Exposure-Response and Subgroup Analyses to Support Body Weight-Based Dosing of Brentuximab Vedotin in Children and Young Adults with Newly Diagnosed High-Risk Classical Hodgkin Lymphoma.

PURPOSE: To evaluate the relationships between brentuximab vedotin (BV) pharmacokinetics, age, and body weight (BW) with efficacy and safety in pediatric and young adult patients with previously untreated, high-risk classical Hodgkin lymphoma (cHL) in the phase 3 AHOD1331 study. PATIENTS AND METHODS: Overall, 296 patients (age 2-21 years) in the overall population were randomized to and received BV + chemotherapy; the pharmacokinetic subpopulation comprised 24 patients (age <13 years). Age- and/or BW-based (pharmacokinetic surrogates) subgroup analyses of efficacy and safety were conducted for the overall population. Exposure-response analyses were limited to the pharmacokinetic subpopulation. RESULTS: There were no visible trends in disease characteristics across pediatric age subgroups, while BW increased with age. Observed antibody-drug conjugate exposures in patients aged <12 years were lower than those in adults administered BV 1.8 mg/kg every 3 weeks (Q3W), as exposure increased with BW. Nevertheless, no detrimental impact on event-free survival (EFS) was seen in younger subgroups: 3-year EFS was 96.2% (2-<12-years) and 92.0% (12-<18-years), with no events observed in those aged <6 years. Neither early response nor lack of need for radiation therapy was associated with high pharmacokinetic exposure. No evidence of exposure-driven grade ≥2 or ≥3 peripheral neuropathy or grade ≥3 neutropenia was seen in exposure-safety and BW-based subgroup analyses; the incidence of these safety events was comparable across pediatric age subgroups, despite lower exposure in younger children. CONCLUSIONS: No further adjustments based on age or BW are required for the BV dose (1.8 mg/kg Q3W) approved in children.

Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer.

BACKGROUND: No treatment has surpassed platinum-based chemotherapy in improving overall survival in patients with previously untreated locally advanced or metastatic urothelial carcinoma. METHODS: We conducted a phase 3, global, open-label, randomized trial to compare the efficacy and safety of enfortumab vedotin and pembrolizumab with the efficacy and safety of platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. Patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of enfortumab vedotin (at a dose of 1.25 mg per kilogram of body weight intravenously on days 1 and 8) and pembrolizumab (at a dose of 200 mg intravenously on day 1) (enfortumab vedotin-pembrolizumab group) or gemcitabine and either cisplatin or carboplatin (determined on the basis of eligibility to receive cisplatin) (chemotherapy group). The primary end points were progression-free survival as assessed by blinded independent central review and overall survival. RESULTS: A total of 886 patients underwent randomization: 442 to the enfortumab vedotin-pembrolizumab group and 444 to the chemotherapy group. As of August 8, 2023, the median duration of follow-up for survival was 17.2 months. Progression-free survival was longer in the enfortumab vedotin-pembrolizumab group than in the chemotherapy group (median, 12.5 months vs. 6.3 months; hazard ratio for disease progression or death, 0.45; 95% confidence interval [CI], 0.38 to 0.54; P<0.001), as was overall survival (median, 31.5 months vs. 16.1 months; hazard ratio for death, 0.47; 95% CI, 0.38 to 0.58; P<0.001). The median number of cycles was 12 (range, 1 to 46) in the enfortumab vedotin-pembrolizumab group and 6 (range, 1 to 6) in the chemotherapy group. Treatment-related adverse events of grade 3 or higher occurred in 55.9% of the patients in the enfortumab vedotin-pembrolizumab group and in 69.5% of those in the chemotherapy group. CONCLUSIONS: Treatment with enfortumab vedotin and pembrolizumab resulted in significantly better outcomes than chemotherapy in patients with untreated locally advanced or metastatic urothelial carcinoma, with a safety profile consistent with that in previous reports. (Funded by Astellas Pharma US and others; EV-302 ClinicalTrials.gov number, NCT04223856.).

Safety and Clinical Activity of Atezolizumab in Patients with Metastatic Castration-Resistant Prostate Cancer: A Phase I Study.

PURPOSE: Atezolizumab [anti-programmed death-ligand 1 (anti-PD-L1)] is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of atezolizumab monotherapy for mCRPC. PATIENTS AND METHODS: This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments. RESULTS: All 35 evaluable patients [median age, 68 years (range, 45-83 years)] received atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months [95% confidence interval (CI): 5.9-not evaluable], with a 1-year OS rate of 52.3% (95% CI: 34-70); 2-year OS was 35.9% (95% CI: 13-59). Median follow-up was 13.0 months (range, 1.2-28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy. CONCLUSIONS: Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.

