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Background: As a surrogate of malnutrition, degree of weight loss and recovery from head and neck cancer (HNC) treatment is understudied. The influence of modifiable factors that affect weight, including speech/language pathology (SLP) and nutrition counseling, is also poorly defined. We characterize weight loss trends, baseline weight recovery (BWR), and the impact of interdisciplinary care on oncologic outcomes., Methods: Retrospective cohort study assessing 266 newly diagnosed patients with HNC who completed curative-intent radiation (definitive or adjuvant) between January 2016 to January 2022. Relevant treatment factors were analyzed using multivariable Cox regression models., Results: Altogether, 266 patients completed full-course radiation therapy (RT), encompassing definitive chemoRT (53.0%), surgery with chemoRT (18.4%), surgery with RT (17.7%), and RT alone (10.9%). Patient weight reached a nadir at median 3.0 months (IQR 3.0-11.3) after radiation, with a median weight loss of 12.6% (IQR 7.9-18.7). Notably, only 47.4% exhibited BWR. For those who recovered, median time to BWR was 10.5 months (IQR 3.0-24.0). On multivariable analysis, BWR by 6 months was significantly associated with overall survival (HR 0.28 [95% CI 0.10-0.76], p = 0.013), as was SLP consultation (HR 0.40 [95% CI 0.17-0.92], p = 0.031) and nutrition consultation (HR 0.34 [95% CI 0.13-0.89], p = 0.028)., Conclusion: A high proportion of patients with HNC fail to recover baseline weight after treatment; those that do can take longer than expected to return. Failure to recover baseline weight is associated with a notable decrease in survival. Similarly, SLP and nutrition consultation are independent, modifiable determinants correlated with outcomes, supporting the emphasis on multidisciplinary management. Measures to promote BWR may reduce mortality., (© 2024 Wiley Periodicals LLC.)

Fibroblast growth factor receptor (FGFR) 2/3 alterations have been implicated in tumorigenesis in several malignancies, including urothelial carcinoma. Several FGFR inhibitors have been studied or are in development, and erdafitinib is the sole inhibitor to achieve regulatory approval. Given the rapidly evolving treatment landscape for advanced urothelial carcinoma, including regulatory approvals and withdrawals, determining the most appropriate treatment strategies and sequencing for FGFR-altered urothelial carcinoma is becoming increasing critical. However, the clinical efficacy of FGFR inhibitors is limited by acquired resistance similar to that seen with other tyrosine kinase inhibitors. Additional challenges to the clinical use of FGFR inhibitors include treatment-related adverse events and the financial costs associated with treatment. In this review, we describe known mechanisms of FGFR inhibitor resistance, including gatekeeper mutations, domain mutations, and the development of new mutations. In addition, we discuss management strategies, including ongoing clinical trials evaluating FGFR inhibitors, antibody-drug conjugates, and combination therapies with immune checkpoint inhibitors that may provide additional treatment options for localized and metastatic urothelial carcinoma., Competing Interests: Declarations. Financial support and sponsorship: No external funding was used in the preparation of this manuscript. Conflict of interest: David J. Benjamin has the following disclosures: Consulting/advisory role: AIMED BIO, Astellas, AVEO Oncology, Bayer, Eisai, EMD Serono, Exelixis, and Seagen. Speakers’ bureau: Merck. Travel and accommodations: DAVA Oncology, Merck, and Seagen. Alain C. Mita has the following disclosures: Speakers’ bureau: Genentech. Alain C. Mita is an editorial board member of Targeted Oncology. Alain C. Mita was not involved in the selection of peer reviewers for the manuscript or any of the subsequent editorial decisions. Ethical approval and consent to participate: Not applicable. Consent for publication: Not applicable. Code availability: Not applicable. Availability of data and materials: Not applicable. Author contributions: DJB—conceptualization, investigation, writing—original draft, writing—review and editing; ACM—writing—original draft, writing—review and editing, supervision., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objective: Circulating tumor DNA assays have robust potential as molecular surveillance tools. They may also exacerbate patient distress without improving outcomes. We investigate patient acceptability of a validated ctHPVDNA assay (NavDx) during cancer surveillance for HPV(+) oropharyngeal cancer (OPC)., Methods: Consented HPV(+) OPC participants completed the NCCN Distress Thermometer, the Hospital Anxiety Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-General (FACT-G) scale both (1) before NavDx blood draw, and (2) after results were provided. Patients then completed a series of focused questions related to their perceptions of the assay., Results: Overall, 55 patients completed the study, with 98.2 % showing no recurrence. For the NCCN Distress Thermometer, median patient distress decreased (2.0 (IQR 1-5) vs. 1.0 (IQR 0-3)) (p < 0.001) in association with NavDx. Using scores ≥ 4 as a cutoff point to define clinically elevated distress, scores also improved (36.4 % vs. 18.2 %, p = 0.031). For HADS, anxiety significantly improved (5.0 (IQR 2.0-7.0) vs. 3.0 (IQR 1.0-6.5)) (p = 0.037), but not depression (3.0 (IQR 1.0-7.0) vs. 3.0 (IQR 1.0-6.5)) (p = 0.870). FACT-G scores showed no substantial differences. On survey questionnaires, 95.5 % of patients believed the test to be helpful, and 100 % felt "somewhat" or "extremely" confident in the assay as a monitoring tool. While 59.1 % felt that it reduced anxiety, 88.4 % concordantly felt that it did not introduce anxiety., Conclusion: ctHPVDNA as a molecular surveillance tool reduced distress levels in HPV(+) OPC patients, with notably high patient confidence in the approach. Further investigation is warranted to judiciously incorporate this emerging modality in surveillance guidelines., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Dr. Zumsteg’s spouse does legal work for Johnson & Johnson, Merck, Allergan, and Boehringer Ingelheim through her law firm]., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Patients with cancer are at increased risk of death from COVID-19 and have reduced immune responses to SARS-CoV2 vaccines, necessitating regular boosters. We performed comprehensive chart reviews, surveys of patients attitudes, serology for SARS-CoV-2 antibodies and T cell receptor (TCR) β sequencing for cellular responses on a cohort of 982 cancer patients receiving active cancer therapy accrued between November-3-2020 and Mar-31-2023. We found that 92 · 3% of patients received the primer vaccine, 70 · 8% received one monovalent booster, but only 30 · 1% received a bivalent booster. Booster uptake was lower under age 50, and among African American or Hispanic patients. Nearly all patients seroconverted after 2+ booster vaccinations (>99%) and improved cellular responses, demonstrating that repeated boosters could overcome poor response to vaccination. Receipt of booster vaccinations was associated with a lower risk of all-cause mortality (HR = 0 · 61, p  = 0 · 024). Booster uptake in high-risk cancer patients remains low and strategies to encourage booster uptake are needed., Competing Interests: N.M. holds a consultant or advisory role at Amgen, Kite, Epizyme, TG Therapeutics, ADC Therapeutics, and has research funding from Miltenyi, Teva, and Amgen. J.G. holds a consultant or advisory role at EMD Serono; Elsevier; Exelixis; QED Therapeutics; Natera, Basilea, HalioDx, Eisai, Janssen. O.H. has obtained consulting fees/support meetings/travel/Financial interests in Alkermes, Amgen, Bactonix, Beigene, Bioatla, BMS, Esai, Roche, Genentech, Georgiamune, GigaGen, Grit Bio, GSK, Idera, Immunocore, Incyte, Instilbio, IO Bio, Iovance, Janssen, KSQ, Merck Moderna, Novartis, Obsidian, Pfizer, Regeneron, Sanofi, Seattle Genetics, Tempus, Vial, Zelluna. K.R. holds a consultant or advisory role at Amgen, AstraZeneca, Blueprint, Boehringer Ingelheim, Daiichi Sankyo, EMD Soreno, Genentech, GSK, Janssen, Lilly, Merck KGA, Mirati, Seattle Genetics, Takeda. J.D. holds a consultant or advisory role Kite Pharma and Morphosys. R.V. is on the Speaker’s Bureau for: Amgen, Bristol Myers Squib, Glaxo Smith Klein, Janssen, Karyopharm, and Takeda Pharmaceuticals. A.M. holds a consultant or advisory role at Novartis and Morphosys and has research funding from Amgen and Pfizer., (© 2024 The Authors. Published by Elsevier Inc.)

