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There are many design options for toxicity-driven phase 1 dose-finding in oncology drug development. Ultimately, if the target DLT-rate is 25%, the most commonly selected target, do the physicians need to have an acceptable interval of 0.16 to 0.33 or would it be just as reasonable to set the range as 0% to 33% DLT rate for the permissible doses? For the BLRM or related methods, this includes the DLT definition, the DLT-target, and the DLT-target acceptable range which are all very related. There are methods that are simple, traditional and transparent, such as the 3 + 31 or rolling 6 design2 that do not target a dose limiting toxicity (DLT)-rate and are focused on exploring escalating doses subject to limits on patient risk. [Extracted from the article]

Dose-finding in cancer clinical trials has been dominated by algorithmic designs on the principle that the highest tolerable dose is also the most effective dose. This assumption no longer applies to the biologic treatments that are characterized by different toxicity and/or efficacy profiles to the extent that the best therapeutic dose might be well below any dose that produces serious toxicity. As such, we propose a two-stage design with focus on immunotherapy trials, incorporating both safety and efficacy information. The first stage establishes the safety profile of each dose, with escalation decisions based on likelihood principles. Continuous immunologic outcomes are used to evaluate the relative efficacy of the doses. The second stage employs an adaptive randomization to assign patients to doses showing higher efficacy. Safety is being continuously monitored throughout Stage 2, where some doses may be ‘closed’ due to unacceptable toxicity. The proposed design is compared to the modified toxicity probability interval (mTPI) design using percent dose allocation and estimation of outcomes under different scenarios. We show that by using an efficacy-driven adaptive randomization with safety constraints, the allocation distribution is skewed towards more efficacious doses, and thus limit the number of patients exposed to toxic or non-therapeutic doses. Supplementary materials for this article are available online. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the clinical efficacy and tolerability of the combination of bevacizumab (B) and erlotinib (E) compared to sorafenib (S) as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Methods: A total of 90 patients with advanced HCC, Child-Pugh class A–B7 cirrhosis, and no prior systemic therapy were randomly assigned (1: 1) to receive either 10 mg/kg B intravenously every 14 days and 150 mg E orally daily (n = 47) (B+E) or 400 mg S orally twice daily (n = 43). The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), objective response rate based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1), time to progression, and safety and tolerability. Results: The median OS was 8.55 months (95% CI: 7.00–13.9) for patients treated with B+E and 8.55 months (95% CI: 5.69–12.2) for patients receiving S. The hazard ratio (HR) for OS was 0.92 (95% CI: 0.57–1.47). The median EFS was 4.37 months (95% CI: 2.99–7.36) for patients receiving B+E and 2.76 months (95% CI: 1.84–4.80) for patients receiving S. The HR for EFS was 0.67 (95% CI: 0.42–1.07; p = 0.09), favoring B+E over S. When OS was assessed among patients who were Child-Pugh class A, the median OS was 11.4 months (95% CI: 7.5–15.7) for patients treated with B+E (n = 39) and 10.26 months (95% CI: 5.9–13.0) for patients treated with S (n = 38) (HR = 0.88; 95% CI: 0.53–1.46). Conclusions: There was no difference in efficacy between the B+E and S arms, although the safety and tolerability profile tended to favor B+E over S based on competing risk analysis. [ABSTRACT FROM AUTHOR]

Introduction: The majority of smokers do not intend to quit in the near term, making unmotivated smokers a key group to target in public health efforts. Although it is often assumed that continuing smokers will have stable rates of smoking over time, limited research has addressed this issue, particularly among smokers not seeking treatment. In the current study, the aims were to (1) characterize the trajectory of naturalistic smoking among unmotivated smokers and (2) examine relationships between naturalistic smoking trajectories and other smoking-related variables.Methods: The study sample comprised 579 control-group (ie, untreated) smokers within a parent clinical trial, who completed a total of nine assessments over 1 year.Results: Trajectory modeling identified four smoking trajectory groups: stable (72%), shallow decreasers (20%), steep decreasers (5%), and increasers (3%). Membership in the decreasing groups was associated with higher motivation to quit, greater history of quit attempts, and higher cigarettes per day. Females were more likely to be in the increasing versus stable group.Conclusions: Findings provide needed information on stability and change in cigarette consumption over the course of 1 year among an untreated sample of smokers and identified baseline sociodemographic and smoking-related predictors of smoking trajectory group. Refining understanding of these groups is critical in updating population-based tobacco policy modeling efforts and informing cessation induction efforts that capitalize on naturalistic changes in smoking rate over time.Implications: In the current study, we found that approximately 25% of smokers who endorsed low quit motivation at baseline reduced their cigarette consumption over the course of a year, while 3% increased their cigarette consumption and the majority of smokers (72%) maintained a stable pattern. Refining understanding of smoking trajectories is critical in updating population-based tobacco policy modeling efforts and informing cessation induction efforts that capitalize on naturalistic changes in smoking rate over time. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to determine the effects of National Comprehensive Cancer Network (NCCN) guideline-adherent initiation of postoperative radiation therapy (PORT) and different time-to-PORT intervals on the overall survival (OS) of patients with head and neck squamous cell carcinoma (HNSCC).Methods: The National Cancer Data Base was reviewed for the period of 2006-2014, and patients with HNSCC undergoing surgery and PORT were identified. Kaplan-Meier survival estimates, Cox regression analysis, and propensity score matching were used to determine the effects of initiating PORT within 6 weeks of surgery and different time-to-PORT intervals on survival.Results: This study included 41,291 patients. After adjustments for covariates, starting PORT >6 weeks postoperatively was associated with decreased OS (adjusted hazard ratio [aHR], 1.13; 99% confidence interval [CI], 1.08-1.19). This finding remained in the propensity score-matched subset (hazard ratio, 1.21; 99% CI, 1.15-1.28). In comparison with starting PORT 5 to 6 weeks postoperatively, initiating PORT earlier was not associated with improved survival (aHR for ≤ 4 weeks, 0.93; 99% CI, 0.85-1.02; aHR for 4-5 weeks, 0.92; 99% CI, 0.84-1.01). Increasing durations of delay beyond 7 weeks were associated with small, progressive survival decrements (aHR, 1.09, 1.10, and 1.12 for 7-8, 8-10, and >10 weeks, respectively).Conclusions: Nonadherence to NCCN guidelines for initiating PORT within 6 weeks of surgery was associated with decreased survival. There was no survival benefit to initiating PORT earlier within the recommended 6-week timeframe. Increasing durations of delay beyond 7 weeks were associated with small, progressive survival decrements. Cancer 2017;123:4841-50. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Background: Adherence to evidence-based treatment guidelines has been proposed as a measure of cancer care quality. The objective of this study was to determine the rate and predictors of care that does not adhere to National Comprehensive Cancer Network guidelines regarding commencing postoperative radiation therapy (PORT) within 6 weeks of surgery for patients with head and neck squamous cell carcinoma (HNSCC).Methods: The National Cancer Data Base was reviewed from 2006 to 2014, and patients with HNSCC who underwent curative-intent surgery followed by PORT were identified. Multivariable logistic regression analysis was used to determine the factors associated with nonadherence to guidelines regarding the timing of initiating PORT.Results: In total, 47,273 patients were included in the study. 55.7% of patients (26,340/47,273) failed to commence PORT within 6 week of surgery. The percentage of patients who failed to initiate PORT within 6 week of surgery increased over time. On multivariable analysis, the factors associated with failure to initiate timely, guideline-adherent PORT included black race, public insurance [Medicare, Medicaid] or uninsured status, lower levels of education, increased severity of comorbidity, increased postoperative length of stay, 30-day unplanned hospital readmission, treatment at an academic medical center, and the receipt of surgery and PORT at different facilities.Conclusions: Over 50% of patients with HNSCC who undergo surgery and PORT receive care that does not adhere to National Comprehensive Cancer Network guidelines with regard to initiating PORT within 6 weeks of surgery. Sociodemographic, oncologic, treatment, and hospital factors are all associated with failure to receive guideline-directed care and should be explored in future studies. Cancer 2017;123:2651-60. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

The article presents a study by Sara Giordano, Elizabeth Garrett-Mayer, Navdha Mittal, Kristin Smith, Lee Shulman, Carolyn Passaglia, William Gradishar, and Mary Ellen Pavone on the association between BRCA1 mutations and the susceptibility of women to breast and ovarian cancer.