Real-world practice patterns in veterans with metastatic castration-resistant prostate cancer.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) is incurable, with most patients surviving less than 3 years. However, many treatments that extend survival have been approved in the past decade. OBJECTIVE: To describe the patient demographics, disease characteristics, treatment patterns, and outcomes in a cohort of Veterans diagnosed with mCRPC in the Veterans Health Administration. DESIGN: We identified 3,637 Veterans diagnosed with prostate cancer between January 2006 and August 2015 with evidence of mCRPC through December 2016. We described the most commonly used systemic mCRPC treatments according to mCRPC diagnosis era: Epoch 1 (2006-2010) or Epoch 2 (2011-2016). Patient demographics, disease characteristics, and treatment patterns were examined using descriptive statistics. An unadjusted Kaplan-Meier method was used to estimate the median time to biochemical progression and overall survival (OS) with 95% confidence intervals. RESULTS: The median age at initial prostate cancer diagnosis was 68 years. Approximately 67% of patients were non-Hispanic white, 29% were black, and 4% were other/unknown. A high-risk Gleason score (8-10) was reported in 748 (67%) of patients in Epoch 1 and 1578 (63%) of patients in Epoch 2, and the median prostate-specific antigen level at initial prostate cancer diagnosis was higher in Epoch 1 patients than in Epoch 2 patients (68 vs. 35 ng/ml). Following mCRPC diagnosis, the most common first-line therapies in Epoch 1 patients were docetaxel (83%) and abiraterone (9%), whereas Epoch 2 patients mainly received abiraterone (47%), docetaxel (36%), and enzalutamide (15%). In Epoch 1 and Epoch 2 patients, the median time to biochemical progression (unadjusted) was 9 and 13 months, respectively, and the median OS (unadjusted) was 15 and 23 months, respectively. CONCLUSIONS: The introduction of new therapies has resulted in increased use of the noncytotoxic agents abiraterone and enzalutamide as first-line treatment in lieu of docetaxel. Our results suggest that more recently diagnosed patients (Epoch 2) have a delayed time to biochemical progression and longer OS (unadjusted) compared with patients diagnosed earlier (Epoch 1).

First-in-Human, First-in-Class Phase I Trial of the Anti-CD47 Antibody Hu5F9-G4 in Patients With Advanced Cancers.

PURPOSE: To evaluate the safety, pharmacokinetics, and pharmacodynamics of Hu5F9-G4 (5F9), a humanized IgG4 antibody that targets CD47 to enable phagocytosis. PATIENTS AND METHODS: Adult patients with solid tumors were treated in four cohorts: part A, to determine a priming dose; part B, to determine a weekly maintenance dose; part C, to study a loading dose in week 2; and a tumor biopsy cohort. RESULTS: Sixty-two patients were treated: 11 in part A, 14 in B, 22 in C, and 15 in the biopsy cohort. Part A used doses that ranged from 0.1 to 3 mg/kg. On the basis of tolerability and receptor occupancy studies that showed 100% CD47 saturation on RBCs, 1 mg/kg was selected as the priming dose. In subsequent groups, patients were treated with maintenance doses that ranged from 3 to 45 mg/kg, and most toxicities were mild to moderate. These included transient anemia (57% of patients), hemagglutination on peripheral blood smear (36%), fatigue (64%), headaches (50%), fever (45%), chills (45%), hyperbilirubinemia (34%), lymphopenia (34%), infusion-related reactions (34%), and arthralgias (18%). No maximum tolerated dose was reached with maintenance doses up to 45 mg/kg. At doses of 10 mg/kg or more, the CD47 antigen sink was saturated by 5F9, and a 5F9 half-life of approximately 13 days was observed. Strong antibody staining of tumor tissue was observed in a patient at 30 mg/kg. Two patients with ovarian/fallopian tube cancers had partial remissions for 5.2 and 9.2 months. CONCLUSION: 5F9 is well tolerated using a priming dose at 1 mg/kg on day 1 followed by maintenance doses of up to 45 mg/kg weekly.

Incorporating VEGF-targeted therapy in advanced urothelial cancer.

