 months (95% CI 14·2-18·8; 336 deaths) in group A versus 13·4 months (12·0-15·3; 310 deaths) in group C (stratified hazard ratio 0·85 [95% CI 0·73-1·00]; one-sided p=0·023). The most common grade 3-4 treatment-related adverse events were anaemia (168 [37%] of 454 patients who received atezolizumab plus chemotherapy vs 133 [34%] of 389 who received placebo plus chemotherapy), neutropenia (167 [37%] vs 115 [30%]), decreased neutrophil count (98 [22%] vs 95 [24%]), thrombocytopenia (95 [21%] vs 70 [18%]), and decreased platelet count (92 [20%] vs 92 [24%]). Serious adverse events occurred in 243 (54%) patients who received atezolizumab plus chemotherapy and 196 (50%) patients who received placebo plus chemotherapy. Treatment-related deaths occurred in nine (2%; acute kidney injury, dyspnoea, hepatic failure, hepatitis, neutropenia, pneumonitis, respiratory failure, sepsis, and thrombocytopenia [n=1 each]) patients who received atezolizumab plus chemotherapy and four (1%; unexplained death, diarrhoea, febrile neutropenia, and toxic hepatitis [n=1 each]) who received placebo plus chemotherapy. INTERPRETATION: Progression-free survival benefit with first-line combination of atezolizumab plus platinum-based chemotherapy did not translate into a significant improvement in overall survival in the ITT population of IMvigor130. Further research is needed to understand which patients might benefit from first-line combination treatment. No new safety signals were observed. FUNDING: F Hoffmann-La Roche.
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Carcinoma de Células Transicionales , Neutropenia , Trombocitopenia , Neoplasias de la Vejiga Urinaria , Humanos , Masculino , Femenino , Adolescente , Adulto , Carcinoma de Células Transicionales/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Análisis de Supervivencia , Platino (Metal)/uso terapéutico , Método Doble CiegoRESUMEN
PURPOSE: Poly (ADP-ribose) polymerase (PARP) inhibitors have demonstrated clinical benefit for patients with solid tumors bearing germline or somatic alterations in DNA damage response (DDR) genes. Somatic alterations in DDR genes are common in advanced urothelial cancer, raising the possibility that PARP inhibition may confer therapeutic benefit in a molecularly selected subgroup of patients with metastatic urothelial cancer (mUC). METHODS: This single-arm, open-label, multi-institutional, investigator-initiated phase II study evaluated the antitumor activity of olaparib 300 mg twice a day in participants with mUC harboring somatic DDR alterations. Patients had progressed despite previous platinum-based chemotherapy, or were cisplatin-ineligible, and harbored somatic alterations in at least one of a prespecified list of DDR genes. The primary end point was objective response rate; secondary end points were safety, progression-free survival (PFS), and overall survival (OS). RESULTS: Overall, 19 patients with mUC were enrolled and received olaparib; the trial closed early before slow accrual. The median age was 66 years (range, 45-82). Nine patients (47.4%) had received previous cisplatin chemotherapy. Ten patients (52.6%) had alterations in homologous recombination (HR) genes: eight patients (42.1%) had pathogenic BRCA2 mutations and two patients carried alterations in other HR genes. No patients achieved a partial response although six patients achieved stable disease lasting 2.13-16.1 months (median, 7.69). The median PFS was 1.9 months (range, 0.8-16.1), and the median OS was 9.5 months (range, 1.5-22.1). CONCLUSION: Single-agent olaparib showed limited antitumor activity in patients with mUC and DDR alterations, which may be related to poorly characterized functional implications of particular DDR alterations and/or cross-resistance with platinum-based chemotherapy in a disease where such therapy represents standard first-line treatment.