Comparisons of crude incidence and mortality rates for acute myeloid leukemia cannot be used to determine whether cancer clusters exist. Geographic data should be analyzed via spatial modeling with appropriate adjustments for known prognostic factors. [ABSTRACT FROM AUTHOR]

PURPOSE: TAPUR is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. The results of a cohort of patients with colorectal cancer (CRC) with BRAF mutations treated with cobimetinib (C) plus vemurafenib (V) are reported. METHODS: Eligible patients had advanced CRC, no standard treatment options, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, tumors with BRAF V600E/D/K/R mutations, and no MAP2K1/2 , MEK1/2 , or NRAS mutations. C was taken 60 mg orally once daily for 21 days followed by seven days off, and V was taken 960 mg orally twice daily. Simon's two-stage design was used with a primary study end point of objective response or stable disease of at least 16 weeks duration. Secondary end points were progression-free survival, overall survival, and safety. RESULTS: Thirty patients were enrolled from August 2016 to August 2018; all had CRC with a BRAF V600E mutation except one patient with a BRAF K601E mutation. Three patients were not evaluable for efficacy. Eight patients with partial responses and six patients with stable disease of at least 16 weeks duration were observed for disease control and objective response rates of 52% (95% CI, 35 to 65) and 30% (95% CI, 14 to 50), respectively. The null hypothesis of 15% disease control rate was rejected (P <.0001). Thirteen patients had at least one grade 3 adverse event or serious adverse event at least possibly related to C + V: anemia, decreased lymphocytes, dyspnea, diarrhea, elevated liver enzymes, fatigue, hypercalcemia, hypophosphatemia, rash, photosensitivity, and upper gastrointestinal hemorrhage. CONCLUSION: The combination of C + V has antitumor activity in heavily pretreated patients with CRC with BRAF mutations. Cobimetinib + vemurafenib showed a positive signal of activity in patients with colorectal cancer with BRAF mutations @ASCO #TAPUR. [ABSTRACT FROM AUTHOR]

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results of a cohort of patients with various solid tumors with germline or somatic BRCA1/2 mutations treated with talazoparib are reported. METHODS: Eligible patients had advanced solid tumors, measurable disease (RECIST), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Patients with germline BRCA -mutated human epidermal growth factor receptor 2–negative locally advanced or metastatic breast cancer were not eligible for this study. Primary end point was disease control (DC) determined by investigator assessment of objective response (OR) or stable disease (SD) of at least 16 weeks duration (SD16+). The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power = 0.82; α =.10). Secondary end points were OR, progression-free survival, overall survival, duration of response, duration of SD, and safety. RESULTS: Twenty-eight patients (20 cancer types) with BRCA1/2 mutations were enrolled from December 2019 to September 2021 and collapsed into a single histology pooled cohort for analysis. All patients were evaluable for efficacy. One complete response, nine partial response, and six SD16+ were observed for DC and OR rates of 57% (one-sided 90% CI, 43 to 100) and 36% (95% CI, 19 to 56), respectively. The null hypothesis of a 15% DC rate was rejected (P <.001). Patients with OR had the following tumor types: breast (2), nonmelanoma skin, mesothelioma, stomach, uterus, non–small cell lung cancer, ovary, hepatocellular carcinoma, and pancreas. Thirteen patients had at least one grade 3-5 adverse event (AE) or serious AE at least possibly related to talazoparib. All were consistent with the drug label except bilirubin increase and hyponatremia (both grade 3 AEs). CONCLUSION: Talazoparib demonstrated antitumor activity in patients with advanced solid tumors and BRCA1/2 mutations, including cancer types for which poly ADP-ribose polymerase inhibitors are not yet US Food and Drug Administration–approved. Talazoparib showed activity in patients with BRCA-mutated tumors for which PARP inhibitors are not yet FDA-approved. @ASCO #TAPUR [ABSTRACT FROM AUTHOR]

PURPOSE: Artificial intelligence (AI) models can generate scientific abstracts that are difficult to distinguish from the work of human authors. The use of AI in scientific writing and performance of AI detection tools are poorly characterized. METHODS: We extracted text from published scientific abstracts from the ASCO 2021-2023 Annual Meetings. Likelihood of AI content was evaluated by three detectors: GPTZero, Originality.ai, and Sapling. Optimal thresholds for AI content detection were selected using 100 abstracts from before 2020 as negative controls, and 100 produced by OpenAI's GPT-3 and GPT-4 models as positive controls. Logistic regression was used to evaluate the association of predicted AI content with submission year and abstract characteristics, and adjusted odds ratios (aORs) were computed. RESULTS: Fifteen thousand five hundred and fifty-three abstracts met inclusion criteria. Across detectors, abstracts submitted in 2023 were significantly more likely to contain AI content than those in 2021 (aOR range from 1.79 with Originality to 2.37 with Sapling). Online-only publication and lack of clinical trial number were consistently associated with AI content. With optimal thresholds, 99.5%, 96%, and 97% of GPT-3/4–generated abstracts were identified by GPTZero, Originality, and Sapling respectively, and no sampled abstracts from before 2020 were classified as AI generated by the GPTZero and Originality detectors. Correlation between detectors was low to moderate, with Spearman correlation coefficient ranging from 0.14 for Originality and Sapling to 0.47 for Sapling and GPTZero. CONCLUSION: There is an increasing signal of AI content in ASCO abstracts, coinciding with the growing popularity of generative AI models. Analysis of 15,553 ASCO meeting abstracts with 3 AI detectors suggests rise in AI content in 2023. [ABSTRACT FROM AUTHOR]