Patients with relapsed or refractory urothelial carcinoma (UC) have poor prognosis coupled with few options for systemic treatment. The role of angiogenesis in the evolution of cancers has been established, and studies have shown that it plays a key role in the pathogenesis of UC. Many targeted agents have been used in phase I-II trials for the treatment of UC, with encouraging but modest results. Recently, studies combining angiogenesis inhibitors with other chemotherapeutic agents were able to achieve objective responses higher than most commonly used second-line therapies in UC. Future efforts in investigating these therapies in UC rely on identification of biomarkers and other predictors of response to anti-VEGF therapy.

Current Standards in Treatment of Radioiodine Refractory Thyroid Cancer.

OPINION STATEMENT: Radioiodine refractory differentiated thyroid cancer (RAI-R DTC) is a challenging malignancy with limited prognosis and treatment options. Recently, clinical trials with targeted therapies have advanced the outlook of these patients, and inhibition of the vascular endothelial growth factor (VEGF) axis has led to the approval of small-molecule tyrosine kinase inhibitors (TKIs) for first-line treatment of radioiodine refractory disease. In addition to approved therapies (sorafenib and lenvatinib), other multi-targeted tyrosine kinase inhibitors that are commercially available have been recognized as viable treatment options for RAI-R DTC. Our preference is to initially use lenvatinib, given the dramatic progression-free survival (PFS) improvement versus placebo, with the caveat that 24 mg daily is not often tolerated and lower doses often used. In patients with BRAF V600E mutation, BRAF inhibitors are now considered for treatment, especially if patients are at high risk from antiangiogenic therapy. Research is continuing to evolve in identifying mechanisms related to radioiodine refractoriness, and trials are evaluating therapeutic molecules to overcome this resistance. Clinical care of patients with RAI-R DTC requires careful consideration of both patient and disease characteristics. Many patients with asymptomatic and indolent disease can be followed for years without treatment while others with high volume or rapidly progressive disease merit early intervention.

Phase II Study of Pazopanib and Paclitaxel in Patients With Refractory Urothelial Cancer.

INTRODUCTION: Currently, no standard treatments are available for relapsed or refractory urothelial carcinoma (UC). Paclitaxel has demonstrated efficacy in the treatment of UC when used alone or combined with other cytotoxic therapies. We designed a phase II trial combining paclitaxel with pazopanib, a commonly used antiangiogenic agent with significant antitumor activity in various solid tumors. PATIENTS AND METHODS: We enrolled 32 patients with refractory UC who had demonstrated disease progression after 2 previous chemotherapeutic regimens. The patients received paclitaxel 80 mg/m2 on days 1, 8, and 15 of a 28-day cycle and oral pazopanib 800 mg daily. The primary endpoint was the overall response rate (ORR). The secondary endpoints included progression-free survival, overall survival, and a safety assessment of the combination. RESULTS: Of the 28 evaluable patients, a complete response was observed in 3 patients and a partial response in 12, with an ORR of 54% (95% confidence interval, 33.9-72.5). The median progression-free and overall survival was 6.2 and 10 months, respectively. The most frequent side effects noted (all grades) were fatigue (63%), diarrhea (44%), and nausea and vomiting (41%). Hematologic toxicities were common and included (all grades) anemia (69%), neutropenia (38%), and thrombocytopenia (47%). Growth factor support was required for 44% of the patients. CONCLUSION: The combination of paclitaxel and pazopanib resulted in a promising ORR of 54% in patients with advanced pretreated UC. This represents a greater response rate and median survival than found with other existing second-line regimens for UC and is worthy of further study.

Role of Somatostatin Analogues in the Treatment of Neuroendocrine Tumors.

Neuroendocrine tumors (NETs) are rare epithelial neoplasms with neuroendocrine differentiation originating most commonly in the lungs and gastroenteropancreatic. Treatment includes surgery and other local therapies; treatment of inoperable disease centers around symptom management and control of tumor growth. Somatostatin analogues (SSAs) have been a mainstay of managing hormone-related symptoms. Emerging evidence suggests that they are effective therapies for tumor control also. Peptide receptor radionuclide therapy with radiolabeled SSAs is a new, promising treatment for inoperable or metastatic NETs. This article reviews the role of SSAs in the treatment of NETs.

Androgen-glucocorticoid interactions in the era of novel prostate cancer therapy.