Purpose: Subprotocol K2 (EAY131-K2) of the NCI-MATCH platform trial was an open-label, single-arm, phase II study designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 mutations or fusions., Methods: Central confirmation of tumor FGFR1-4 mutations or fusions was required for outcome analysis. Patients with urothelial carcinoma were excluded. Enrolled subjects received oral erdafitinib at a starting dose of 8 mg daily continuously until intolerable toxicity or disease progression. The primary end point was objective response rate (ORR) with key secondary end points of safety, progression-free survival (PFS), and overall survival (OS)., Results: Thirty-five patients were enrolled, and 25 patients were included in the primary efficacy analysis as prespecified in the protocol. The median age was 61 years, and 52% of subjects had received ≥3 previous lines of therapy. The confirmed ORR was 16% (4 of 25 [90% CI, 5.7 to 33.0], P = .034 against the null rate of 5%). An additional seven patients experienced stable disease as best-confirmed response. Four patients had a prolonged PFS including two with recurrent WHO grade IV, IDH1-/2-wildtype glioblastoma. The median PFS and OS were 3.6 months and 11.0 months, respectively. Erdafitinib was manageable with no new safety signals., Conclusion: This study met its primary end point in patients with several pretreated solid tumor types harboring FGFR1-3 mutations or fusions. These findings support advancement of erdafitinib for patients with fibroblast growth factor receptor-altered tumors outside of currently approved indications in a potentially tumor-agnostic manner.

Purpose: Despite fibroblast growth factor receptor ( FGFR ) inhibitors being approved in tumor types with select FGFR rearrangements or gene mutations, amplifications of FGFR represent the most common FGFR alteration across malignancies. Subprotocol K1 (EAY131-K1) of the National Cancer Institute-MATCH platform trial was designed to evaluate the antitumor efficacy of the oral FGFR1-4 inhibitor, erdafitinib, in patients with tumors harboring FGFR1-4 amplification., Methods: EAY131-K1 was an open-label, single-arm, phase II study with central confirmation of presence of FGFR1-4 amplification in tumors. Patients with urothelial carcinoma were excluded. Enrolled patients received oral erdafitinib at a starting dose of 8 mg once daily continuously with escalation to 9 mg once daily continuously, on the basis of predefined time point assessments of phosphate levels, until disease progression or intolerable toxicity. The primary end point was centrally assessed objective response rate (ORR), with key secondary end points being 6-month progression-free survival (PFS6), PFS, overall survival (OS), and safety., Results: Thirty-five patients were enrolled into this study with 18 included in the prespecified primary efficacy analysis. The median age of the 18 patients was 60 years, and 78% had received ≥3 previous lines of therapy. There were no confirmed responses to erdafitinib; however, five patients experienced stable disease (SD) as best response. One patient with an FGFR1 -amplified breast cancer had a prolonged PFS >168 days (5.5 months). The median PFS was 1.7 months (90% CI, 1.1 to 1.8 months) and the median OS was 4.2 months (90% CI, 2.3 to 9.3 months). The estimated PFS6 rate was 13.8% (90% CI, 3.3 to 31.6). The majority of toxicities were grade 1 to 2 in nature, although there was one grade 5 treatment-related adverse event., Conclusion: Erdafitinib did not meet its primary end point of efficacy as determined by ORR in treatment-refractory solid tumors harboring FGFR1-4 amplifications. Our findings support that rearrangements and gene mutations, but not amplifications, of FGFR remain the established FGFR alterations with approved indications for FGFR inhibition.

Background: The comparative impact of histologic variants and grade has not been well described., Methods: Salivary cancer histologies were profiled using hospital and population-based cancer registries. Multivariable models were employed to assess relationships between histology, grade, and survival., Results: On univariate analysis, histologic variants exhibited a wide spectrum of mortality risk (5-year overall survival (OS): 86% (acinic cell carcinoma), 78% (mucoepidermoid carcinoma), 72% (adenoid cystic carcinoma), 64% (carcinoma ex-pleomorphic adenoma), 52% (adenocarcinoma NOS), and 47% (salivary duct carcinoma) (p < 0.001). However, on multivariable analysis these differences largely vanished. Worsening grade corresponded with deteriorating survival (5-year OS: 89% [low-grade], 81% [intermediate-grade], 45% [high-grade]; p < 0.001), which was upheld on multivariable analysis and propensity score matching. Recursive partitioning analysis generated TNM + G schema (c-index 0.75) superior to the existing system (c-index 0.73)., Conclusion: Grade represents a primary determinant of salivary cancer prognosis. Integrating grade into stage strengthens current staging systems., (© 2023 Wiley Periodicals LLC.)

Background: Elective neck dissection is a standard of care for pharynx and most larynx cancer patients undergoing surgery, based largely on historical series. It is unclear if this is necessary for all patients in the modern era., Methods: Patients with cN0 oropharynx, larynx, and hypopharynx cancers diagnosed from 2010-2015 undergoing primary surgery were identified in the National Cancer Data Base., Results: Inclusion criteria were met by 4117 cN0 patients. The presence of lymphovascular invasion (LVI) was the strongest independent predictor of pN+ (odds ratio [OR] = 4.19, 95% confidence interval [CI] 3.56-4.93, p < 0.001). Histologic grade strongly predicted pN+ (OR 2.58, 95% CI 1.88-3.59, p < 0.001). A nomogram predicted less than 10% of cN0 patients had pN+ risk <15%., Conclusion: LVI and grade are the strongest predictors of pN+ among patients with cN0 pharynx and larynx cancer. Even in the modern era, pN+ rates warrant neck dissection for cN0 patients., Level of Evidence: 3 Laryngoscope, 133:1660-1666, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

Background: Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1., Objective: The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles., Patients and Methods: Eligible patients had the following: confirmed diagnosis of ovarian cancer (OC), triple-negative breast cancer (TNBC), or small-cell lung cancer (SCLC); previous treatment for metastatic/recurrent disease; and measurable disease. Patients were grouped into six matched cohorts based on tumor type and presence/absence of biomarkers and received oral adavosertib 175 mg twice a day on days 1-3 and 8-10 of a 21-day treatment cycle., Results: Eighty patients received treatment in the expansion phase; median total treatment duration was 2.4 months. The most common treatment-related adverse events (AEs) were diarrhea (56.3%), nausea (42.5%), fatigue (36.3%), vomiting (18.8%), and decreased appetite (12.5%). Treatment-related grade ≥ 3 AEs and serious AEs were reported in 32.5% and 10.0% of patients, respectively. AEs led to dose interruptions in 22.5%, reductions in 11.3%, and discontinuations in 16.3% of patients. One patient died following serious AEs of deep vein thrombosis (treatment related) and respiratory failure (not treatment related). Objective response rate, disease control rate, and progression-free survival were as follows: 6.3%, 68.8%, 4.5 months (OC BRCA wild type); 3.3%, 76.7%, 3.9 months (OC BRCA mutation); 0%, 69.2%, 3.1 months (TNBC biomarker [CCNE1/MYC/MYCL1/MYCN] non-amplified [NA]); 0%, 50%, 2 months (TNBC biomarker amplified); 8.3%, 33.3%, 1.3 months (SCLC biomarker NA); and 0%, 33.3%, 1.2 months (SCLC biomarker amplified)., Conclusion: Adavosertib monotherapy was tolerated and demonstrated some antitumor activity in patients with advanced solid tumors., Trial Registration: ClinicalTrials.gov identifier NCT02482311; registered June 2015., (© 2023. The Author(s).)

Background: Nodal staging systems vary substantially across solid tumors, implying heterogeneity in the behavior of nodal variables in various contexts. We hypothesized, in contradiction to this, that metastatic lymph node (LN) number is a universal and dominant predictor of outcome across solid tumors., Methods: We performed a retrospective cohort analysis of 1 304 498 patients in the National Cancer Database undergoing surgery between 2004 and 2015 across 16 solid cancer sites. Multivariable Cox regression analyses were constructed using restricted cubic splines to model the association between nodal number and mortality. Recursive partitioning analysis (RPA) was used to derive nodal classification systems for each solid cancer based on metastatic LN count. The reproducibility of these findings was assessed in 1 969 727 patients from the Surveillance, Epidemiology, and End Results registry. Two-sided tests were used for all statistical analyses., Results: Consistently across disease sites, mortality risk increased continuously with increasing number of metastatic LNs (P < .001 for all spline segments). Each RPA-derived nodal classification system produced multiple prognostic groups spanning a wide spectrum of mortality risk (P < .001). Multivariable models using these RPA-derived nodal classifications demonstrated improved concordance with mortality compared with models using American Joint Committee on Cancer staging in sites where nodal classification is not based on metastatic LN count. Each RPA-derived nodal classification system was reproducible in a large validation cohort for all-cause and cause-specific mortality (P < .001). High quantitative nodal burden was the single strongest tumor-intrinsic variable associated with mortality in 12 of 16 disease sites., Conclusions: Quantitative metastatic LN burden is a fundamental driver of mortality across solid cancers and should serve as a foundation for pathologic nodal staging across solid tumors., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Longitudinal studies of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced immune responses in patients with cancer are needed to optimize clinical care. In a prospective cohort study of 366 (291 vaccinated) patients, we measured antibody levels [anti-spike (IgG-(S-RBD) and anti-nucleocapsid immunoglobulin] at three time points. Antibody level trajectories and frequency of breakthrough infections were evaluated by tumor type and timing of treatment relative to vaccination. IgG-(S-RBD) at peak response (median = 42 days after dose 2) was higher ( P = 0.002) and remained higher after 4 to 6 months ( P = 0.003) in patients receiving mRNA-1273 compared with BNT162b2. Patients with solid tumors attained higher peak levels ( P = 0.001) and sustained levels after 4 to 6 months ( P < 0.001) compared with those with hematologic malignancies. B-cell targeted treatment reduced peak ( P = 0.001) and sustained antibody responses ( P = 0.003). Solid tumor patients receiving immune checkpoint inhibitors before vaccination had lower sustained antibody levels than those who received treatment after vaccination ( P = 0.043). Two (0.69%) vaccinated and one (1.9%) unvaccinated patient had severe COVID-19 illness during follow-up. Our study shows variation in sustained antibody responses across cancer populations receiving various therapeutic modalities, with important implications for vaccine booster timing and patient selection. SIGNIFICANCE: Long-term studies of immunogenicity of SARS-CoV-2 vaccines in patients with cancer are needed to inform evidence-based guidelines for booster vaccinations and to tailor sequence and timing of vaccinations to elicit improved humoral responses., (©2021 The Authors; Published by the American Association for Cancer Research.)