Introduction: Despite extensive studies of the impact of COVID-19 on patients with cancer, there is a dearth of information from the Middle East and North Africa (MENA) region. Our study aimed to report pertinent MENA COVID-19 and Cancer Registry (MCCR) findings on patient management and outcomes. Methods: MCCR was adapted from the American Society of Clinical Oncology COVID-19 Registry to collect data specifically from patients with cancer and SARS-CoV-2 infection from 12 centers in eight countries including Saudi Arabia, Jordan, Lebanon, Turkey, Egypt, Algeria, United Arab Emirates, and Morocco. The Registry included data on patients and disease characteristics, treatment, and patient outcomes. Logistic regression was used to assess associations with mortality. Results: Between November 29, 2020, and June 8, 2021, data were captured on 2008 patients diagnosed with COVID-19 from the beginning of the pandemic. Median age was 56 years (16–98), 56.4% were females, and 26% were current or ex-smokers. Breast cancer (28.5%) was the leading diagnosis and 50.5% had metastatic disease. Delays of planned treatment (.14 days) occurred in 80.3% for surgery, 48.8% for radiation therapy, and 32.9% for systemic therapy. Significant reduction in the delays of all three treatment modalities occurred after June 1, 2020. All-cause mortality rates at 30 and 90 days were 17.1% and 23.4%, respectively. All-cause mortality rates at 30 days did not change significantly after June 1, 2020; however, 90-day mortality increased from 33.4% to 42.9% before and after that date (p ¼ 0.015). Multivariable regression analysis showed the following predictors of higher 30- and 90-day mortality: age older than 70 years, having metastatic disease, disease progression, and being off chemotherapy. Conclusion: Patients with cancer in the MENA region experienced similar risks and outcome of COVID-19 as reported in other populations. Although there were fewer treatment delays after June 1, 2020, 90-day mortality increased, which may be attributed to other risk factors such as disease progression or new patients who presented with more advanced disease. [ABSTRACT FROM AUTHOR]

PURPOSE: With the advent of precision medicine, molecular tumor boards (MTBs) were established to interpret genomic results and guide decision making for targeted therapy in oncology patients. There are currently no universal guidelines for how MTBs should operate and thus variance can be seen depending on which MTB is reviewing the case. This study assesses the concordance of MTB recommendations when a participant case is reviewed by two different MTBs, establishes potential reasons for discordance, and advocates for the establishment of standard MTB operating guidelines. PATIENTS AND METHODS: Participants with advanced cancer, who had exhausted all standard treatment options were screened for the Targeted Agent and Profiling Utilization Registry (TAPUR) Study. Cases were submitted for MTB review if the treatment proposal was outside the protocol genomic matching rules, or if multiple treatment options were identified. Of the 306 cases submitted for review by the TAPUR MTB from 2016 to 2018, 107 were randomly selected for secondary review by a different MTB group. Recommendations from the original review were not disclosed. Concordance between MTB group recommendations was assessed. Concordance was defined as agreement between MTB reviews on the genomic alteration and study drug match proposed by the clinical site. Thematic qualitative analysis was conducted for the discordant cases to assess reasons for discordance. RESULTS: Complete or partial concordance was observed in 79% of cases (95% CI, 70 to 86; one-sided P =.25). Most discordant analyses were due to disagreements on the strength of evidence regarding efficacy of the proposed treatment (32%). CONCLUSION: When presented with identical participant cases, different MTB review groups make the same or similar treatment recommendations approximately 80% of the time. Over 300 cases have been submitted to TAPUR Study molecular tumor board (MTB). When presented with the same study participant cases, different MTB review groups make the same or similar treatment recommendations most of the time in the context of a precision medicine study for patients with advanced cancer. [ABSTRACT FROM AUTHOR]

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket trial evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancer and genomic alterations known to be drug targets. Results from cohorts of patients with metastatic breast cancer (BC) with FGFR1 and FGFR2 alterations treated with sunitinib are reported. METHODS: Eligible patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease of at least 16 weeks duration (SD16+) according to RECIST v1.1. Secondary end points included OR, progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Forty patients with BC with FGFR1 (N = 30; amplification only n = 26, mutation only n = 1, both n = 3) or FGFR2 (N = 10; amplification only n = 2, mutation only n = 6, both n = 2) alterations were enrolled. Three patients in the FGFR1 cohort were not evaluable for efficacy; all patients in the FGFR2 cohort were evaluable. For the FGFR1 cohort, two patients with partial response and four with SD16+ were observed for DC and OR rates of 27% (90% CI, 13 to 100) and 7% (95% CI, 1 to 24), respectively. The null hypothesis of 15% DC rate was not rejected (P =.169). No patients achieved DC in the FGFR2 cohort (P = 1.00). Thirteen of the 40 total patients across both cohorts had at least one grade 3-4 adverse event or serious adverse event at least possibly related to sunitinib. CONCLUSION: Sunitinib did not meet prespecified criteria to declare a signal of antitumor activity in patients with BC with either FGFR1 or FGFR2 alterations. Other treatments and clinical trials should be considered for these patient populations. Sunitinib did not demonstrate antitumor activity in patients with FGFR1-/2-amplified or -mutated breast cancer. @ASCO #TAPUR [ABSTRACT FROM AUTHOR]

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket study evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers with genomic alterations known to be drug targets. The results in a cohort of patients with solid tumors with BRAF mutations treated with cobimetinib plus vemurafenib are reported. METHODS: Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. The primary end point was disease control (DC), defined as complete response (CR) or partial response (PR) or stable disease of at least 16-weeks duration (SD16+). Low-accruing histology-specific cohorts with BRAF mutations treated with cobimetinib plus vemurafenib were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated on the basis of a one-sided exact binomial test with a null DC rate of 15% versus 35% (power,.82; α,.10). The secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Thirty-one patients with solid tumors with BRAF mutations were enrolled. Twenty-eight patients were evaluable for efficacy. Patients had tumors with BRAF V600E (n = 26), K601E (n = 2), or other (n = 3) mutations. Two patients with CR (breast and ovarian cancers; V600E), 14 with PR (13 V600E, one N581I), and three with SD16+ (two V600E, one T599_V600insT) were observed with a DC rate of 68% (P <.0001; one-sided 90% CI, 54 to 100) and an OR rate of 57% (95% CI, 37 to 76). Nineteen patients experienced ≥one drug-related grade 3-5 adverse event or serious adverse event including one death attributed to treatment-related kidney injury. CONCLUSION: Cobimetinib plus vemurafenib showed antitumor activity in patients with advanced solid tumors with BRAF V600E mutations; additional study is warranted to confirm the antitumor activity in tumors with non-V600E BRAF mutations. @ASCO #TAPUR results build upon efficacy of BRAF + MEK inhibitors in patients with advanced solid tumors and BRAF V600E mutations [ABSTRACT FROM AUTHOR]

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a phase II basket study evaluating the antitumor activity of commercially available targeted agents in patients with advanced cancers with genomic alterations known to be drug targets. Results of a cohort of patients with solid tumors with ATM mutations treated with nivolumab plus ipilimumab are reported. METHODS: Eligible patients had measurable disease (RECIST v.1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and no standard treatment options. Primary end point was disease control (DC), defined as complete (CR) or partial (PR) response or stable disease (SD) of at least 16 weeks duration (SD16+). Low-accruing histology-specific cohorts with ATM mutations treated with nivolumab plus ipilimumab were collapsed into a single histology-pooled cohort for this analysis. The results were evaluated based on a one-sided exact binomial test with a null DC rate of 15% versus 35% (power =.84; α =.10). Secondary end points were objective response (OR), progression-free survival, overall survival, duration of response, duration of SD, and safety. RESULTS: Twenty-nine patients with 10 tumor types with ATM mutations were enrolled from January 2018 to May 2020. One patient was not evaluable for efficacy. One CR, three PR, and three SD16+ were observed for DC and OR rates of 24% (P =.13; one-sided 90% CI: 14 to 100) and 14% (95% CI: 4 to 32), respectively. The null hypothesis of 15% DC rate was not rejected. Eleven patients had one treatment-related grade 3 adverse event (AE) or serious AE. There were two treatment-related patient deaths including immune-related encephalitis and respiratory failure. CONCLUSION: Nivolumab plus ipilimumab did not meet prespecified criteria to declare a signal of activity in patients with solid tumors with ATM mutations. Nivolumab + ipilimumab did not meet @ASCO #TAPUR criteria to declare antitumor activity in patients w/ ATM-mutated solid tumors. [ABSTRACT FROM AUTHOR]

