Citations

ABSTRACTAnetumab ravtansine, like other ADC drugs, has high inter‐patient variability in its pharmacokinetic (PK) and pharmacodynamic (PD) outcomes, which raises concerns about whether current dosing regimens are optimal for patients. The objective of this study was to evaluate covariates, especially body habitus and the innate immune system (IIS), which may affect anetumab ravtansine PK and PD as part of two clinical trials in patients with ovarian cancer and mesothelioma. Biomarkers of Fcγ receptors(FcγR) CD64 on IIS cells, total body weight (TBW), body surface area (BSA), and other covariates, such as sex and age, were analyzed for an association with anetumab ravtansine PK. Higher FcγR CD64, TBW, and BSA were associated with higher clearance (CL) of anetumab ravtansine (p < 0.05). However, there was no relationship between TBW or BSA and FcγR CD64. Female patients had a lower anetumab ravtansine CL (0.030 ± 0.007 L/h) compared to male patients (0.042 ± 0.006 L/h) (p < 0.05). In both studies, patients with stable disease (SD) and partial response (PR) had higher anetumab ravtansine AUC0‐inf compared to patients with progressive disease (PD). Individualizing the dose of anetumab ravtansine and potentially other ADCs based only on TBW is not optimal, whereas precision dosing of an ADC based on the inclusion of novel metrics of IIS biomarkers, body habitus, and sex may be more appropriate to reduce variability in PK exposure, reduce toxicity, and improve response.

Importance High-quality evidence regarding suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) is necessary to guide care. Objective To determine whether suppressive valacyclovir compared with placebo delays the occurrence of new or worsening stromal keratitis (SK), endothelial keratitis (EK), iritis, or dendriform epithelial keratitis (DEK) during 12 months of treatment and if treatment benefit persisted at 18 months (secondary end point). Design, Setting, and Participants The Zoster Eye Disease Study (ZEDS) was a randomized clinical trial conducted in 95 sites from November 2017 to June 2024. Immunocompetent, nonpregnant adults with a history of an HZO rash, documented active keratitis or iritis within 1 year, and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater were eligible. After determined to be eligible, participants were randomized in 4 strata: age at onset (&amp;lt;60 years vs ≥60 years) and disease duration (&amp;lt;6 months vs ≥6 months). Interventions A total of 12 months of double-masked daily valacyclovir, 1000 mg, or placebo. Main Outcomes and Measures The primary outcome was time to first occurrence within 12 months of new or worsening SK, EK, iritis, or DEK. Results A total of 527 participants (median [IQR] age, 60 [50-68] years; 266 female [50.5%]; 266 in the valacyclovir group; 261 in the placebo group) were randomized in 4 strata; 481 completed 12 months, and 460 completed 18 months. Data were analyzed by intention to treat. At 12 months, primary end points occurred in 86 participants (33%) assigned to placebo and 74 (28%) assigned to valacyclovir, and at 18 months in 104 participants (40%) assigned to placebo and 86 (32%) assigned to valacyclovir. The hazard ratio (HR) of the primary end point at 12 months was 0.77 for participants taking valacyclovir vs placebo (HR, 0.77; adjusted 95% CI, 0.56-1.05; P = .09) and 0.73 at the secondary end point at 18 months (HR, 0.73; adjusted 95% CI, 0.55-0.97; P = .03). There was a reduction of multiple other secondary end points at 12 months (HR, 0.70; 95% CI, 0.52-0.95; P = .02) and 18 months (HR, 0.72; 95% CI, 0.55-0.95; P = .02). Conclusions and Relevance Although the primary outcome did not show a benefit of suppressive valacyclovir treatment, secondary study outcomes showed treatment superiority at the 18-month end point and reduced number of multiple episodes of keratitis or iritis at both 12 and 18 months. These results support consideration of 1 year of suppressive valacyclovir treatment for HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Importance Evidence regarding suppressive valacyclovir treatment on postherpetic neuralgia is necessary to guide care. Objective To test the hypothesis that suppressive treatment with 1000 mg/d of oral valacyclovir for 12 months reduces the prevalence, severity, and duration of postherpetic neuralgia compared with placebo at 12 and 18 months in participants with herpes zoster ophthalmicus (HZO). Design, Setting, and Participants Multicenter, placebo-controlled randomized clinical trial including 527 immunocompetent, nonpregnant adults with history of HZO rash, documented keratitis, or iritis within 1 year and an estimated glomerular filtration rate of 45 mL/min/1.73 m 2 or greater. The study was conducted at 95 participating sites (in Canada, New Zealand, and the US) from November 2017 to June 2024 and participant visits occurred every 3 months. Intervention Treatment with 1000 mg/d of valacyclovir or placebo for 12 months. Main Outcomes and Measures Prevalence of postherpetic neuralgia, severity as determined by pain score (a score of ≥3 on a scale of 1-10), pain duration (≥3 months after HZO onset), and total daily dose of pain medication. Results Of the 527 participants (490 completed 12 months of treatment and 460 completed 18 months), 73 (14%) had postherpetic neuralgia and were analyzed by age at HZO onset (&amp;lt;60 years or ≥60 years) and disease duration (recent [&amp;lt;6 months] or chronic [≥6 months]). Of the 73 participants with postherpetic neuralgia (34 in the valacyclovir group and 39 in the placebo group), the mean age was 62.4 years (SD, 13.6 years), 59% were female, 5% were Black or African American, and 10% were Hispanic. The prevalence of postherpetic neuralgia at 12 months was not reduced by valacyclovir (12/32 [38%]) compared with placebo (14/35 [40%]) (between-group difference, 2.5% [95% CI, −20.8% to 25.8%]; P &amp;gt;.99). The participants who were younger than 60 years at HZO onset and had a chronic disease duration had lower pain scores in the valacyclovir group (mean score, 0.3 [SD, 0.9]) vs the placebo group (mean score, 0.8 [SD, 1.9]) at 12 months ( P = .045) and at 18 months (mean score, 0.2 [SD, 0.9] vs 1.0 [SD, 2.3], respectively; P = .02). There was a decrease in pain duration in the valacyclovir group at 18 months (mean, 13.6 [SD, 11.4] months) vs the placebo group (mean, 18.7 [SD, 29.5] months) (linear mixed-effects model between-group difference, −3.39 months [95% CI, −6.73 to −0.04 months]; P = .046). The total daily dose of neuropathic pain medication was lower in the valacyclovir group (mean, 271.4 [SD, 593.8] mg/d) vs the placebo group (mean, 363.4 [SD, 592.2] mg/d) at 12 months (linear mixed-effects model P = .006) and at 18 months (mean, 209.0 [SD, 412.8] mg/d vs 286.2 [SD, 577.9] mg/d, respectively; linear mixed-effects model P = .01). Conclusions and Relevance One year of suppressive treatment with valacyclovir was associated with a lower dosage of neuropathic pain medication. Participants in the valacyclovir group, who were younger at HZO onset and had a chronic disease duration, had lower pain scores. These secondary outcomes support consideration of 1 year of suppressive treatment with valacyclovir to reduce dosage of pain medications and pain due to HZO. Trial Registration ClinicalTrials.gov Identifier: NCT03134196