Background: Modern disease staging systems have restructured human papillomavirus (HPV)-negative (HPV-) and HPV-positive (HPV+) oropharyngeal carcinoma (OPC) into distinct pathologic nodal systems. Given that quantitative lymph node (LN) burden is the dominant prognostic factor in most head and neck cancers, we investigated whether HPV- and HPV+ OPC warrant divergent pathologic nodal classification., Methods: Multivariable Cox regression models of OPC surgical patients identified via U.S. cancer registry data were constructed to determine associations between survival and nodal characteristics. Nonlinear associations between metastatic LN number and survival were modeled with restricted cubic splines. Recursive partitioning analysis (RPA) was used to derive unbiased nodal schema., Results: Mortality risk escalated continuously with each successive positive LN in both OPC subtypes, with analogous slope. Survival hazard increased by 18.5% (hazard ratio [HR], 1.19 [95% CI, 1.16-1.21]; P < .001) and 19.1% (HR, 1.19 [95% CI, 1.17-1.21]; P < .001), with each added positive LN for HPV- and HPV+ OPC, respectively, up to identical change points of 5 positive LNs. Extranodal extension (ENE) was an independent predictor of HPV- OPC (HR, 1.55 [95% CI, 1.20-1.99]; P < .001) and HPV+ OPC (HR 1.73 [95% CI, 1.36-2.20]; P < .001) mortality. In RPA for both diseases, metastatic LN was the principal nodal covariate driving survival, with ENE as a secondary determinant. Given the similarities across analyses, we propose a concise, unifying HPV-/HPV+ OPC pathologic nodal classification schema: N1, 1-5 LN+/ENE-; N2, 1-5 LN+/ENE+; N3, >5 LN+., Conclusion: HPV- and HPV+ OPC exhibit parallel relationships between nodal characteristics and relative mortality. In both diseases, metastatic LN number represents the principal nodal covariate governing survival, with ENE being an influential secondary element. A consolidated OPC pathologic nodal staging system that is based on these covariates may best convey prognosis., Lay Summary: The current nodal staging system for oropharyngeal carcinoma (OPC) has divided human papillomavirus (HPV)-negative (HPV-) and HPV-positive (HPV+) OPC into distinct systems that rely upon criteria that establish them as separate entities, a complexity that may undermine the core objective of staging schema to clearly communicate prognosis. Our large-scale analysis revealed that HPV- and HPV+ pathologic nodal staging systems in fact mirror each other. Multiple analyses produced conspicuously similar nodal staging systems, with metastatic lymph node number and extranodal extension delineating the highest risk groups that shape prognosis. We propose unifying HPV- and HPV+ nodal systems to best streamline prognostication and maximize staging accuracy., (© 2021 American Cancer Society.)

Background: Although pathologic tumor grade is a well-established prognostic risk factor that impacts staging and treatment decisions across multiple cancer types, its role in head and neck squamous cell carcinoma (HNSCC) is less certain., Methods: HNSCC patients diagnosed from 2010 to 2015 and undergoing primary surgery in the National Cancer Data Base were identified. Propensity score matching and multivariable Cox regression were performed., Results: Among 27 041 HNSCC patients, 13 941 had oral cavity cancers (OCC). Intermediate-grade (hazard ratio [HR] 1.16, 95% CI 1.07-1.26, P < .001) and high-grade (HR 1.38, 95% CI 1.26-1.52, P < .001) tumors had worse survival than low-grade tumors. This magnitude was comparable to other well-established prognostic factors, including margin positivity, extranodal extension, and lymphovascular invasion. By contrast, there was no association between grade and survival in larynx/hypopharynx or HPV(-) oropharynx cancer., Conclusions: The prognostic impact of pathologic grade is highly variable across head and neck subsites and is the strongest among OCC patients., (© 2020 Wiley Periodicals LLC.)

Importance: Transoral robotic surgery has been widely adopted since approval by the US Food and Drug Administration in December 2009, despite limited comparative data., Objective: To compare the long-term outcomes of transoral robotic surgery with those of nonrobotic surgery for patients with early-stage oropharyngeal cancer., Design, Setting, and Participants: A retrospective cohort comparative effectiveness analysis was performed of patients in the National Cancer Database with clinical T1 and T2 oropharyngeal squamous cell carcinoma diagnosed between January 1, 2010, and December 31, 2015, who underwent definitive robotic and nonrobotic surgery. Multivariable Cox proportional hazards regression analysis and propensity score matching were performed in patients with known human papillomavirus status to adjust for patient- and disease-related covariates. Survival after robotic and nonrobotic surgery was also compared in 3 unrelated cancers: prostate, endometrial, and cervical cancer. Statistical analysis was performed from April 10, 2019, to May 21, 2020., Main Outcomes and Measures: Overall survival., Results: Of 9745 patients (7652 men [78.5%]; mean [SD] age, 58.8 [9.6] years) who met inclusion criteria, 2694 (27.6%) underwent transoral robotic surgery. There was a significant increase in the use of robotic surgery from 18.3% (240 of 1309) to 35.5% (654 of 1841) of all surgical procedures for T1 and T2 oropharyngeal cancers from 2010 to 2015 (P = .003). Robotic surgery was associated with lower rates of positive surgical margins (12.5% [218 of 1746] vs 20.3% [471 of 2325]; P < .001) and lower use of adjuvant chemoradiotherapy (28.6% [500 of 1746] vs 35.7% [831 of 2325]; P < .001). Among 4071 patients with known human papillomavirus status, robotic surgery was associated with improved overall survival compared with nonrobotic surgery in multivariable Cox proportional hazards regression (hazard ratio [HR], 0.74; 95 CI, 0.61-0.90; P = .002). Similar results were seen when analyzing only the subset of facilities offering both robotic and nonrobotic surgery. The 5-year overall survival was 84.8% vs 80.3% among patients undergoing robotic vs nonrobotic surgery in propensity score-matched cohorts (P = .001). By contrast, there was no evidence that robotic surgery was associated with improved survival in other cancers, such as prostate cancer (HR, 0.92; 95% CI, 0.79-1.07; P = .26), endometrial cancer (HR, 0.97; 95% CI, 0.90-1.04; P = .36), and cervical cancer (HR, 1.27; 95% CI, 0.96-1.69; P = .10)., Conclusions and Relevance: This study suggests that transoral robotic surgery was associated with improved surgical outcomes and survival compared with nonrobotic surgery in patients with early-stage oropharyngeal cancer. Evaluation in comparative randomized trials is warranted.

Purpose: This first-in-human, phase I study evaluated ASTX660, an oral, small-molecule antagonist of cellular/X-linked inhibitors of apoptosis proteins in patients with advanced solid tumors or lymphoma., Patients and Methods: ASTX660 was administered orally once daily on a 7-day-on/7-day-off schedule in a 28-day cycle. Dose escalation followed a standard 3+3 design to determine the MTD and recommended phase II dose (RP2D). Dose expansion was conducted at the RP2D., Results: Forty-five patients received ASTX660 (range 15-270 mg/day). Dose-limiting toxicity of grade 3 increased lipase with or without increased amylase occurred in 3 patients at 270 mg/day and 1 patient at 210 mg/day. The MTD was determined to be 210 mg/day and the RP2D 180 mg/day. Common treatment-related adverse events included fatigue (33%), vomiting (31%), and nausea (27%). Grade ≥3 treatment-related adverse events occurred in 7 patients, most commonly anemia (13%), increased lipase (11%), and lymphopenia (9%). ASTX660 was rapidly absorbed, with maximum concentration achieved at approximately 0.5-1.0 hour. An approximately 2-fold accumulation in AUC exposures was observed on day 7 versus 1. ASTX660 suppressed cellular inhibitor of apoptosis protein-1 in peripheral blood mononuclear cells, which was maintained into the second cycle beyond the off-therapy week at the 180-mg/day RP2D and above. Clinical activity was seen in a patient with cutaneous T-cell lymphoma., Conclusions: ASTX660 demonstrated a manageable safety profile and exhibited evidence of pharmacodynamic and preliminary clinical activity at the 180-mg/day RP2D. The phase II part of the study is ongoing., (©2020 American Association for Cancer Research.)