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Inhibidores de Poli(ADP-Ribosa) Polimerasas , Neoplasias Urológicas , Anciano , Anciano de 80 o más Años , Humanos , Persona de Mediana Edad , Cisplatino , Daño del ADN , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Neoplasias Urológicas/tratamiento farmacológico , Urotelio/patologíaRESUMEN
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
Pharmacogenomics is a crucial piece of personalized medicine. Preemptive pharmacogenomic testing is only used sparsely in the inpatient setting and there are few models to date for fostering the adoption of pharmacogenomic treatment in the inpatient setting. We created a multi-institutional project in Chicago to enable the translation of pharmacogenomics into inpatient practice. We are reporting our implementation process and barriers we encountered with solutions. This study, 'Implementation of Point-of-Care Pharmacogenomic Decision Support Accounting for Minority Disparities', sought to implement pharmacogenomics into inpatient practice at three sites: The University of Chicago, Northwestern Memorial Hospital, and the University of Illinois at Chicago. This study involved enrolling African American adult patients for preemptive genotyping across a panel of actionable germline variants predicting drug response or toxicity risk. We report our approach to implementation and the barriers we encountered engaging hospitalists and general medical providers in the inpatient pharmacogenomic intervention. Our strategies included: a streamlined delivery system for pharmacogenomic information, attendance at hospital medicine section meetings, use of physician and pharmacist champions, focus on hospitalists' care and optimizing system function to fit their workflow, hand-offs, and dealing with hospitalists turnover. Our work provides insights into strategies for the initial engagement of inpatient general medicine providers that we hope will benefit other institutions seeking to implement pharmacogenomics in the inpatient setting.
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Pacientes Internos , Farmacogenética , Adulto , Humanos , Medicina de Precisión , Pruebas de Farmacogenómica , FarmacéuticosRESUMEN
Urothelial Cancer - Genomic Analysis to Improve Patient Outcomes and Research (NCT02643043), UC-GENOME, is a genomic analysis and biospecimen repository study in 218 patients with metastatic urothelial carcinoma. Here we report on the primary outcome of the UC-GENOME-the proportion of subjects who received next generation sequencing (NGS) with treatment options-and present the initial genomic analyses and clinical correlates. 69.3% of subjects had potential treatment options, however only 5.0% received therapy based on NGS. We found an increased frequency of TP53E285K mutations as compared to non-metastatic cohorts and identified features associated with benefit to chemotherapy and immune checkpoint inhibition, including: Ba/Sq and Stroma-rich subtypes, APOBEC mutational signature (SBS13), and inflamed tumor immune phenotype. Finally, we derive a computational model incorporating both genomic and clinical features predictive of immune checkpoint inhibitor response. Future work will utilize the biospecimens alongside these foundational analyses toward a better understanding of urothelial carcinoma biology.
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Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Humanos , Carcinoma de Células Transicionales/genética , Genómica , Secuenciación de Nucleótidos de Alto Rendimiento , Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
The present study builds on our prior work that demonstrated an association between pharmacogenetic interactions and 90-day readmission. In a substantially larger, more diverse study population of 19,999 adults tracked from 2010 through 2020 who underwent testing with a 13-gene pharmacogenetic panel, we included additional covariates to evaluate aggregate contribution of social determinants and medical comorbidity with the presence of identified gene-x-drug interactions to moderate 90-day hospital readmission (primary outcome). Univariate logistic regression analyses demonstrated that strongest associations with 90 day hospital readmissions were the number of medications prescribed within 30 days of a first hospital admission that had Clinical Pharmacogenomics Implementation Consortium (CPIC) guidance (CPIC medications) (5+ CPIC medications, odds ratio (OR) = 7.66, 95% confidence interval 5.45−10.77) (p < 0.0001), major comorbidities (5+ comorbidities, OR 3.36, 2.61−4.32) (p < 0.0001), age (65 + years, OR = 2.35, 1.77−3.12) (p < 0.0001), unemployment (OR = 2.19, 1.88−2.64) (p < 0.0001), Black/African-American race (OR 2.12, 1.47−3.07) (p < 0.0001), median household income (OR = 1.63, 1.03−2.58) (p = 0.035), male gender (OR = 1.47, 1.21−1.80) (p = 0.0001), and one or more gene-x-drug interaction (defined as a prescribed CPIC medication for a patient with a corresponding actionable pharmacogenetic variant) (OR = 1.41, 1.18−1.70). Health insurance was not associated with risk of 90-day readmission. Race, income, employment status, and gene-x-drug interactions were robust in a multivariable logistic regression model. The odds of 90-day readmission for patients with one or more identified gene-x-drug interactions after adjustment for these covariates was attenuated by 10% (OR = 1.31, 1.08−1.59) (p = 0.006). Although the interaction between race and gene-x-drug interactions was not statistically significant, White patients were more likely to have a gene-x-drug interaction (35.2%) than Black/African-American patients (25.9%) who were not readmitted (p < 0.0001). These results highlight the major contribution of social determinants and medical complexity to risk for hospital readmission, and that these determinants may modify the effect of gene-x-drug interactions on rehospitalization risk.