Great strides have been made in the treatment of castration-resistant prostate cancer (CRPC) with the development of new antiandrogens (enzalutamide) and more potent androgen synthesis inhibitors (abiraterone) that have both improved patient outcomes. These new drugs have also helped unravel the complex biology of androgen-androgen receptor driven prostate cancer and brought into prominence various mechanisms triggering the development of drug resistance and tumour cell survival despite use of androgen deprivation therapy (ADT). The complex role of glucocorticoids in the treatment, management and progression of patients with CRPC is integral to these advances. Historically, glucocorticoid treatment has resulted in both subjective and objective responses in patients with advanced-stage prostate cancer. With the use of these new therapeutic agents, however, unexpected glucocorticoid-related mechanisms that can cause iatrogenic stimulation of prostate cancer growth have emerged, which might contribute to drug resistance and disease progression despite optimal ADT. For example, the upregulation of glucocorticoid receptors (GRs) during enzalutamide therapy results in glucocorticoid-GR-mediated regulation of androgen target genes, leading to escape from enzalutamide blockade. Thus, understanding the biological role of glucocorticoids in patients with prostate cancer is of major importance in the era of new and evolving antiandrogen therapies.

Second-line therapies in metastatic urothelial carcinoma.

Patients with relapsed or refractory urothelial carcinoma (UC) face a poor prognosis and a dearth of available treatment options that improve their survival. End-organ function and performance status play a vital role in the choice of second-line therapies. Evidence supporting the use of cytotoxic chemotherapy, as single agents or in combination, arises from small phase 2 studies with modest responses. With the evolution of genomic testing in UC, several pathways amenable to available targeted therapies have emerged. Encouraging patient participation in clinical trials is critical to improve patient outcomes and to advance the current modest treatment armamentarium.

Role of somatostatin analogues in the treatment of neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare epithelial neoplasms with neuroendocrine differentiation that most commonly originate in the lungs and gastrointestinal tract. Many patients have advanced disease not amenable to surgery or local management. Some tumors also secrete amines, such as serotonin, that lead to syndromes of hormone excess, such as diarrhea and flushing. Thus, management of patients with NETs often requires a dual approach, including hormone symptom management and systemic tumor control. Somatostatin analogues have long been a mainstay of managing the hormone-related symptoms, and increasing evidence also supports their use for tumor control in patients with well-differentiated NETs. This article reviews the role of somatostatin analogues in the treatment of NETs.

Treatment of acute lymphoblastic leukemia in adults.

Acute lymphoblastic leukemia (ALL) in adults is an uncommon but devastating malignant proliferation of lymphoid precursors. Treatment programs for adult patients are largely based on pediatric regimens. However, cure rates in adults have been limited to 30-40% for the past several decades as opposed to the 80% cure rate in children. Treatment of adolescents and young adults is evolving with the adoption of more aggressive "pediatric-inspired" treatment programs. The role of allogeneic stem cell transplant is first remission remains controversial in spite of recent data suggesting improved outcomes in patients younger than 35. Kinase inhibitors in combination with standard chemotherapy have significantly improved outcomes in ALL associated with the Philadelphia chromosome. The treatment of ALL in the elderly remains challenging. Promising new agents such as nelarabine and clofarabine may improve the outlook. This article reviews the current state of the art for the treatment of ALL in adults.

Improvement of psoriasis during sunitinib therapy for renal cell carcinoma.

Sunitinib is an oral tyrosine kinase inhibitor, which is indicated for the treatment of renal cell carcinoma and gastrointestinal stromal tumors. The authors report the case of a patient who underwent treatment for renal cell carcinoma and noted additional benefit by improvement in his psoriatic skin lesions. This may be attributed to the antiangiogenic activity of sunitinib by inhibition of vascular endothelial growth factor receptors.

Gender differences in self-reported use, perceived efficacy, and interest in future use of nicotine-dependence treatments: A cross-sectional survey in adults at a tertiary care center for nicotine dependence.

BACKGROUND: Clinical trials have assessed the effectiveness of nicotine-dependence treatments (NDTs), alone or in combination, and reported that men and women have variable responses to these treatments. The variations in therapeutic responses highlight the need to explore gender-specific preferences for NDTs, including complementary and alternative medicine (CAM), which has become increasingly popular in the US population for the cessation of tobacco use. OBJECTIVE: The aim of this study was to assess gender differences in the self-reported use, perceived efficacy, and interest in future use of NDTs, including CAM, in an outpatient setting. METHODS: This cross-sectional survey was conducted in men and women at a tertiary care NDT clinic. The primary inclusion criterion was the willingness and ability of the patients to participate in the survey. RESULTS: Data from 1171 patients were included (599 men, 572 women; mean age: men, 46.2 years; women, 46.5 years). Of these, 68% of women and 65% of men reported use of nicotine-replacement therapy (NRT), other prescription medication, or counseling/group support. In men and women, NRT was the most commonly used type of pharmacologic treatment, of which the patch was the most popular (77% and 75%). A significantly greater proportion of women than men perceived the nicotine inhaler to be efficacious (67% vs 50%; P = 0.027). No other significant gender differences were found among NRTs. Among non-NRT methods, bupropion sustained release (SR) and counseling/group support were used by significantly more women than men (53% vs 43% [P = 0.007] and 16% vs 11% [P = 0.026], respectively). Compared with men, significantly greater proportions of women reported current or previous use of CAM for nicotine abstinence and expressed an interest in future use of CAM (34% vs 22% [P < 0.001] and 71% vs 64% [P = 0.006]). CONCLUSIONS: In this sample of patients at an NDT clinic, significantly more women than men reported previous use of bupropion SR, counseling, and CAM. More women than men expressed an interest in the future use of CAM. Based on these findings, an improved understanding of gender-based differences in the use of conventional and nonconventional NDTs might improve the rates of success of nicotine-cessation efforts among women.