Abstract Purpose: Germline alterations in homologous recombination repair (gHRR) genes affect the pathogenesis, treatment options, and survival of patients with cancer. However, distinct gHRR gene alterations may differentially affect treatment response and oncogenic signaling. In this study, we interrogated genomic and transcriptomic data and assessed clinical outcomes of patients with gHRR mutations across four BRCA-associated cancers (breast, ovarian, pancreatic, and prostate cancers) to identify therapeutic vulnerabilities. Experimental Design: We assessed 24,309 patients undergoing matched tumor/normal next-generation DNA and RNA sequencing. Annotated gHRR gene variants [germline BRCA1, germline BRCA2, germline PALB2, germline ATM (gATM), and germline CHEK2] were analyzed. HRs were used to assess survival outcomes comparing germline versus sporadic groups. Somatic alterations and their frequencies were compared across gHRR-altered groups. Differential gene expression and gene set enrichment analysis were used to compare transcriptomic profiles. Results: Somatic TP53 mutations were depleted in gATM carriers (P &lt; 0.05) across all four BRCA-associated cancers by up to 2.5-fold. Tumors with germline BRCA1/2 mutations were associated with improved survival in patients with ovarian cancer and had consistent enrichment of TP53 mutations in all four cancers. gATM mutations displayed elevated p53 transcriptional activity in all four cancers, with significance reached in breast and prostate cancers (P &lt; 0.01). In breast, ovarian, and prostate cancers, gATM tumors demonstrated significantly increased inflammatory pathways (P &lt; 0.001). Finally, using gene dependency data, we found that cell lines that were highly dependent on ATM were co-dependent on canonical p53 function. Conclusions: gATM-associated cancers seem to require intact p53 activity and this synthetic essentiality may be used to guide targeted therapies that perturb canonical TP53 function.

Abstract Purpose: Selinexor is a first-in-class, central nervous system (CNS)–penetrant, oral inhibitor of exportin 1 (XPO1), the main nuclear exporter of many key tumor suppressors. We report a phase I trial of selinexor in children and adolescents with recurrent CNS and solid tumors (NCT02323880). Patients and Methods: A rolling six design was used to evaluate the maximum tolerated dose (MTD) and first dose pharmacokinetics of selinexor administered once (35–45 mg/m2) or twice (20–35 mg/m2) weekly during a 28-day cycle (part A). Ten additional patients with high-grade glioma (HGG) were treated at the MTD administered once weekly (part B). Results: In part A, 49 patients were enrolled. Continuous twice weekly dosing was limited by extended hematologic toxicity. The MTD on a twice weekly schedule for 3 weeks on/1 week off (twice weekly 3/1) was 20 mg/m2/dose. Dose-limiting toxicities (DLTs) on this schedule included fatigue, acute reversible neurologic changes, neutropenia, thrombocytopenia, and aspartate aminotransferase/alanine aminotransferase increase. On a continuous once weekly schedule, the MTD was 35 mg/m2/dose; DLTs included seizure and thrombocytopenia. In part B (HGG expansion), there were no additional DLTs observed. Non-DLTs included lymphopenia, leukopenia, neutropenia, thrombocytopenia, anorexia, fatigue, hypophosphatemia, nausea, and vomiting. There were no objective responses. The median number of cycles received was 1 (range, 1–9); eight of 59 patients (13.5%) received 5 to 9 cycles, five of whom had HGG. Conclusions: Selinexor-related toxicities were primarily hematologic and neurologic, requiring dose or dose-frequency reduction. The MTD and recommended initial phase II dose of selinexor in children and adolescents with recurrent solid and CNS tumors is 35 mg/m2/dose once weekly.