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The integration of genomic data into personalized treatment planning has revolutionized oncology care. Despite this, patients with cancer remain vulnerable to high rates of adverse drug events and medication inefficacy, affecting prognosis and quality of life. Pharmacogenomics is a field seeking to identify germline genetic variants that contribute to an individual's unique drug response. Although there is widespread integration of genomic information in oncology, somatic platforms, rather than germline biomarkers, have dominated the attention of cancer providers. Patients with cancer potentially stand to benefit from improved integration of both somatic and germline genomic information, especially because the latter may complement treatment planning by informing toxicity risk for drugs with treatment-limiting tolerabilities and narrow therapeutic indices. Although certain germline pharmacogenes, such as TPMT, UGT1A1, and DPYD, have been recognized for decades, recent attention has illuminated modern potential dosing implications for a whole new set of anticancer agents, including targeted therapies and antibody-drug conjugates, as well as the discovery of additional genetic variants and newly relevant pharmacogenes. Some of this information has risen to the level of directing clinical action, with US Food and Drug Administration label guidance and recommendations by international societies and governing bodies. This review is focused on key new pharmacogenomic evidence and oncology-specific dosing recommendations. Personalized oncology care through integrated pharmacogenomics represents a unique multidisciplinary collaboration between oncologists, laboratory science, bioinformatics, pharmacists, clinical pharmacologists, and genetic counselors, among others. The authors posit that expanded consideration of germline genetic information can further transform the safe and effective practice of oncology in 2022 and beyond.
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Neoplasias , Farmacogenética , Células Germinativas , Humanos , Oncología Médica , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Calidad de VidaRESUMEN
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
Enfortumab vedotin is a first-in-class Nectin-4-directed antibody-drug conjugate approved by the US Food and Drug Administration for the treatment of patients with locally advanced or metastatic urothelial cancer (la/mUC) previously treated with a platinum-based chemotherapy and a programmed death receptor-1/programmed death-ligand 1 (PD-1/L1) inhibitor, or patients with la/mUC who are ineligible for cisplatin-based chemotherapy and have previously received one or more prior lines of therapy. Enfortumab vedotin is the only drug to have demonstrated survival benefit versus chemotherapy in a randomized controlled trial in patients with la/mUC previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor. The development of dermatologic events following the administration of enfortumab vedotin is anticipated given the expression of Nectin-4 in epidermal keratinocytes and skin appendages (eg, sweat glands and hair follicles). There is the potential for rare but severe and possibly fatal cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrosis, as described in the boxed warning of the US prescribing information for enfortumab vedotin. This manuscript describes the presumed pathophysiology and manifestations of dermatologic reactions related to enfortumab vedotin, and presents recommendations for prevention and treatment, to provide oncologists and other healthcare providers with an awareness of these potential adverse events to best anticipate and manage them.
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Carcinoma de Células Transicionales , Inmunoconjugados , Neoplasias Urológicas , Anticuerpos Monoclonales , Carcinoma de Células Transicionales/tratamiento farmacológico , Moléculas de Adhesión Celular/metabolismo , Moléculas de Adhesión Celular/uso terapéutico , Femenino , Humanos , Inmunoconjugados/efectos adversos , Masculino , Nectinas , Platino (Metal)/uso terapéutico , Receptor de Muerte Celular Programada 1/uso terapéutico , Neoplasias Urológicas/tratamiento farmacológicoRESUMEN
BACKGROUND: The EV-201 trial (NCT03219333) demonstrated a clinically meaningful and durable response rate and a tolerable safety profile with enfortumab vedotin (EV) in patients with locally advanced/metastatic urothelial carcinoma (LA/mUC) treated with prior PD-1/PD-L1 inhibitor therapy and platinum-containing chemotherapy (cohort 1). Patient-reported outcome (PRO) measures were included in EV-201 as exploratory endpoints. OBJECTIVE: To evaluate PRO data for cohort 1 of EV-201 to better understand the relationship between EV therapy and health-related quality of life (HRQoL). DESIGN, SETTING, AND PARTICIPANTS: Enrolled patients with LA/mUC who received EV were invited to electronically complete two HRQoL instruments (EORTC QLQ-C30 and EQ-5D-3L) at baseline and day 1 of each cycle until treatment discontinuation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patient demographics, completion and