PURPOSE: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study is a phase II pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancer with genomic alterations known to be drug targets. Results in a cohort of patients with non–small-cell lung cancer (NSCLC) with CDKN2A alterations treated with palbociclib are reported. METHODS: Eligible patients were ≥ 18 years old with advanced NSCLC, no remaining standard treatment options, measurable disease, Eastern Cooperative Oncology Group performance status of 0 to 2, and adequate organ function. Patients with NSCLC with CDKN2A alterations and no Rb mutations received palbociclib 125 mg orally once daily for 21 days, followed by 7 days off. Simon's two-stage design was used with a primary study end point of objective response or stable disease (SD) of at least 16 weeks in duration. Secondary end points are progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Twenty-nine patients were enrolled from January 2017 to June 2018; two patients were not evaluable for response but were included in safety analyses. One patient with partial response and six patients with SD were observed, for a disease control rate of 31% (90% CI, 19% to 40%). Median PFS was 8.1 weeks (95% CI, 7.1 to 16.0 weeks), and median OS was 21.6 weeks (95% CI, 14.1 to 41.1 weeks). Eleven patients had at least 1 grade 3 or 4 adverse event (AE) or serious AE (SAE) possibly related to palbociclib (most common, cytopenias). Other AEs or SAEs possibly related to the treatment included anorexia, fatigue, febrile neutropenia, hypophosphatemia, sepsis, and vomiting. CONCLUSION: Palbociclib monotherapy demonstrated evidence of modest antitumor activity in heavily pretreated patients with NSCLC with CDKN2A alterations. Additional investigation is necessary to confirm efficacy and utility of palbociclib in this population. [ABSTRACT FROM AUTHOR]

PURPOSE: The Targeted Agent and Profiling Utilization Registry (TAPUR) Study identifies signals of antitumor activity of commercially available targeted agents in patients with advanced cancers that harbor genomic alterations known as drug targets. In this article, data from two cohorts of patients with pancreatic and biliary cancers with CDKN2A loss or mutation treated with palbociclib are reported. METHODS: Eligible patients age 12 years and older with advanced measurable or evaluable solid tumors are provided treatment according to protocol-specified genomic matching rules. The primary study end point is objective response or stable disease of at least 16 weeks duration. For each cohort, a Simon two-stage design was used with a futility evaluation after 10 patients. Secondary end points include safety, progression-free survival (PFS), and overall survival (OS). RESULTS: Between July 2016 and November 2017, 12 and 10 patients with pancreatic and biliary cancer, respectively, with CDKN2A loss or mutation were treated with palbociclib. Twenty evaluable patients (10 per cohort) were included in the analysis. No patients had objective response or stable disease at 16 weeks, and both cohorts were closed. Two patients, neither with response, were determined to be ineligible. All patients were evaluated for safety, PFS, and OS. A median PFS of 7.2 weeks (90% CI, 4.0 to 8.0 weeks) and median OS of 12.4 weeks (90% CI, 4.7 to 23.1 weeks) were observed in the pancreatic cohort. A median PFS of 7.3 weeks (90% CI, 3.9 to 7.9 weeks) and median OS of 11.1 weeks (90% CI, 5.1 to 14.0 weeks) were observed in the biliary cohort. No unexpected toxicities were observed. CONCLUSION: Palbociclib monotherapy does not have clinical activity in patients with advanced pancreatic or biliary cancers with CDKN2A loss or mutation. Toxicity is similar to reported experience with palbociclib in other tumor types. [ABSTRACT FROM AUTHOR]

Introduction: Evidence-based cessation methods including nicotine replacement therapy (NRT), non-NRT medications, quitlines, and behavioral treatments are underutilized by smokers attempting to quit. Although a number of studies have demonstrated a relationship between state-level tobacco policies (eg, taxation, appropriations) and cessation, whether such state-level factors influence likelihood of using an evidence-based treatment is unclear. Accordingly, the aims of the present study were: (1) to describe evidence-based cessation method utilization by state and (2) to examine the effect of state-level factors on cessation method utilization above and beyond individual-level predictors.Methods: Data were utilized from the 2010-2011 Tobacco Use Supplement to the Current Population Survey (TUS-CPS). Participants included 9232 smokers who reported a past-year quit attempt. Data on 11 state-level predictors were collated from national datasets. Analyses were based on: (1) descriptive characterization of quit method usage, (2) logistic regression models to determine state-level factors as predictors of quit method utilization, controlling for individual-level predictors, (3) cluster analyses grouping states with similar state-level factors, and (4) examination of cluster as a predictor of cessation method.Results: Tobacco control appropriations significantly predicted NRT, quitline, and behavioral treatment utilization. Additional state-level factors that demonstrated significant relationships included Medicaid coverage of non-NRT medications and behavioral treatment, tobacco tax rate, smoking prevalence, and percentage of population uninsured. State clustering significantly predicted quit method across all four methods.Conclusions: State-level factors influence the likelihood of residents utilizing evidence-based quit methods. Results are discussed in terms of implications for tobacco policy at the state level.Implications: Results from the present study highlight state tobacco control appropriations as a robust predictor of evidence-based cessation method utilization. Other significant state-level predictors of evidence-based cessation method utilization included Medicaid coverage of non-NRT medications and behavioral treatment, tobacco tax rate, smoking prevalence, and percentage of population uninsured. Moreover, state-level predictors clustered together to significantly predict evidence-based cessation method utilization. Thus, increasing tobacco control appropriations, extending health insurance coverage, maximizing revenue from tobacco taxation and tobacco settlements, and ultimately decreasing smoking prevalence are important targets for individual states to promote utilization of evidence-based cessation methods. [ABSTRACT FROM AUTHOR]

The article provides a summary of discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forums on March 18th, June 10th, and July 8th of 2021, organized by the ASA BIOP Statistical Methods in Oncology Scientific Working Group in coordination with the U.S. Food and Drug Administration (FDA) Oncology Center of Excellence and the LUNGevity Foundation. Diverse stakeholders including oncologists, patient advocates, experts from regulatory agencies across the world, academicians, and representatives from the pharmaceutical industry engaged in a lively discussion on strategies for and designs of dose-optimization studies in cancer drug development. Dose-optimization is one of the major challenges in oncology drug development. The discussions were focused on considerations in designing dose-optimization studies of products for treatment of cancer patients in pre-approval and post-approval stages. Presenters and panelists discussed diverse ideas and methods and agreed that a shift in paradigm is required in oncology drug development that should improve dose optimization while not unnecessarily delaying patient access to potentially efficacious new treatments. [ABSTRACT FROM AUTHOR]