Use of complementary and alternative medicine treatments by patients with obstructive sleep apnea hypopnea syndrome.

STUDY OBJECTIVES: To assess the proportion of patients with obstructive sleep apnea hypopnea syndrome (OSAHS) reporting previous or current use and interest in future use of complementary and alternative medicine (CAM) therapies. DESIGN: Cross-sectional, point-of-care, anonymous survey. SETTING: Sleep disorders center at a Midwest tertiary care center. PARTICIPANTS: Six hundred forty-six consecutive patients undergoing polysomnography. MEASUREMENTS: The survey instrument comprised 45 items specifically related to CAM therapies, in addition to obtaining baseline data. RESULTS: Response rate was 81% (522/646). A total of 406/522 (78%) patients were diagnosed with OSAHS. Mean age +/- SD was 57 +/- 14 years, and 267 participants (66%) were men. Overall, 237 (58%) participants reported ever using CAM. Ever and current CAM use specifically for improving sleep was reported by 20% and 7% of the participants, respectively. Twenty-six percent of participants reported ever using biologic products, and 52% reported ever using nonbiologic CAM treatments. A high proportion (58%) of the participants showed interest in future CAM use for improving sleep. CONCLUSION: A high proportion of patients with OSAHS report previous or current use, and interest in future use, of CAM treatments. This underscores the need to conduct further research in this field.

Gender-specific differences in a patient population with obstructive sleep apnea-hypopnea syndrome.

BACKGROUND: Sleep-related breathing disorders are increasingly recognized as an important cause of morbidity and mortality. Women with obstructive sleep apnea-hypopnea syndrome (OSA) are less likely to be assessed or to receive a diagnosis, and they may have poorer survival rates. OBJECTIVE: This study assessed gender-specific differences in patients with OSA. METHODS: Data were collected with a prospective, point-of-care, anonymous 25-question survey about basic medical information and therapies for patients undergoing polysomnography at the sleep center of a US tertiary care center from January 1 through March 31, 2005. RESULTS: Of the 646 consecutive patients who received the survey, 522 (80.8%) patients completed it, and 406 subsequently received a diagnosis of OSA. Of those 406 patients, 267 (65.8%) were men. Overall mean age was 57 years (56.4 years for men; 56.7 years for women). Alcohol use was more common in men (132 [49.4%]) than in women (43 [30.90,6]) (P < 0.001). Women were more likely to have the following associated comorbidities: obesity (body mass index > or =30) (P = 0.047), fibromyalgia (P < 0.001), migraine (P < 0.001), depression (P = 0.01), and irritable bowel syndrome (P = 0.01). The 4 most frequently reported sleep-related symptoms in both sexes were snoring (279 [68.7%]), lack of energy (235 [57.9%]), difficulty staying asleep (206 [50.7%]), and daytime sleepiness (204 [50.2%]). Lack of energy (P = 0.01), difficulty falling asleep (P = 0.02), and night sweats (P = 0.01) were observed more frequently in women than in men. There was no significant gender difference in the recalled duration of sleep-related symptoms. The mean (SD) apnea-hypopnea index (AHI) was 26.6 (26.6) for men and 22.1 (26.5) for women (P = 0.02). Conventional medications (including prescription and over-the-counter medications) for sleep-related problems were used more by women (35 [25.2%]) than by men (29 [10.9%]) (P < 0.001). CONCLUSIONS: The majority of patients who received a diagnosis of OSA were men (male-female ratio, 2:1), and the mean AHI was higher in men than in women. However, women presented with more nonspecific symptoms than did men, although there was no significant gender-specific difference in the recalled duration of symptoms. In addition, women reported more comorbidities and used significantly more conventional medications for sleep-related problems.