compliance rates, and PRO scores were analysed using descriptive statistics. Selected EORTC QLQ-C30 scores were analysed post hoc using a repeated-measures mixed model. RESULTS AND LIMITATIONS: Among treated patients (n = 125), 95% completed both baseline questionnaires. Compliance rates were ≥86% throughout the study. Descriptive analyses showed that global health status, physical functioning, and symptom scores remained stable over time, with average scores similar at each cycle. Lower pain and fatigue scores were observed in responders at cycles following an objective response. Pain was lower at cycle 3 than at baseline in patients with bone metastases. Mean EQ-5D-3L utility score (0.80 at baseline; range from 0.77 at cycle 2 to 0.91 at cycle 10) and visual analogue scale scores (66.9 at baseline; range from 65.5 at cycle 2 to 78.4 at cycle 10) remained similar over time. Variability and the small sample size limited definitive conclusions. CONCLUSIONS: PRO scores remained stable throughout EV treatment, further supporting the overall value of EV in the treatment of patients with LA/mUC. The potential benefit of EV therapy on overall HRQoL and symptoms such as pain and fatigue is currently being explored. PATIENT SUMMARY: In this study of adult patients with advanced cancer of the urinary tract that progressed after previous medications, quality of life, ability to function, and symptoms did not worsen on treatment with enfortumab vedotin, which is an antibody + drug combination. Some improvements in pain and fatigue were reported by patients, but further research needs to be conducted. These data complement the efficacy and safety data from the EV-201 trial.
Asunto(s)
Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Adulto , Anticuerpos Monoclonales , Carcinoma de Células Transicionales/tratamiento farmacológico , Fatiga , Femenino , Humanos , Inhibidores de Puntos de Control Inmunológico , Masculino , Dolor , Platino (Metal)/uso terapéutico , Receptor de Muerte Celular Programada 1 , Calidad de Vida , Neoplasias de la Vejiga Urinaria/tratamiento farmacológicoRESUMEN
BACKGROUND: Pharmacogenomics, which offers a potential means by which to inform prescribing and avoid adverse drug reactions, has gained increasing consideration in other medical settings but has not been broadly evaluated during perioperative care. METHODS: The Implementation of Pharmacogenomic Decision Support in Surgery (ImPreSS) Trial is a prospective, single-center study consisting of a prerandomization pilot and a subsequent randomized phase. We describe findings from the pilot period. Patients planning elective surgeries were genotyped with pharmacogenomic results, and decision support was made available to anesthesia providers in advance of surgery. Pharmacogenomic result access and prescribing records were analyzed. Surveys (Likert-scale) were administered to providers to understand utilization barriers. RESULTS: Of eligible anesthesiology providers, 166 of 211 (79%) enrolled. A total of 71 patients underwent genotyping and surgery (median, 62 years; 55% female; average American Society of Anesthesiologists (ASA) score, 2.6; 58 inpatients and 13 ambulatories). No patients required postoperative intensive care or pain consultations. At least 1 provider accessed pharmacogenomic results before or during 41 of 71 surgeries (58%). Faculty were more likely to access results (78%) compared to house staff (41%; P = .003) and midlevel practitioners (15%) ( P < .0001). Notably, all administered intraoperative medications had favorable genomic results with the exception of succinylcholine administration to 1 patient with genomically increased risk for prolonged apnea (without adverse outcome). Considering composite prescribing in preoperative, recovery, throughout hospitalization, and at discharge, each patient was prescribed a median of 35 (range 15-83) total medications, 7 (range 1-22) of which had annotated pharmacogenomic results. Of 2371 prescribing events, 5 genomically high-risk medications were administered (all tramadol or omeprazole; with 2 of 5 pharmacogenomic results accessed), and 100 genomically cautionary mediations were administered (hydralazine, oxycodone, and pantoprazole; 61% rate of accessing results). Providers reported that although results were generally easy to access and understand, the most common reason for not considering results was because remembering to access pharmacogenomic information was not yet a part of their normal clinical workflow. CONCLUSIONS: Our pilot data for result access rates suggest interest in pharmacogenomics by anesthesia providers, even if opportunities to alter prescribing in response to high-risk genotypes were infrequent. This pilot phase has also uncovered unique considerations for implementing pharmacogenomic information in the perioperative care setting, and new strategies including adding the involvement of surgery teams, targeting patients likely to need intensive care and dedicated pain care, and embedding pharmacists within rounding models will be incorporated in the follow-on randomized phase to increase engagement and likelihood of affecting prescribing decisions and clinical outcomes.