PURPOSE: The Targeted Agent and Profiling Utilization Registry Study is a pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from a cohort of patients with lung cancer and ERBB2 mutation or amplification treated with pertuzumab plus trastuzumab (P + T) are reported. METHODS: Eligible patients had advanced lung cancer of any histology, no standard treatment options, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and tumors with ERBB2 mutation or amplification. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) per RECIST v. 1.1 or stable disease (SD) of at least 16 weeks duration (SD16+). Secondary end points included safety, duration of response, duration of SD, progression-free survival, and overall survival. RESULTS: Twenty-eight patients with lung cancer (27 non–small-cell, 1 small-cell) and ERBB2 mutation (n = 15), ERBB2 amplification (n = 12), or both (n = 1) were enrolled from November 2016 to July 2020. All patients were evaluable for efficacy and toxicity. Three patients with partial response (two ERBB2 mutation; one both mutation and amplification) and seven patients with SD16+ (five ERBB2 mutation; two amplification) were observed for a DC rate of 37% (95% CI, 21 to 50; P =.005) and OR rate of 11% (95% CI, 2 to 28). Five patients had one or more grade 3 or 4 adverse or serious adverse events at least possibly related to P + T. CONCLUSION: Combination P + T showed evidence of antitumor activity in heavily pretreated patients with non–small-cell lung cancer and ERBB2 mutation or amplification, particularly those with ERBB2 exon 20 insertion mutations. Pertuzumab + trastuzumab had antitumor activity in pretreated patients with ERBB2-mutated NSCLC @ASCO #TAPUR. [ABSTRACT FROM AUTHOR]

Background: The availability of safe and effective COVID‐19 vaccines has enabled protections against serious COVID‐19 outcomes, which are particularly important for patients with cancer. The American Society of Clinical Oncology Registry enabled the study of COVID‐19 vaccine uptake in patients with cancer who were positive for severe acute respiratory syndrome‐coronavirus 2. Methods: Medical oncology practices entered data on patients who were in cancer treatment. The cohort included patients who had severe acute respiratory syndrome‐coronavirus 2 infection in 2020 and had visits and vaccine data after December 31, 2020. The primary end point was the time to first vaccination from January 1, 2021. Cumulative incidence estimates and Cox regression with death as a competing risk were used to describe the time to vaccine uptake and factors associated with vaccine receipt. Results: The cohort included 1155 patients from 56 practices. Among 690 patients who received the first vaccine dose, 92% received the second dose. The median time to vaccine was 99 days. After adjustment, older patients were associated with a higher likelihood of vaccination compared with patients younger than 50 years in January through March 2021, and age exhibited a linear effect, with older patients showing higher rates of vaccination. Metastatic solid tumors (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.73–0.98) or non–B‐cell hematologic malignancies (HR, 0.71; 95% CI, 0.54–0.93) compared with nonmetastatic solid tumors, and any comorbidity (HR, 0.83; 95% CI, 0.73–0.95) compared with no comorbidity, were associated with lower vaccination rates. Area‐level social determinants of health (lower education attainment and higher unemployment rates) were associated with lower vaccination rates. Conclusions: Patient age, cancer type, comorbidity, area‐level education attainment, and unemployment rates were associated with differential vaccine uptake rates. These findings should inform strategies to communicate about vaccine safety and efficacy to patients with cancer. Among patients who had cancer and severe acute respiratory syndrome‐coronavirus 2 infection before vaccine availability (e.g., before January 1, 2021), significant variation in vaccine uptake was noted depending on age, cancer type, comorbidity, and two area‐level social determinant of health variables (based on patients' home zip codes)—specifically, the percentage of residents aged 25 years and older with only a high school diploma and the unemployment rate. In the face of ongoing surges of COVID‐19, the emergence of variants, and the evolving role of additional vaccine doses and boosters, the findings—including the identification of subgroups of patients with cancer who remain unvaccinated—should be used to inform strategies to communicate information about vaccine safety and efficacy and vaccine recommendations to these patients. [ABSTRACT FROM AUTHOR]

Tobacco control policies are effective in promoting quit attempts and increase the likelihood that smokers use evidence-based cessation treatments (e.g., nicotine replacement therapies (NRT), non-NRT medications, behavioral treatment, and/or quitlines). However, what is less clear is how these policies might differentially impact different groups of smokers, perhaps in some cases even widening disparities in the use of evidence-based tobacco dependence treatments. This paper examined how different state-level tobacco control policies impact the use of evidence-based cessation treatments by race/ethnicity, gender, socio-economic status (SES), age, and smoking history. Participants included 9110 adult smokers reporting a past-year quit attempt within the 2010-2011 Tobacco Use Supplement to the Current Population Survey. Lasso regression modeling was used to identify a subset of interactions between tobacco policies and individual smoker characteristics that predicted use of evidence-based cessation treatment. Significant interactions were fitted via participant-weighted generalized linear models to determine effect sizes and relations to each cessation treatment outcome. Results highlighted that various state level tobacco control policies differentially impacted the reported use of both prescription and non-prescription stop smoking medications by race/ethnicity, age, and SES. The relationship between state level tobacco control policies and the use of behavioral treatments and quitlines did not differ by smoker characteristics. In sum, tobacco control policies differentially impact the use of FDA approved stop smoking medications across different race/ethnicity, age, and SES groups. Understanding such effects can help to target interventions to ensure equal access to evidence-based tobacco dependence treatments. [ABSTRACT FROM AUTHOR]

The primary endpoint of most dose-finding cancer trials is patient toxicity, and the primary goal is to identify the maximum tolerated dose (MTD), that is, the highest dose that falls below or within a pre-specified toxicity tolerability threshold. Conventionally, dose-finding methods have utilized a binary toxicity endpoint based on whether or not a patient experiences a dose limiting-toxicity (DLT). Improving upon this, in recent years several methods have been developed for modeling toxicity scores, a novel continuous endpoint designed to more precisely estimate patient toxicity burden. Separately, drug-combination trials have become increasingly prevalent, and due to added complexities regarding estimating 'true' dose ordering and potential for more complex patient toxicity profiles, provide an ideal setting which may benefit from the improved precision of toxicity scores. In this paper, we merge two frameworks based on the Continual Reassessment Method (CRM) - the Quasi-CRM and the Partial Order CRM (POCRM) – to propose a novel approach for modeling toxicity scores in a combination-trial setting. We demonstrate that utilizing toxicity scores has the potential to greatly improve correct dose-selection over a variety of trial scenarios. We further present a simple adaptation to the toxicity-score model to control for potential over-dosing issues such that it adheres to the conventional DLT definition and will, at worst, perform equivalently to that of the traditional binary DLT framework. We demonstrate that extending toxicity scores to the combination-trial setting offers potential for improvement over the conventional binary endpoint models. [ABSTRACT FROM AUTHOR]