Background: Patients with clinical stage I human papillomavirus (HPV)-positive oropharyngeal squamous cell cancer (OPSCC) according to the American Joint Committee on Cancer (AJCC) eighth edition classification comprise a heterogeneous group formerly classified as stage I to stage IVA according to the seventh edition of the AJCC classification. These patients historically were treated with disparate treatment regimens, particularly with respect to the use of concurrent chemotherapy., Methods: The National Cancer Data Base was queried for patients with AJCC eighth edition clinical stage I HPV-positive OPSCC (AJCC seventh edition stage T1-2N0-2bM0) who were diagnosed from 2010 to 2014 and underwent definitive radiotherapy. Concurrent chemotherapy with definitive radiotherapy was defined as chemotherapy administered within 7 days of the initiation of radiotherapy., Results: The current analysis included 4473 patients with HPV-positive stage I OPSCC with a median follow-up of 36.3 months. A total of 3127 patients (69.9%) received concurrent chemotherapy. Concurrent chemotherapy was found to be associated with improved overall survival on multivariable analyses (hazard ratio [HR], 0.782; 95% CI, 0.645-0.948 [P = .012]). The effect of chemotherapy on survival varied based on lymph node involvement (P for interaction = .001). Specifically, chemotherapy was associated with improved survival for patients with lymph node-positive stage I disease (stage III-IVA according to the AJCC seventh edition: HR, 0.682; 95% CI, 0.557-0.835 [P < .001]), but not for patients with N0 disease (stage I-II according to the AJCC seventh edition: HR, 1.646; 95% CI, 1.011-2.681 [P = .05]). Similar results were noted among propensity score-matched cohorts., Conclusions: Treatment with concurrent chemotherapy was associated with improved overall survival for patients with lymph node-positive, but not lymph node-negative, AJCC eighth edition stage I HPV-positive OPSCC undergoing definitive radiotherapy, thereby supporting different treatment paradigms for these patients., (© 2019 American Cancer Society.)

Importance: Current treatment options for progressive ovarian cancer provide limited benefit, particularly in patients whose disease has become resistant to platinum-based chemotherapy., Objective: To assess the efficacy and safety of avelumab, an anti-programmed death-ligand 1 agent, in a cohort of patients with previously treated recurrent or refractory ovarian cancer., Design, Setting, and Participants: In an expansion cohort of a phase 1b, open-label study (JAVELIN Solid Tumor), 125 patients with advanced ovarian cancer who had received chemotherapy including a platinum agent were enrolled between November 6, 2013, and August 27, 2015. Statistical analysis was performed from December 31, 2016, to October 9, 2018., Intervention: Patients received avelumab, 10 mg/kg, every 2 weeks until disease progression, unacceptable toxic effects, or withdrawal from the study., Main Outcomes and Measures: Prespecified end points in this cohort included confirmed best overall response (per Response Evaluation Criteria In Solid Tumors, version 1.1), immune-related best overall response, duration of response, progression-free survival, overall survival, results of programmed death-ligand 1 expression-based analyses, and safety., Results: A total of 125 women (median age, 62.0 years [range, 27-84 years]) who had received a median of 3 prior lines of treatment (range, 0-10) for advanced disease were enrolled in the study. Patients received avelumab for a median of 2.8 months (range, 0.5-27.4 months), with a median follow-up of 26.6 months (range, 16-38 months). A confirmed objective response occurred in 12 patients (9.6%; 95% CI, 5.1%-16.2%), including a complete response in 1 patient (0.8%) and a partial response in 11 patients (8.8%). The 1-year progression-free survival rate was 10.2% (95% CI, 5.4%-16.7%) and median overall survival was 11.2 months (95% CI, 8.7-15.4 months). Infusion-related reactions occurred in 25 patients (20.0%). Other frequent treatment-related adverse events (any grade event occurring in ≥10% of patients) were fatigue (17 [13.6%]), diarrhea (15 [12.0%]), and nausea (14 [11.2%]). Grade 3 or higher treatment-related adverse events occurred in 9 patients (7.2%), of which only the level of lipase increased (3 [2.4%]) occurred in more than 1 patient. Twenty-one patients (16.8%) had an immune-related adverse event of any grade. No treatment-related deaths occurred., Conclusions and Relevance: Avelumab demonstrated antitumor activity and acceptable safety in heavily pretreated patients with recurrent or refractory ovarian cancer., Trial Registration: ClinicalTrials.gov identifier: NCT01772004.

Purpose DFP-10917 is a novel deoxycytidine analog with a unique mechanism of action. Brief exposure to high concentrations of DFP-10917 inhibits DNA polymerase resulting in S-phase arrest, while prolonged exposure to DFP-10917 at low concentration causes DNA fragmentation, G2/M-phase arrest, and apoptosis. DFP-10917 demonstrated activity in tumor xenografts resistant to other deoxycytidine analogs. Experimental design Two phase I studies assessed the safety, pharmacokinetic, pharmacodynamic and preliminary efficacy of DFP-10917. Patients with refractory solid tumors received DFP-10917 continuous infusion 14-day on/7-day off and 7-day on/7-day off. Enrollment required age > 18 years, ECOG Performance Status 0-2 and adequate organ function. Results 29 patients were dosed in both studies. In 14-day infusion, dose-limiting toxicities (DLT) consisting of febrile neutropenia and thrombocytopenia occurred at 4.0 mg/m 2 /day. At 3.0 mg/m 2 /day, 3 patients experienced neutropenia in cycle 2. The dose of 2.0 mg/m 2 /day was well tolerated in 6 patients. In 7-day infusion, grade 4 neutropenia was DLT at 4.0 mg/m 2 /day. The maximum tolerated dose was 3 mg/m 2 /day. Other toxicities included nausea, vomiting, diarrhea, neutropenia, and alopecia. Eight patients had stable disease for >12 weeks. Paired comet assays performed for 7 patients showed an increase in DNA strand breaks at day 8. Pharmacokinetic data showed dose-proportionality for steady-state concentration and AUC of DFP-10917 and its primary metabolite. Conclusion Continuous infusion of DFP-10917 is feasible and well tolerated with myelosuppression as main DLT. The recommended doses are 2.0 mg/m 2 /day and 3.0 mg/m 2 /day on the 14-day and 7-day continuous infusion schedules, respectively. Preliminary activity was suggested. Pharmacodynamic data demonstrate biological activity at the tested doses.

Background: There is increasing evidence that primary tumor ablation can improve survival for some cancer patients with distant metastases. This may be particularly applicable to head and neck squamous cell carcinoma (HNSCC) because of its tropism for locoregional progression., Methods: This study included patients with metastatic HNSCC undergoing systemic therapy identified in the National Cancer Data Base. High-intensity local treatment was defined as radiation doses ≥ 60 Gy or oncologic resection of the primary tumor. Multivariate Cox regression, propensity score matching, landmark analysis, and subgroup analysis were performed to account for imbalances in covariates, including adjustments for the number and location of metastatic sites in the subset of patients with this information available., Results: In all, 3269 patients were included (median follow-up, 51.5 months). Patients undergoing systemic therapy with local treatment had improved survival in comparison with patients receiving systemic therapy alone in propensity score-matched cohorts (2-year overall survival, 34.2% vs 20.6%; P < .001). Improved survival was associated only with patients receiving high-intensity local treatment, whereas those receiving lower-intensity local treatment had survival similar to that of patients receiving systemic therapy without local treatment. The impact of high-intensity local therapy was time-dependent, with a stronger impact within the first 6 months after the diagnosis (adjusted hazard ratio [AHR], 0.255; 95% confidence interval [CI], 0.210-0.309; P < .001) in comparison with more than 6 months after the diagnosis (AHR, 0.622; 95% CI, 0.561-0.689; P < .001) in the multivariate analysis. A benefit was seen in all subgroups, in landmark analyses of 1-, 2-, and 3-year survivors, and when adjusting for the number and location of metastatic sites., Conclusions: Aggressive local treatment warrants prospective evaluation for select patients with metastatic HNSCC. Cancer 2017;123:4583-4593. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Background: Dinaciclib is a potent inhibitor of cell cycle and transcriptional cyclin-dependent kinases. This Phase 1 study evaluated the safety, tolerability and pharmacokinetics of various dosing schedules of dinaciclib in advanced solid tumour patients and assessed pharmacodynamic and preliminary anti-tumour activity., Methods: In part 1, patients were enrolled in escalating cohorts of 2-h infusions administered once every 3 weeks, utilising an accelerated titration design until a recommended phase 2 dose (RP2D) was defined. In part 2, 8- and 24-h infusions were evaluated. Pharmacokinetic parameters were determined for all schedules. Pharmacodynamic effects were assessed with an ex vivo stimulated lymphocyte proliferation assay performed in whole blood.Effects of dinaciclib on retinoblastoma (Rb) phosphorylation and other CDK targets were evaluated in skin and tumour biopsies. In addition to tumour size, metabolic response was evaluated by 18F-fluorodeoxyglucose-positron emission tomography., Results: Sixty-one patients were enrolled to parts 1 and 2. The RP2Ds were 50, 7.4 and 10.4 mg m -2 as 2- 8- and 24-hour infusions, respectively. Dose-limiting toxicities included pancytopenia, neutropenic fever, elevated transaminases, hyperuricemia and hypotension. Pharmacokinetics demonstrated rapid distribution and a short plasma half-life. Dinaciclib suppressed proliferation of stimulated lymphocytes. In skin and tumour biopsies, dinaciclib reduced Rb phosphorylation at CDK2 phospho-sites and modulated expression of cyclin D1 and p53, suggestive of CDK9 inhibition. Although there were no RECIST responses, eight patients had prolonged stable disease and received between 6 and 30 cycles. Early metabolic responses occurred., Conclusions: Dinaciclib is tolerable at doses demonstrating target engagement in surrogate and tumour tissue.