Asunto(s)
Farmacogenética , Tramadol , Humanos , Femenino , Masculino , Farmacogenética/métodos , Estudios Prospectivos , Oxicodona , Pantoprazol , Succinilcolina , Atención Perioperativa , Dolor , Hidralazina , OmeprazolRESUMEN
BACKGROUND: In recent years, there has been increasing evidence supporting the role of germline pharmacogenomic factors predicting toxicity for anticancer therapies. Although somatic genomic data are used frequently in oncology care planning, germline pharmacogenomic testing is not. This study hypothesizes that comprehensive germline pharmacogenomic profiling could have high relevance for cancer care. METHODS: Between January 2011 and August 2020, patients at the University of Chicago Medical Center were genotyped across custom germline pharmacogenomic panels for reasons unrelated to cancer care. Actionable anticancer pharmacogenomic gene/drug interactions identified by the FDA were defined including: CYP2C9 (erdafitinib), CYP2D6 (gefitinib), DPYD (5-fluorouracil and capecitabine), TPMT (thioguanine and mercaptopurine), and UGT1A1 (belinostat, irinotecan, nilotinib, pazopanib, and sacituzumab-govitecan hziy). The primary objective was to determine the frequency of individuals with actionable or high-risk genotypes across these 5 key pharmacogenes, thus potentially impacting prescribing for at least 1 of these 11 commonly prescribed anticancer therapies. RESULTS: Data from a total of 1586 genotyped individuals were analyzed. The oncology pharmacogene with the highest prevalence of high-risk, actionable genotypes was UGT1A1, impacting 17% of genotyped individuals. Actionable TPMT and DPYD genotypes were found in 9% and 4% of patients, respectively. Overall, nearly one-third of patients genotyped across all 5 genes (161/525, 31%) had at least one actionable genotype. CONCLUSIONS: These data suggest that germline pharmacogenomic testing for 5 key pharmacogenes could identify a substantial proportion of patients at risk with standard dosing, an estimated impact similar to that of somatic genomic profiling. LAY SUMMARY: Differences in our genes may explain why some drugs work safely in certain individuals but can cause side effects in others. Pharmacogenomics is the study of how genetic variations affect an individual's response to medications. In this study, an evaluation was done for important genetic variations that can affect the tolerability of anticancer therapy. By analyzing the genetic results of >1500 patients, it was found that nearly one-third have genetic variations that could alter recommendations of what drug, or how much of, an anticancer therapy they should be given. Performing pharmacogenomic testing before prescribing could help to guide personalized oncology care.
Asunto(s)
Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Pruebas de Farmacogenómica , Citocromo P-450 CYP2D6/genética , Genotipo , Humanos , Farmacogenética , Pruebas de Farmacogenómica/métodosRESUMEN
OBJECTIVES: Integration of pharmacogenomics into clinical care is being studied in multiple disciplines. We hypothesized that understanding attitudes and perceptions of anesthesiologists, critical care and pain medicine providers would uncover unique considerations for future implementation within perioperative care. METHODS: A survey (multiple choice and Likert-scale) was administered to providers within our Department of Anesthesia and Critical Care prior to initiation of a department-wide prospective pharmacogenomics implementation program. The survey addressed knowledge, perceptions, experiences, resources and barriers. RESULTS: Of 153 providers contacted, 149 (97%) completed the survey. Almost all providers (92%) said that genetic results influence drug therapy, and few (22%) were skeptical about the usefulness of pharmacogenomics. Despite this enthusiasm, 87% said their awareness about pharmacogenomic information is lacking. Feeling well-informed about pharmacogenomics was directly related to years in practice/experience: only 38% of trainees reported being well-informed, compared to 46% of those with 1-10 years of experience, and nearly two-thirds with 11+ years (P < 0.05). Regarding barriers, providers reported uncertainty about availability of testing, turnaround time and whether testing is worth financial costs. CONCLUSIONS: Anesthesiology, critical care and pain medicine providers are optimistic about the potential clinical utility of pharmacogenomics, but are uncertain about practical aspects of testing and desire clear guidelines on the use of results. These findings may inform future institutional efforts toward greater integration of genomic results to improve medication-related outcomes.