PURPOSE: The TAPUR Study is a pragmatic basket trial evaluating antitumor activity of commercially available targeted agents in patients with advanced cancers harboring potentially actionable genomic alterations. Data from a cohort of patients with endometrial cancer (EC) with ERBB2 or ERBB3 (ERBB2/3) amplification, overexpression, or mutation treated with pertuzumab plus trastuzumab (P + T) are reported. METHODS: Eligible patients had advanced EC, no standard treatment options, measurable disease (RECIST v1.1), Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and tumors with ERBB2/3 amplification, overexpression, or mutation. Simon's two-stage design was used with a primary end point of disease control (DC), defined as objective response (OR) or stable disease (SD) of at least 16 weeks (SD16+) duration. Secondary end points include safety, duration of response, duration of SD, progression-free survival (PFS), and overall survival (OS). RESULTS: Twenty-eight patients were enrolled from March 2017 to November 2019; all patients were evaluable for efficacy and toxicity. Seventeen patients had tumors with ERBB2/3 amplification and/or overexpression, eight with both ERBB2 amplification and ERBB2/3 mutations, and three with only ERBB2 mutations. Ten patients had DC (two partial response and eight SD16+); all 10 had ERBB2 amplification, and 6 of the 10 patients with DC had >1 ERBB2/3 alteration. DC and OR rates were 37% (95% CI, 21 to 50) and 7% (95% CI, 1 to 24), respectively; the median PFS and median OS were 16 weeks (95% CI, 10-28) and 61 weeks (95% CI, 24-105), respectively. One patient experienced a grade 3 serious adverse event (muscle weakness) at least possibly related to P + T. CONCLUSION: P + T has antitumor activity in heavily pretreated patients with EC with ERBB2 amplification and warrants additional study. Pertuzumab + trastuzumab had antitumor activity in patients with endometrial cancer with ERBB2/3 alterations @ASCO #TAPUR. [ABSTRACT FROM AUTHOR]

This article provides a summary of discussions from the American Statistical Association (ASA) Biopharmaceutical (BIOP) Section Open Forum on April 8, 2021, and May 13, 2021, organized by the ASA BIOP Statistical Methods in Oncology Scientific Working Group in coordination with the United States Food and Drug Administration (U.S. FDA) Oncology Center of Excellence (OCE) and LUNGevity Foundation. In most cancer trials, disproportionately low numbers of older adults and certain racial minority groups are enrolled, even though a high incidence of cancer is observed in these subpopulations. This results in a lack of sufficient information on efficacy and safety of new treatments in such demographic subpopulations. Discussions with a diverse group of stakeholders including oncologists, patient advocates, experts from international regulatory agencies, academicians, and representatives of the pharmaceutical industry focused on designing future pre- and post-market studies to evaluate treatment effect in demographically underrepresented (UR) cancer populations such as racial and ethnic minority groups and older adults. It is noted that often there is poor or no representation of pediatric cancer patients as well. However, not all adult cancers are observed in pediatric patients and vice-a-versa and these discussions mainly focused on adult cancers. It is recognized that inclusion of broader patient populations can introduce heterogeneity and if the trial includes patients with more comorbidities or poorer prognosis may increase the chances of rejecting an effective therapy. However, there are clinical trial designs and statistical methods to include and evaluate treatment effects in UR cancer patients. Importantly, a commitment and a concerted effort from all stakeholders to change the current practice is necessary to better understand the benefit/risk in these demographically UR patients in cancer clinical trials. [ABSTRACT FROM AUTHOR]

PURPOSE: The TAPUR Study is a phase II basket trial that aims to evaluate activity of approved targeted agents in patients with advanced cancers with potentially actionable genomic variants. Data from a cohort of patients with metastatic castrate-resistant prostate cancer (mCRPC) and BRCA1 / 2 mutations treated with olaparib are reported. METHODS: Eligible patients with measurable mCRPC were matched to treatment according to protocol-specified genomic matching rules. Patients had no remaining standard treatment options, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Simon's two-stage design was used with a primary end point of disease control, defined as objective response or stable disease of at least 16-week duration. Secondary end points include radiographic progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Thirty patients with mCRPC with BRCA1 / 2 mutations were treated with olaparib. The disease control rate was 69% (95% CI, 51 to 81), and the objective response rate was 58% (95% CI, 37 to 77). The median radiographic progression-free survival and the median overall survival were 38.4 (95% CI, 16.3 to 52.1) weeks and 76.4 (95% CI, 49.3 to 106.0) weeks, respectively. Six of 30 (20%) patients experienced grade 3-4 adverse or serious adverse events including anemia, aspiration, decreased WBC count, and fatigue. CONCLUSION: Olaparib has antitumor activity in patients with mCRPC with BRCA1 / 2 mutations and warrants further study to determine how to best integrate it into the standard treatment of patients with BRCA1 / 2 -mutated prostate cancer. Olaparib showed a positive signal of activity in real-world patients w/prostate cancer w/BRCA1 or BRCA2 mutations @ASCO #TAPUR. [ABSTRACT FROM AUTHOR]

Background: The current study was conducted to determine the effect of postoperative radiotherapy (PORT) on overall survival in patients with surgically managed pT3-T4aN0 laryngeal squamous cell carcinoma (SCC).Methods: A review of the National Cancer Data Base from 2004 through 2013 was performed. Patients with surgically managed pT3-4aN0 laryngeal SCC with negative surgical margins were included. Univariable and multivariable Cox regression analyses were used to determine factors associated with survival.Results: A total of 1460 patients were included, 46.2% of whom had pT3N0 disease (674 patients) and 53.8% of whom had pT4aN0 disease (786 patients). Approximately 72.0% of the patients with pT3N0 disease (485 patients) and 50.1% of the patients with pT4aN0 disease (394 patients) received PORT. PORT was not found to be associated with improved overall survival on univariable analysis for patients with pT3N0 disease (hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62-1.14), but was for patients with pT4aN0 disease (HR, 0.57; 95% CI, 0.45-0.71). For patients with pT3N0 SCC of the larynx, in a multivariable Cox regression analysis adjusting for age >65 years, severity of comorbidities, larynx subsite, extent of laryngectomy, and number of lymph nodes removed, PORT was not found to be associated with improved survival (adjusted HR, 0.88; 95% CI, 0.64-1.21). For patients with pT4aN0 disease, the administration of PORT was associated with improved survival on multivariable analysis adjusting for age >65 years, severity of comorbidities, larynx subsite, number of lymph nodes removed, and type of hospital (adjusted HR, 0.58; 95% CI, 0.46-0.73).Conclusions: For patients with surgically managed pT3N0 laryngeal SCC with negative margins, PORT does not appear to be associated with improved survival. Despite a survival benefit, nearly 50% of patients with pT4aN0 laryngeal SCC and negative surgical margins do not receive standard-of-care PORT. Cancer 2017;123:2248-2257. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

Objective Lymphovascular space invasion (LVSI) is a poor prognostic indicator in uterine cancer, primarily due to its association with lymph node metastases. We sought to determine if LVSI provides any prognostic information for uterine cancer subjects in the absence of nodal disease. Methods A retrospective review was performed using a database of women treated for uterine cancer at MUSC from 2005 to 2012. Subjects with negative nodes after complete staging were identified. Multiple regression modeling was used to adjust for demographic and histopathologic covariates. The C-index was calculated for models of survival that included LVSI and those that did not. Competing risks analysis was conducted to examine factors associated with time to recurrence. Results Two hundred and five subjects were completely staged and had negative nodes, 24 with LVSI and 181 without. Factors significantly associated with survival included age, race, stage, grade, histology, and LVSI. Regression models for recurrence-free survival (RFS) and overall survival (OS) had similar C-indices regardless of whether LVSI was included. Competing risks analysis confirmed no significant difference in time to recurrence for subjects with LVSI compared to those without, after adjusting for other prognostic factors ( P = 0.53). Conclusions LVSI is associated with shorter recurrence-free and overall survival in uterine cancer subjects with negative lymph nodes. However, after adjusting for other prognostic factors, LVSI status does not provide additional prognostic information. This finding suggests that recurrence-free and overall survival for uterine cancer patients with negative lymph nodes can be estimated without factoring in LVSI. [ABSTRACT FROM AUTHOR]