Background: The treatment of head and neck cancers is complex and associated with significant morbidity, requiring multidisciplinary care and physician expertise. Thus, facility characteristics, such as clinical volume and academic status, may influence outcomes., Methods: The current study included 46,567 patients taken from the National Cancer Data Base who were diagnosed with locally advanced invasive squamous cell carcinomas of the oropharynx, larynx, and hypopharynx and were undergoing definitive radiotherapy. High-volume facilities (HVFs) were defined as the top 1% of centers by the number of patients treated from 2004 through 2012. Multivariable Cox regression and propensity score matching were performed to account for imbalances in covariates., Results: The median follow-up was 55.1 months. Treatment at a HVF (hazard ratio, 0.798; 95% confidence interval, 0.753-0.845 [P<.001]) and treatment at an academic facility (hazard ratio, 0.897; 95% confidence interval, 0.871-0.923 [P<.001]) were found to be independently associated with improved overall survival in multivariable analysis. In propensity score-matched cohorts, the 5-year overall survival rate was 61.6% versus 55.5% for patients treated at an HVF versus lower-volume facilities, respectively (P<.001). Similarly, the 5-year overall survival rate was 52.3% versus 49.7% for patients treated at academic versus nonacademic facilities (P<.001). Analysis of facility volume as a continuous variable demonstrated continual improvement in survival with an increased number of patients treated. The impact of facility volume and academic designation on survival was observed when using a variety of thresholds to define HVF, and across the vast majority of subgroups, including both oropharyngeal and nonoropharyngeal subsites., Conclusions: Patients with locally advanced head and neck squamous cell carcinoma who are undergoing curative radiotherapy at HVFs and academic centers appear to have improved survival. Cancer 2017;123:3933-42. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

The tumor-selective viral replication capacity and pro-apoptotic effects of oncolytic reovirus have been reported to be dependent on the presence of an activated RAS pathway in several solid tumor types. However, the mechanisms of selective anticancer efficacy of the reovirus-based formulation for cancer therapy (Reolysin, pelareorep) have not been rigorously studied in soft tissue sarcomas (STS). Here we report that Reolysin triggered a striking induction of the anti-angiogenic chemokine interferon-γ-inducible protein 10 (IP-10)/CXCL10 (CXC chemokine ligand 10) in both wild type and RAS mutant STS cells. Further analysis determined that Reolysin treatment possessed significant anti-angiogenic activity irrespective of RAS status. In addition to CXCL10 induction, Reolysin dramatically downregulated the expression of hypoxia inducible factor (HIF)-1α, HIF-2α and inhibited vascular endothelial growth factor (VEGF) secretion. CXCL10 antagonism significantly diminished the anti-angiogenic effects of Reolysin indicating that it is a key driver of this phenomenon. Xenograft studies demonstrated that Reolysin significantly improved the anticancer activity of the anti-angiogenic agents sunitinib, temsirolimus, and bevacizumab in a manner that was associated with increased CXCL10 levels. This effect was most pronounced following treatment with Reolysin in combination with temsirolimus. Further analysis in additional sarcoma xenograft models confirmed the significant increase in CXCL10 and increased anticancer activity of this combination. Our collective results demonstrate that Reolysin possesses CXCL10-driven anti-angiogenic activity in sarcoma models, which can be harnessed to enhance the anticancer activity of temsirolimus and other agents that target the tumor vasculature., Competing Interests: CONFLICTS OF INTEREST The authors have no conflicts of interest to declare.

Purpose We assessed the safety and antitumor activity of avelumab, a fully human anti-programmed death-ligand 1 (PD-L1) IgG1 antibody, in patients with refractory metastatic urothelial carcinoma. Methods In this phase Ib, multicenter, expansion cohort, patients with urothelial carcinoma progressing after platinum-based chemotherapy and unselected for PD-L1 expression received avelumab 10 mg/kg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary objectives included confirmed objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), progression-free survival, overall survival (OS), and PD-L1-associated clinical activity. PD-L1 positivity was defined as expression by immunohistochemistry on ≥ 5% of tumor cells. Results Forty-four patients were treated with avelumab and followed for a median of 16.5 months (interquartile range, 15.8 to 16.7 months). The data cutoff was March 19, 2016. The most frequent treatment-related adverse events of any grade were fatigue/asthenia (31.8%), infusion-related reaction (20.5%), and nausea (11.4%). Grades 3 to 4 treatment-related adverse events occurred in three patients (6.8%) and included asthenia, AST elevation, creatine phosphokinase elevation, and decreased appetite. The confirmed objective response rate by independent central review was 18.2% (95% CI, 8.2% to 32.7%; five complete responses and three partial responses). The median duration of response was not reached (95% CI, 12.1 weeks to not estimable), and responses were ongoing in six patients (75.0%), including four of five complete responses. Seven of eight responding patients had PD-L1-positive tumors. The median progression-free survival was 11.6 weeks (95% CI, 6.1 to 17.4 weeks); the median OS was 13.7 months (95% CI, 8.5 months to not estimable), with a 12-month OS rate of 54.3% (95% CI, 37.9% to 68.1%). Conclusion Avelumab was well tolerated and associated with durable responses and prolonged survival in patients with refractory metastatic UC.

Purpose: Cabazitaxel has not been studied in patients with hepatic impairment (HI). This phase I study assessed cabazitaxel safety and pharmacokinetics in patients with HI., Methods: Patients with advanced, non-hematologic cancer, and normal hepatic function (Cohort 1: C-1), or mild (C-2), moderate (C-3), severe (C-4) HI received cabazitaxel starting doses of 25, 20, 10, and 10 mg/m 2 , respectively. Doses were escalated in patients with HI based on Cycle 1 dose-limiting toxicities (DLTs). Adverse events and the cabazitaxel pharmacokinetic profile were assessed., Results: In C-2, three patients receiving cabazitaxel 25 mg/m 2 experienced DLTs; maximum tolerated dose (MTD) was 20 mg/m 2 . In C-3, two patients receiving 20 mg/m 2 experienced DLTs; MTD was 15 mg/m 2 . C-4 was discontinued early due to DLTs. The most frequent cabazitaxel-related, grade 3-4 toxicity was neutropenia (42%). Cabazitaxel clearance normalized to body surface area (CL/BSA) was lower in C-1 (geometric mean [GM] 13.4 L/h/m 2 ) than expected (26.4 L/h/m 2 ), but similar in C-2 (23.5 L/h/m 2 ) and C-3 (27.9 L/h/m 2 ). CL/BSA in C-4 was 18.1 L/h/m 2 . Compared with C-2, CL/BSA increased 19% in C-3 (GM ratio 1.19; 90% CI 0.74-1.91), but decreased 23% in C-4 (0.77; 0.39-1.53). Cabazitaxel free fraction was unaltered. No significant correlation was found between grade 3-4 toxicities and pharmacokinetic parameters., Conclusions: Mild-moderate HI did not cause substantial decline in cabazitaxel clearance. Cabazitaxel dose reductions in patients with mild-moderate HI, and a contraindication in patients with severe HI, are justified based on safety data., Competing Interests: Compliance with ethical standardsConflict of interestJohn Sarantopoulos, Jimmy Hwang, James Mier, and Aiwu He have no conflicts of interest to disclose. Olivier Rixe has been a member of advisory boards for Areva Med and Sisene Oncology. John C. Morris has participated at speaker bureaus for Boehringer Ingelheim. Alain C. Mita has participated at speaker bureaus for Genentech. James L. Wade is a stockholder of Celgene and Seattle Genetics. A. Craig Lockhart has received research funding from Amgen, Bayer, Lilly, Novartis, Pfizer, and Genentech. David I. Quinn has received research funding and honoraria from Sanofi and has been a member of advisory boards for Sanofi. Chung-Tsen Hsueh has been a member of advisory boards for Bayer, Merrimack, and Onyx. Pierre-François Clot is an employee of Sanofi. Wenping Zhang, Claudine Wack, and Jian Yin are employees and stock holders of Sanofi.Ethical approvalAll procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional and/or National Research Committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