PURPOSE To investigate the clinical behavior of breast cancer in young BRCA carriers according to the specific BRCA gene ( BRCA1 v BRCA2 ) and the association of the timing of genetic testing (before v at diagnosis) with prognosis. METHODS This was an international, multicenter, hospital-based, retrospective cohort study that included 4,752 patients harboring germline pathogenic/likely pathogenic variants (PVs) in BRCA1 or BRCA2 , who were diagnosed with stage I-III invasive breast cancer at 40 years or younger between January 2000 and December 2020 in 78 centers worldwide (ClinicalTrials.gov identifier: NCT03673306 ). RESULTS Compared with BRCA2 carriers (n = 1,683), BRCA1 carriers (n = 3,069) had more frequently hormone receptor–negative (74.4% v 15.5%) and high-grade (77.5% v 49.1%) tumors. Similar outcomes were observed in BRCA1 and BRCA2 carriers but with a different pattern and risk of disease-free survival events over time. Compared with patients tested for BRCA at diagnosis (ie, between 2 months before and up to 6 months after diagnosis; n = 1,671), those tested before diagnosis (ie, any time up to 2 months before diagnosis; n = 411) had smaller tumors (T1: 61.3% v 32.4%), less nodal involvement (N0: 65.9% v 50.8%), less frequently received chemotherapy (84.4% v 92.9%), and axillary dissection (37.5% v 47.4%). Patients tested before diagnosis had better overall survival (OS; unadjusted hazard ratio [HR], 0.61 [95% CI, 0.40 to 0.92]); however, this result lost statistical significance after adjustment for potential confounders including tumor stage (adjusted HR, 0.74 [95% CI, 0.47 to 1.15]). CONCLUSION This global study provides evidence on the different clinical behavior of breast cancer in young BRCA1 and BRCA2 carriers. Identifying a BRCA PV in healthy individuals was associated with earlier-stage breast cancer diagnosis and lower treatment burden, as well as better unadjusted OS.

Abstract Prevention trials in oncology are some of the most important cancer clinical trials that can be designed, implemented, analyzed, and interpreted. They are pivotal in the goal of stopping the development of cancer before it starts. Prevention trials are unique in that they not only have some of the same requirements and challenges as treatment trials but also have challenges that may make their design more complex. This paper aims to discuss some types of prevention trials and highlight their most common design challenges, including large sample size requirements, slow accrual rates with long accrual duration, extended follow-up periods with trial adherence issues and missing data, endpoints that require extended follow-up or have a high level of confounding, and problems with optimizing study design. This article provides real study examples and suggestions for designing prevention clinical trials while mitigating the known issues they face.

Abstract Interpreting cancer clinical trial results often depends on addressing issues of multiplicity. When testing multiple hypotheses, unreliable findings can occur by chance due to the inflation of the type I error rate, the probability of mistakenly rejecting the null hypothesis when the null hypothesis is true. In this setting, researchers may often set the type I error rate (or the alpha level) low to limit false positive findings and the interpretation of a causal relationship where none exists. Conversely, overly conservative type I error control may result in declaring findings, that do not meet multiplicity-adjusted alpha levels, as false when they are actually true, reducing opportunities for new discovery. This presentation focuses on multiplicity adjustment in the context of clinical trials conducted within the NCI’s Community Oncology Research Program (NCORP). Because federally sponsored trials often require long-term participation from patients and represent a substantial investment by taxpayers, striking the right balance between optimizing what is learned from these trials, while avoiding false positive results, should be a priority.

Abstract The intracluster correlation coefficient (ICC) measures the correlation of observations within clusters and is a key parameter for power and sample size calculations for cluster randomized trials (CRTs). To facilitate the design of future CRTs within the National Cancer Institute Community Oncology Research Program (NCORP), all studies from the NCORP website were reviewed to identify completed CRTs. ICCs for primary and secondary outcomes (when available) were ascertained from these trials and summarized in this article as a resource for future trial development. Although ICCs are relatively small for many outcome cluster combinations, that is not always the case, so consideration should always be given to the specific outcome of interest, trial design, and type of cluster when estimating an ICC to facilitate trial development.