Background: The American Society of Clinical Oncology (ASCO) surveyed cancer patients to assess practice patterns related to weight, diet, and exercise as a part of cancer care. Methods: An online survey was distributed between March and June 2020 through ASCO channels and patient advocacy organizations. Direct email communication was sent to more than 25,000 contacts, and information about the survey was posted on Cancer.Net. Eligibility criteria included being aged at least 18 years, living in the United States, and having been diagnosed with cancer. Logistic regression was used to determine factors associated with recommendation and referral patterns. Results: In total, 2419 individuals responded to the survey. Most respondents were female (60.1%), 61.1% had an early‐stage malignancy, and 48.4% were currently receiving treatment. Breast cancer was the most common cancer (35.7%). The majority of respondents consumed ≤2 servings of fruits and vegetables/d (50.5%) and exercised ≤2 times/wk (50.1%). Exercise was addressed at most or some oncology visits in 56.8% of respondents, diet in 50.1%, and weight in 28.0%. Respondents whose oncology provider provided diet and/or exercise recommendations were more likely to report changes in these behaviors vs. those whose oncology provider did not (exercise: 79.6% vs 69.0%, P <.001; diet 81.1% vs 71.3%, P <.001; weight 81.0% vs 73.3%, P =.003). Conclusions: In a national survey of oncology patients, slightly more than one‐half reported attention to diet and exercise during oncology visits. Provider recommendations for diet, exercise, and weight were associated with positive changes in these behaviors, reinforcing the importance of attention to these topics as a part of oncology care. In a national survey of 2419 oncology patients conducted by the American Society of Clinical Oncology, slightly more than one‐half of respondents reported attention to diet and exercise during oncology visits. Provider recommendations for diet, exercise, and weight were associated with positive changes in these behaviors, reinforcing the importance of attention to these topics as part of oncology care. [ABSTRACT FROM AUTHOR]

Objectives: The Medical University of South Carolina implemented a patient-centered multidisciplinary breast clinic program (MDBC) in August 2012. In this study, patient satisfaction with the MDBC care delivery model and communication with healthcare providers was examined to inform the refinement of the MDBC program. Methods: During the first 10 months of the MDBC, patients were asked to complete a 14-question postconsultation telephone survey. A statistical analysis was performed to explore potential associations between age, race, and stage with overall patient satisfaction scores. Results: Overall, patients (N = 52, 56% white, 42% African American, 2% Hispanic; mean age 61 years) rated the quality of care highly (mean 4.7, range [1 = poor to 5 = excellent]) and felt comfortable with their plan of care (mean 1.63, range [1 = extremely comfortable to 5 = not at all comfortable]). No statistically significant differences in overall satisfaction were found by age, race, or stage; however, patient responses were commonly not optimal (ie, either "no" or "yes, but not as much as I would like") when asked if the care team addressed the impact of their diagnosis on personal relationships (40.4%) or emotional health (28.9%). Conclusions: Patients were highly satisfied with the care they received in the MDBC program. Findings suggest that this model is well suited to a diverse patient population and have highlighted quality improvement targets such as increased emphasis on providers' communication about psychosocial issues. [ABSTRACT FROM AUTHOR]

Background: As most smokers initiate smoking during adolescence, assessment of smoking motives that underlie trajectories of dependence is critical for both prevention and cessation efforts. In the current study, we expected participants with higher nicotine dependence would smoke (a) less for positive reinforcement (PR) and (b) more for negative reinforcement (NR) motives. We secondarily assessed the relative contribution of PR to NR motives across levels of dependence. Methods: Data were drawn from a study on cue-elicited craving among occasional versus daily adolescent smokers aged 16–20 years (N = 111). Smoking motives were assessed in relation to 3 commonly used measures of nicotine dependence: (a) Fagerström Test for Nicotine Dependence (FTND), (b) Autonomy over Smoking Scale (AUTOS), and (c) Nicotine Dependence Syndrome Scale (NDSS). Results: Compared to occasional smokers, daily smokers had significantly higher scores on each dependence measure and endorsed more prominent NR smoking motives. Each measure of nicotine dependence was strongly associated with NR motives for smoking, although measures differed in their association with PR motives. As expected, the FTND, AUTOS, and NDSS each significantly predicted smoking motive difference score (PR − NR), such that higher dependence was associated with more prominent NR motives for smoking. Conclusions: Results are consistent with our understanding of dependence and provide further support for 3 common measures of nicotine dependence among early stage smokers. [ABSTRACT FROM PUBLISHER]

The transcription factor FOXO3 is a well-established tumor suppressor whose activity, stability, and localization are regulated by phosphorylation and acetylation. Previous data by our laboratory demonstrated amplified thromboxane-A2 signaling was associated with poor prognoses in bladder cancer patients and overexpression of the thromboxane-A2 isoform-β receptor (TPβ), but not TPα, induced malignant transformation of immortalized bladder cells in vivo. Here, we describe a mechanism of TP mediated modulation of FOXO3 activity and localization by phosphorylation and deacetylation in a bladder cancer cell model. In vitro gain and loss of function studies performed in non-transformed cell lines, UROsta and SV-HUC, revealed knockdown of FOXO3 expression by shRNA increased cell migration and invasion, while exogenously overexpressing TPβ raised basal phosphorylated (p)FOXO3-S294 levels. Conversely, overexpression of ERK-resistant, mutant FOXO3 reduced increases in UMUC3 cell migration and invasion, including that mediated by TP agonist (U46619). Additionally, stimulation of UMUC3 cells with U46619 increased pFOXO3-S294 expression, which could be attenuated by treatment with a TP antagonist (PTXA2) or ERK inhibitor (U0126). Initially U46619 caused nuclear accumulation of pFOXO3-S294; however, prolonged stimulation increased FOXO3 cytoplasmic localization. U46619 stimulation decreased overall FOXO3 transcriptional activity, but was associated with increased expression of its pro-survival target, manganese superoxide dismutase. The data also shows that TP stimulation increased the expression of the histone deacetylase, SIRT1, and corresponded with decreased acetylated-FOXO3. Collectively, the data suggest a role for TP signaling in the regulation of FOXO3 activity, mediated in part through phosphorylation and deacetylation. [ABSTRACT FROM AUTHOR]

Background: An ASCO taskforce comprised of representatives of oncology clinicians, the American Cancer Society National Lung Cancer Roundtable (NLCRT), LUNGevity, the GO2 Foundation for Lung Cancer, and the ROS1ders sought to: characterize U.S. oncologists' biomarker ordering and treatment practices for advanced non‐small‐cell lung cancer (NSCLC); ascertain barriers to biomarker testing; and understand the impact of delays on treatment decisions. Methods: We deployed a survey to 2374 ASCO members, targeting U.S. thoracic and general oncologists. Results: We analyzed 170 eligible responses. For non‐squamous NSCLC, 97% of respondents reported ordering tests for EGFR, ALK, ROS1, and BRAF. Testing for MET, RET, and NTRK was reported to be higher among academic versus community providers and higher among thoracic oncologists than generalists. Most respondents considered 1 (46%) or 2 weeks (52%) an acceptable turnaround time, yet 37% usually waited three or more weeks to receive results. Respondents who waited ≥3 weeks were more likely to defer treatment until results were reviewed (63%). Community and generalist respondents who waited ≥3 weeks were more likely to initiate non‐targeted treatment while awaiting results. Respondents <5 years out of training were more likely to cite their concerns about waiting for results as a reason for not ordering biomarker testing (42%, vs. 19% with ≥6 years of experience). Conclusions: Respondents reported high biomarker testing rates in patients with NSCLC. Treatment decisions were impacted by test turnaround time and associated with practice setting and physician specialization and experience. [ABSTRACT FROM AUTHOR]