Introduction: This phase I trial was conducted to determine the safety, maximum tolerated dose (MTD)/recommended phase II dose, and efficacy of crizotinib plus erlotinib in patients with advanced NSCLC., Methods: Patients with NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 2 after failure of one or two prior chemotherapy regimens were eligible. Erlotinib, 100 mg, was given continuously once daily starting between day -14 and -7; crizotinib, 200 mg twice daily (dose level 1) or 150 mg twice daily (dose level -1), was added continuously beginning on day 1 of treatment cycle 1. Potential pharmacokinetic interactions between crizotinib and erlotinib were evaluated., Results: Twenty-seven patients received treatment; 26 received crizotinib plus erlotinib. Frequent adverse events were diarrhea, rash, decreased appetite, and fatigue. Dose-limiting toxicities were dehydration, diarrhea, dry eye, dysphagia, dyspepsia, esophagitis and vomiting. The MTD was crizotinib, 150 mg twice daily, with erlotinib, 100 mg once daily. Crizotinib increased the erlotinib area under the concentration-time curve 1.5-fold (dose level -1) and 1.8-fold (dose level 1). The plasma level of crizotinib appeared to be unaffected by coadministration of erlotinib. Two patients whose tumors harbored activating EGFR mutations achieved confirmed partial responses, one at each crizotinib dose level., Conclusions: The MTD of the combination of crizotinib and erlotinib in patients with advanced NSCLC was crizotinib, 150 mg twice daily, with erlotinib, 100 mg once daily, which is less than the approved dose of either agent. The phase II portion of the study was not initiated., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: First-in-human phase I trial to determine the safety, pharmacokinetics, and antitumor activity of BIND-014, a novel, tumor prostate-specific membrane antigen (PSMA)-targeted nanoparticle, containing docetaxel., Experimental Design: Patients with advanced solid tumors received BIND-014 every three weeks (n = 28) or weekly (n = 27), with dose levels ranging from 3.5 to 75 mg/m(2) and 15 to 45 mg/m(2), respectively., Results: BIND-014 was generally well tolerated, with no unexpected toxicities. The most common drug-related toxicities (>20% of patients) on either schedule included neutropenia, fatigue, anemia, alopecia, and diarrhea. BIND-014 demonstrated a dose-linear pharmacokinetic profile, distinct from docetaxel, with prolonged persistence of docetaxel-encapsulated circulating nanoparticles. Of the 52 patients evaluable for response, one had a complete response (cervical cancer on the every three week schedule) and five had partial responses (ampullary adenocarcinoma, non-small cell lung, and prostate cancers on the every-three-week schedule, and breast and gastroesophageal cancers on the weekly schedule). Responses were noted in both PSMA-detectable and -undetectable tumors., Conclusions: BIND-014 was generally well tolerated, with predictable and manageable toxicity and a unique pharmacokinetic profile compared with conventional docetaxel. Clinical activity was noted in multiple tumor types. The recommended phase II dose of BIND-014 is 60 mg/m(2) every three weeks or 40 mg/m(2) weekly. Clin Cancer Res; 22(13); 3157-63. ©2016 AACR., (©2016 American Association for Cancer Research.)

Reovirus is a double-stranded RNA virus with demonstrated oncolysis or preferential replication in cancer cells. The oncolytic properties of reovirus appear to be dependent, in part, on activated Ras signaling. In addition, Ras-transformation promotes reovirus oncolysis by affecting several steps of the viral life cycle. Reovirus-mediated immune responses can present barriers to tumor targeting, serve protective functions against reovirus systemic toxicity, and contribute to therapeutic efficacy through antitumor immune-mediated effects via innate and adaptive responses. Preclinical studies have demonstrated the broad anticancer activity of wild-type, unmodified type 3 Dearing strain reovirus (Reolysin(®)) across a spectrum of malignancies. The development of reovirus as an anticancer agent and available clinical data reported from 22 clinical trials will be reviewed.

Objectives: Alisertib (MLN8237) is an investigational, oral, small-molecule, selective inhibitor of Aurora A kinase. Phase I/II studies of powder-in-capsule (PIC) and enteric-coated tablet formulations of alisertib have determined the recommended phase II dose and have demonstrated anti-tumor activity. This phase I relative bioavailability study characterized the pharmacokinetics of a prototype oral solution (OS) of alisertib (developed for patients unable to swallow solid dosage forms) in reference to the PIC formulation in adult cancer patients., Materials and Methods: A safety evaluation was undertaken first following a 3+3 design (OS starting dose, 15 mg). The relative bioavailability of alisertib OS vs. PIC was then evaluated following single dose administration of alisertib OS 25 mg and PIC 50 mg, using a 2-way crossover study design., Results: The relative bioavailability (geometric mean dose-normalized AUCinf ratio) of alisertib OS vs. PIC formulation was 1.26 (90% confidence interval (CI): 1.09-1.47 (OS, n=17; PIC, n=18 evaluable patients)). These results support a distinguishable difference in bioavailability of alisertib between the two formulations (lower bound of 90% CI>1), with an estimated 26% higher total systemic exposure with alisertib OS vs. PIC. Alisertib absorption from OS was faster than from PIC, with a shorter median tmax (OS, 1 hour; PIC, 2 hours) and a geometric mean dose-normalized Cmax ratio (OS vs. PIC) of 1.90 (90% CI: 1.52 - 2.37)., Conclusions: These findings inform the starting dose of alisertib OS to support further clinical evaluation of alisertib in patients unable to swallow solid dosage forms.

Elevated expression of the antiapoptotic factor survivin has been implicated in cancer cell survival and disease progression. However, its specific contribution to renal cell carcinoma (RCC) pathogenesis is not well defined. We investigated the roles of survivin in RCC tumor progression, resistance to mTOR inhibitors, and evaluated the therapeutic activity of the survivin suppressant YM155 in RCC models. Here, we report that survivin expression levels were significantly higher in RCC cell lines compared with normal renal cells. Stable targeted knockdown of survivin completely abrogated the ability of 786-O RCC tumors to grow in mice, thus demonstrating its importance as a regulator of RCC tumorigenesis. We next explored multiple strategies to therapeutically inhibit survivin function in RCC. Treatment with the mTOR inhibitor temsirolimus partially diminished survivin levels and this effect was augmented by the addition of YM155. Further analyses revealed that, in accordance with their combined anti-survivin effects, YM155 significantly improved the anticancer activity of temsirolimus in a panel of RCC cell lines in vitro and in xenograft models in vivo. Similar to pharmacologic inhibition of survivin, shRNA-mediated silencing of survivin expression not only inhibited RCC tumor growth, but also significantly sensitized RCC cells to temsirolimus therapy. Subsequent experiments demonstrated that the effectiveness of this dual survivin/mTOR inhibition strategy was mediated by a potent decrease in survivin levels and corresponding induction of apoptosis. Our findings establish survivin inhibition as a novel approach to improve RCC therapy that warrants further investigation., (©2015 American Association for Cancer Research.)

Introduction Aldoxorubicin, a prodrug of doxorubicin, binds covalently to serum albumin in the bloodstream and accumulates in tumors. Aldoxorubicin can be administered at doses several-fold higher than doxorubicin can, without associated acute cardiotoxicity. Purpose This study fully evaluated the pharmacokinetic profile of aldoxorubicin (serum and urine). Methods Eighteen patients with advanced solid tumors received aldoxorubicin 230 or 350 mg/m(2) (equivalent in drug load to doxorubicin at doses of 170 or 260 mg/m(2), respectively) once every 21 days. Blood samples were taken in cycle 1 before aldoxorubicin infusion, and at 5, 15, 30, and 60 min, and at 2, 4, 8, 12, 16, 24, 48, and 72 h after infusion. Urine samples were taken in cycle 1 at 24, 48, and 72 h after infusion. Limited blood sampling was done in cycle 3, before aldoxorubicin infusion, and at 60 min and at 2, 4, and 8 h after infusion. Results The long mean half-life (20.1-21.1 h), narrow mean volume of distribution (3.96-4.08 L/m(2)), and slow mean clearance rate (0.136-0.152 L/h/m(2)) suggest that aldoxorubicin is stable in circulation and does not accumulate readily in body compartments outside of the bloodstream. Very little doxorubicin and its major metabolite doxorubicinol, which has been implicated in doxorubicin-associated cardiotoxicity, are excreted in urine. This might explain the lack of cardiotoxicity observed thus far with aldoxorubicin. Conclusions Our findings support dosing and administration schemas used in an ongoing phase 3 clinical study of aldoxorubicin in soft tissue sarcoma, and phase 2 clinical studies in small cell lung cancer, glioblastoma, and Kaposi's sarcoma.

Purpose: Distinct molecular subgroups of medulloblastoma, including hedgehog (Hh) pathway-activated disease, have been reported. We identified and clinically validated a five-gene Hh signature assay that can be used to preselect patients with Hh pathway-activated medulloblastoma., Experimental Design: Gene characteristics of the Hh medulloblastoma subgroup were identified through published bioinformatic analyses. Thirty-two genes shown to be differentially expressed in fresh-frozen and formalin-fixed paraffin-embedded tumor samples and reproducibly analyzed by RT-PCR were measured in matched samples. These data formed the basis for building a multi-gene logistic regression model derived through elastic net methods from which the five-gene Hh signature emerged after multiple iterations. On the basis of signature gene expression levels, the model computed a propensity score to determine Hh activation using a threshold set a priori. The association between Hh activation status and tumor response to the Hh pathway inhibitor sonidegib (LDE225) was analyzed., Results: Five differentially expressed genes in medulloblastoma (GLI1, SPHK1, SHROOM2, PDLIM3, and OTX2) were found to associate with Hh pathway activation status. In an independent validation study, Hh activation status of 25 medulloblastoma samples showed 100% concordance between the five-gene signature and Affymetrix profiling. Further, in medulloblastoma samples from 50 patients treated with sonidegib, all 6 patients who responded were found to have Hh-activated tumors. Three patients with Hh-activated tumors had stable or progressive disease. No patients with Hh-nonactivated tumors responded., Conclusions: This five-gene Hh signature can robustly identify Hh-activated medulloblastoma and may be used to preselect patients who might benefit from sonidegib treatment., (©2014 American Association for Cancer Research.)

Purpose: Cabazitaxel is primarily metabolized by CYP3A. This study evaluated the impact of moderate/strong CYP3A inhibitors [aprepitant (Study Part 2); ketoconazole (Study Part 3)] or strong CYP3A inducers [rifampin (Study Part 4)] on the pharmacokinetics of cabazitaxel., Methods: Adult patients received IV cabazitaxel/cisplatin 15/75 mg/m(2) on Day 1 of 3-week cycles (5/75 mg/m(2) in Cycles 1 and 2 of Part 3 to allow a safety margin to the cabazitaxel MTD). Patients received repeated oral doses of aprepitant, ketoconazole or rifampin before/during Cycle 2. Cabazitaxel clearance was the primary endpoint; clearance and area under the plasma concentration-time curve (AUC) were normalized to body surface area and dose, respectively., Results: The PK population included 13 (Part 2), 23 (Part 3) and 21 patients (Part 4). Repeated aprepitant administration did not affect cabazitaxel clearance [geometric mean ratio (GMR) 0.98; 90 % confidence interval (CI) 0.80-1.19]. Repeated ketoconazole administration resulted in 20 % decrease in cabazitaxel clearance (GMR 0.80; 90 % CI 0.55-1.15), associated with 25 % increase in AUC (GMR 1.25; 90 % CI 0.86-1.81). Repeated rifampin administration resulted in 21 % increase in cabazitaxel clearance (GMR 1.21; 90 % CI 0.95-1.53), associated with 17 % decrease in AUC (GMR 0.83; 90 % CI 0.65-1.05). The GMR of AUC0-24 with rifampin administration was 1.09 (90 % CI 0.9-1.33), suggesting that rifampin had a low impact during the initial phases of cabazitaxel elimination. Safety findings were consistent with previous results., Conclusions: Cabazitaxel pharmacokinetics are modified by drugs strongly affecting CYP3A. Co-administration of cabazitaxel with strong CYP3A inhibitors or inducers should be avoided.

Purpose: ATI-1123 is a liposomal formulation of docetaxel and may be administered without the premedications and hypersensitivity reactions. This Phase I study examines the safety, tolerability, pharmacokinetics (PKs), and antitumor activity of ATI-1123., Methods: Patients with advanced solid malignancies received escalating doses of ATI-1123 intravenously over 1-h every 3 weeks. The dosing commenced using an accelerated titration design and was followed by a modified 3 + 3 Fibonacci schema to determine maximally tolerated dose (MTD). Plasma was analyzed for encapsulated/non-encapsulated docetaxel; PK analyses were performed using model independent method. Response was assessed using RECIST criteria., Results: In total, 29 patients received doses ranging from 15 to 110 mg/m(2). At 110 mg/m(2), two of six patients experienced dose-limiting toxicities including grade 3 stomatitis and febrile neutropenia. The 90 mg/m(2) cohort was expanded to ten patients and identified as the MTD. The most common adverse events were fatigue, nausea, neutropenia, anemia, anorexia, and diarrhea. ATI-1123 exhibited linear and dose proportional PKs. One patient with lung cancer had confirmed partial response, and stable disease was observed in 75 % patients., Conclusions: ATI-1123 demonstrated an acceptable tolerability and favorable PK profile in patients with solid tumors. Our results provide support for Phase II trials to determine the antitumor activity of this drug.

Introduction: Cabazitaxel is a second-generation taxane with in vivo activity against taxane-sensitive and -resistant tumor cell lines and tumor xenografts. Cabazitaxel/cisplatin have therapeutic synergism in tumor-bearing mice, providing a rationale for assessing this combination in patients with solid tumors., Methods: The primary objectives of this study were to determine dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of a cabazitaxel/cisplatin combined regimen (Part 1) and to assess antitumor activity at the MTD (Part 2). Safety and pharmacokinetics (PK) were also examined., Results: Twenty-five patients with advanced solid tumors were enrolled (10 in Part 1; 15 in Part 2). In Part 1, two dose levels were evaluated; the MTD for cabazitaxel/cisplatin (given Q3W) was 15/75 mg/m(2). DLTs occurring during Cycle 1 at the maximum administered dose (20/75 mg/m(2); acute renal failure and febrile neutropenia) and the MTD (febrile neutropenia and hypersensitivity despite pre-medication) were as expected for taxane/platinum combinations. For the 18 patients treated at the MTD, the most frequent possibly related non-hematologic treatment-emergent adverse events (Grade ≥ 3) were nausea (16.7%), fatigue, acute renal failure and decreased appetite (each 11.1%). Neutropenia was the most frequent treatment-emergent Grade ≥ 3 hematologic laboratory abnormality at the MTD (77.8%). The best overall response at the MTD was stable disease, observed in 66.7% of patients. PK results of the combination did not appear to differ from single-agent administration for each agent., Conclusion: Combination treatment with cabazitaxel/cisplatin had a manageable safety profile; no PK interactions were evident. The recommended Phase II dose for this combination is cabazitaxel/cisplatin 15/75 mg/m(2) administered every 3 weeks. Antitumor activity findings suggest that further evaluation of this combination in disease-specific trials is warranted.

Background: CBP501, a synthetic duodecapeptide, increases cisplatin influx into tumor cells through an interaction with calmodulin enhancing cisplatin cytotoxicity, and effects cell cycle progression by abrogating DNA repair at the G2 checkpoint. In phase I clinical trials of CBP501 alone or in combination with cisplatin, the most common toxicity was infusion-related urticaria. Activity of CBP501 plus cisplatin was observed in patients with ovarian cancer and mesothelioma, including some patients previously treated with cisplatin., Methods: Chemotherapy naïve patients with unresectable MPM were stratified by histology and performance status, and randomized 2:1 to pemetrexed/cisplatin plus CBP501 25mg/m(2) IV (Arm A) or pemetrexed/cisplatin alone (Arm B). The primary endpoint was progression free survival (PFS) at 4 months., Results: 65 patients were randomized, and 63 were treated. Patient characteristics in the two arms were balanced. Based on independent radiology review of the treated population, 25/40 patients (63%) in Arm A and 9/23 (39%) in Arm B had PFS≥4mo; the median PFS was 5.1mo (95% CI, 3.9, 6.5) vs 3.4mo (2.5, 6.7). Median OS was 13.3mo (9.2, 16.3) in Arm A and 12.8 (6.5, 16.1) in Arm B. Adverse events were not different than expected from standard chemotherapy, and comparable in the two arms, aside from infusion reactions which occurred in 70% of patients treated with CBP501., Conclusions: While this randomized phase II trial met its primary endpoint of PFS at 4 months, other parameters such as response rate and overall survival suggest that the addition of CBP501 does not improve the efficacy of standard chemotherapy for MPM., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

We previously reported that inhibition of autophagy significantly augmented the anticancer activity of the histone deacetylase (HDAC) inhibitor vorinostat (VOR) through a cathepsin D-mediated mechanism. We thus conducted a first-in-human study to investigate the safety, preliminary efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of the combination of the autophagy inhibitor hydroxychloroquine (HCQ) and VOR in patients with advanced solid tumors. Of 27 patients treated in the study, 24 were considered fully evaluable for study assessments and toxicity. Patients were treated orally with escalating doses of HCQ daily (QD) (d 2 to 21 of a 21-d cycle) in combination with 400 mg VOR QD (d one to 21). Treatment-related adverse events (AE) included grade 1 to 2 nausea, diarrhea, fatigue, weight loss, anemia, and elevated creatinine. Grade 3 fatigue and/or myelosuppression were observed in a minority of patients. Fatigue and gastrointestinal AE were dose-limiting toxicities. Six-hundred milligrams HCQ and 400 mg VOR was established as the maximum tolerated dose and recommended phase II regimen. One patient with renal cell carcinoma had a confirmed durable partial response and 2 patients with colorectal cancer had prolonged stable disease. The addition of HCQ did not significantly impact the PK profile of VOR. Treatment-related increases in the expression of CDKN1A and CTSD were more pronounced in tumor biopsies than peripheral blood mononuclear cells. Based on the safety and preliminary efficacy of this combination, additional clinical studies are currently being planned to further investigate autophagy inhibition as a new approach to increase the efficacy of HDAC inhibitors.

Background: IMO-2055 is a Toll-like receptor 9 (TLR9) agonist that potentially enhances the efficacy of antitumor agents through immune stimulation. The objective of this phase Ib dose-escalation trial (3 + 3 design) was to determine the recommended phase II dose (RP2D) of IMO-2055 when combined with erlotinib and bevacizumab in patients with advanced non-small cell lung cancer (NSCLC)., Methods: Patients with stage 3/4 NSCLC and progressive disease (PD) following chemotherapy received IMO-2055 0.08, 0.16, 0.32, or 0.48 mg/kg once weekly plus erlotinib 150 mg daily and bevacizumab 15 mg/kg every 3 weeks. Patients could receive treatment until PD or unacceptable toxicity., Results: Thirty-six patients were enrolled; 35 received at least one treatment dose. Two dose-limiting toxicities were observed across the dose range (Grade 3 dehydration and fatigue) with neither suggestive of a consistent toxicity pattern. IMO-2055 0.32 mg/kg was adopted as RP2D based on clinical and pharmacodynamic data. The most common treatment-emergent adverse events (TEAEs) were diarrhea (74 %), nausea (51 %), fatigue (51 %), rash (51 %), and injection-site reactions (49 %). Four patients experienced serious TEAEs considered to be study drug related. Five patients died, all due to PD. High-grade neutropenia and electrolyte disturbances previously reported with TLR9 agonists combined with platinum-based therapy were not observed in this study. Five of 33 patients evaluable for response (15 %) achieved partial response; another 20 (61 %) had stable disease, including 13 with stable disease ≥4 months., Conclusions: IMO-2055 demonstrated good tolerability and possible antitumor activity in combination with erlotinib and bevacizumab in heavily pretreated patients with advanced NSCLC.

Study Objective: To assess the dose proportionality of azacitidine pharmacokinetics (PK) after single subcutaneous (SC) doses of 25-100 mg/m2, and determine the effect of renal impairment on PK after single and multiple 75 mg/m2 SC azacitidine doses., Design: Multicenter, phase I, open-label, parallel group study., Setting: Community clinics and major academic centers., Patients: Twenty-seven patients with solid or hematologic malignancies., Interventions: Part 1 evaluated azacitidine dose proportionality in patients with normal renal function randomized to single 25, 50, 75, or 100 mg/m2 SC doses. The 75 mg/m2 dosing group received 4 additional days of SC azacitidine. In Part 2, patients with severe renal impairment (creatinine clearance < 30 ml/min/1.73 m2 Cockcroft-Gault adjusted) received azacitidine 75 mg/m2 for 5 consecutive days., Measurements and Main Results: PK parameters were determined using noncompartmental methods. In patients with normal renal function (n=21), azacitidine area under the plasma-time curve (AUC0-∞) and maximum observed plasma concentration (Cmax) were dose proportional within the 25-100 mg/m2 range. Concentration versus time profiles after single and multiple azacitidine 75 mg/m2 doses were similar in shape for patients with normal (n=6) or impaired renal function (n=6), with higher mean concentrations in the latter group. Higher mean exposures (AUC0-∞ and Cmax) in renally impaired patients were observed; however, individual exposure values were, with few exceptions, within the same range in both groups. No drug accumulation after multiple doses was observed in either group. Terminal half-life and time to maximum plasma concentration were comparable between groups. Azacitidine tolerability was similar in patients with normal or impaired renal function., Conclusion: Azacitidine is dose proportional over the 25-100 mg/m2 dosing range. Overall, renal impairment had no important effect on azacitidine PK. Therefore, no initial azacitidine dose adjustment in patients with renal impairment is required.

Purpose: This phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors., Experimental Design: Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose pharmacokinetics run-in period. Dose escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, pharmacokinetics, and biomarkers in skin and tumor biopsies were assessed., Results: The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of patients) was observed at doses ≥ the MTD in an exposure-dependent manner. Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib exposure increased dose proportionally up to 400 mg daily, and displayed nonlinear pharmacokinetics at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with medulloblastoma and BCC were associated with evidence of hedgehog pathway activation., Conclusions: Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed medulloblastoma, both of which are strongly associated with activated hedgehog pathway, as determined by gene expression., (©2014 AACR.)

Purpose: To evaluate the pharmacokinetics and cardiac repolarization effect (measured by QT/QTc interval) of amrubicin and its active metabolite amrubicinol in non-Japanese patients with advanced solid tumors., Methods: Patients received amrubicin 40 mg/m(2)/day as a 5-min infusion on days 1-3 of a 21-day cycle. During cycle 1, serial blood and plasma samples were collected on days 1-9 and time-matched triplicate electrocardiograms on the "off-drug" visit (1-5 days prior to start of treatment) and days 1-9., Results: Twenty-four patients were treated. Amrubicinol reached peak concentration 2-4 h after amrubicin administration and had a terminal half-life of 53 h. Distribution of amrubicinol into erythrocytes was fivefold greater than into plasma. The molar ratio of amrubicinol to amrubicin in blood was 0.67 on day 3. The presence of an NQO1 polymorphism did not alter drug exposure. The upper bound of the one-sided 95 % confidence interval for the time-matched, baseline-adjusted change from the off-drug day in QTcI (individual correction) was <10 ms at all times and was only >10 ms (10.20 ms) at a single time point for QTcF (Fridericia correction). No relationship was observed between blood amrubicin or amrubicinol concentrations and QTcF changes. All QTcF measurements were <480 ms, and none increased by >60 ms from baseline., Conclusions: Data suggest that amrubicinol is an important active metabolite in humans and that both compounds were not associated with clinically relevant QTc interval prolongation at the dose regimen studied.

Introduction: Vascular-disrupting agents (VDAs) are a new class of oncology drugs, which specifically target established tumor neovasculature and have a relatively low toxicity profile. VDAs generally have non-overlapping side effects when concomitantly used with conventional cytotoxics. Several members of the VDA class have recently progressed through mid-to-late stages of clinical trials., Areas Covered: We examined recent publications on preclinical findings and Phase I/II/III clinical trial data on mechanisms of actions, toxicities, and optimal use of VDA class drugs. It is becoming apparent that VDAs should be used in combination with other classes of cytotoxic agents for the optimization of their effect in treating various cancers. In this article we describe doses, timing of delivery, and sequence of combined therapy. We also address the combined mechanisms of actions of VDAs and conventional cytotoxic medications., Expert Opinion: Vascular-disrupting agents represent a new class of promising anticancer agents, which exhibit synergistic and/or additive effects in combination with many conventional cytotoxics. Pharmacological evaluation of the optimal combinations of VDAs with agents of other classes and drug interactions need to be continued. Further clinical and preclinical studies are required for distinguishing cancer patients' subpopulations that would most benefit from VDAs, identifying tumor biomarkers predictive of response as well as reliable and reproducible imaging and/or biological assays indicative of pharmacodynamic effects, and establishing clinical algorithms for treatment.

The taxanes are recognized as a major class of chemotherapeutic agents; however, mechanisms of innate and acquired resistance can limit their usefulness. Cabazitaxel, a novel taxane with microtubule-stabilizing potency similar to docetaxel, exhibits activity against tumor cell lines resistant to paclitaxel and docetaxel. Cabazitaxel showed linear pharmacokinetics and a terminal elimination half-life comparable with that of docetaxel, findings which support dosing as a single infusion in three-week treatment cycles. Dose-ranging studies recommended doses of 20 or 25 mg/m(2) every three weeks. Antitumor activity was shown in patients with advanced cancer and chemotherapy failure (including taxane failure). Other early studies investigated the efficacy of cabazitaxel in pretreated metastatic breast cancer, either as a single agent or in combination with capecitabine. Objective antitumor response rates of up to 24% and sustained tumor stabilizations were also observed. The TROPIC phase III study, conducted in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel, established cabazitaxel as the first chemotherapeutic agent to offer a survival advantage in this patient population. Across these studies, the dose-limiting hematologic toxicity was neutropenia (including febrile neutropenia), usually controllable with colony-stimulating factor/granulocyte-colony stimulating factor support., (©2012 AACR.)