Background: Therapeutic options for patients with advanced soft‐tissue sarcoma (STS) are limited. The goal of the current phase 2 study was to examine the clinical activity and safety of the combination of gemcitabine plus pazopanib, a multityrosine kinase inhibitor with activity in STS. Methods: The current randomized, phase 2 trial enrolled patients with advanced nonadipocytic STS who had received prior anthracycline‐based therapy. Patients were assigned 1:1 to receive gemcitabine at a dose of 1000 mg/m2 on days 1 and 8 with pazopanib at a dose of 800 mg daily (G+P) or gemcitabine at a dose of 900 mg/m2 on days 1 and 8 and docetaxel at a dose of 100 mg/m2 on day 8 (G+T) every 3 weeks. Crossover was allowed at the time of disease progression. The study used a noncomparative statistical design based on the precision of 95% confidence intervals for reporting the primary endpoints of median progression‐free survival (PFS) and rate of grade ≥3 adverse events (AEs) for these 2 regimens based on the intent‐to‐treat patient population (AEs were graded using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events). Results: A total of 90 patients were enrolled: 45 patients on each treatment arm. The median PFS was 4.1 months for each arm (P =.3, log‐rank test). The best overall response of stable disease or better (complete response + partial response + stable disease) was the same for both treatment arms (64% for both the G+T and G+P arms). The rate of related grade ≥3 AEs was 82% for the G+T arm and 78% for the G+P arm. Related grade ≥3 AEs occurring in ≥10% of patients in the G+T and G+P arms were anemia (36% and 20%, respectively), fatigue (29% and 13%, respectively), thrombocytopenia (53% and 49%, respectively), neutropenia (20% and 49%, respectively), lymphopenia (13% and 11%, respectively), and hypertension (2% and 20%, respectively). Conclusions: The data from the current study have demonstrated the safety and efficacy of G+P as an alternative to G+T for patients with nonadipocytic STS. The results of the current trial suggest similar efficacy and tolerability when comparing the gemcitabine and pazopanib (G+P) regimen with the gemcitabine and docetaxel (G+T) regimen. In patients who are not suitable for treatment with G+T, the G+P regimen is a reasonable alternate for the second‐line treatment of patients with metastatic nonadipocytic sarcomas. [ABSTRACT FROM AUTHOR]

Background and Aims: Within the context of busy clinical settings, health‐care providers need practical, evidence‐based options to engage smokers in quitting. Sampling of nicotine replacement therapy [i.e. provision of nicotine replacement therapy (NRT starter kits)] is a brief, pragmatic strategy to address this need. We aimed to compare the effects of NRT sampling plus standard care (SC), relative to SC alone, provided by primary care providers during routine clinic visits. Design Cluster‐randomized clinical trial. Setting: Twenty‐two primary care clinics in South Carolina, USA. Participants: Adult smokers [n = 1245; 61% female, mean age = 50.7, standard deviation (SD) = 13.5] both motivated and unmotivated to quit, seen during routine clinical visit. Interventions were provider‐delivered SC (n = 652, 12 clinics) cessation advice or SC + a 2‐week supply of both nicotine patch and lozenge, with minimal instructions on use (n = 593; 10 clinics). Measurements The primary outcome was 7‐day point prevalence smoking abstinence at 6‐month follow‐up, using intent‐to‐treat. Additional outcomes included NRT use and quit attempts, assessed at 1, 3 and 6 months following baseline. Findings Seven‐day point prevalence abstinence rates were significantly higher in the NRT sampling group throughout follow‐up, including at 6 months [12 versus 8%, odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.0–2.4]. NRT sampling increased prevalence of any use of NRT (65 versus 25%, OR = 5.8, 95% CI = 4.3–7.7), with higher prevalence of use at 6 months (25 versus 14%, OR = 2.0, 95% CI = 1.5–2.7). NRT sampling increased the rate of quit attempts in the initial month (24 versus 18%, OR = 1.5, 95% CI = 1.0–2.3) but had no significant effect on overall rate of quit attempts (48 versus 45%, OR = 1.2, 95% CI = 0.8–1.7). Conclusion: Providing smokers with a free 2‐week starter kit of nicotine replacement therapy increased quit attempts, use of stop smoking medications and smoking abstinence compared with standard care in a primary care setting. [ABSTRACT FROM AUTHOR]

PURPOSE: Investigators often send reports to sponsors that incorrectly categorize adverse event (AE)s as serious or attribute AEs to investigational drugs. Such errors can contribute to high volumes of uninformative investigational new drug safety reports that sponsors submit to the US Food and Drug Administration and participating investigators, which strain resources and impede the detection of valid safety signals. To improve the quality of serious AE (SAE) reporting by physician-investigators and research staff, ASCO developed and tested a Decision Aid. METHODS: A preliminary study with crossover design was conducted in a convenience sample. Physician-investigators and research staff were randomly assigned to receive case studies. Case studies were assessed for seriousness and attribution, first unassisted and then with the Decision Aid. Participants completed a feedback survey about the Decision Aid. Effectiveness of reporting and attribution are reported as odds ratios (ORs) with 95% CI. Power to detect associations was limited because of a small sample size. RESULTS: The Decision Aid did not significantly affect accuracy of determining seriousness (OR, 0.87; 95% CI, 0.31 to 2.46), but it did significantly increase accuracy of attributing an SAE to a drug (OR, 3.60; 95% CI, 1.15 to 11.4). Most of the 29 participants reported that the Decision Aid was helpful (93%) and improved decision-making time (69%) and confidence in reporting (83%), and that they would use the Decision Aid in practice (83%). CONCLUSION: The Decision Aid shows promise as a method to improve the quality of SAE attribution, which may improve the detection of valid safety signals and reduce the administrative burden of uninformative investigational new drug safety reports. Study of the Decision Aid in a larger sample with analysis stratified by participant role and SAE reporting experience would further assess the tool's impact. [ABSTRACT FROM AUTHOR]

Traditionally, drug development has evaluated dose, safety, activity, and comparative benefit in a sequence of phases using trial designs and endpoints specifically devised for each phase. Innovations in drug development seek to consolidate the phases and rapidly expand accrual with "seamless" trial designs. Although consolidation and rapid accrual may yield efficiencies, widespread use of seamless first-in-human (FiH) trials without careful consideration of objectives, statistical analysis plans, or trial oversight raises concerns. A working group formed by the National Cancer Institute convened to consider and discuss opportunities and challenges for such trials as well as encourage responsible use of these designs. We reviewed all abstracts presented at American Society of Clinical Oncology annual meetings from 2010 to 2017 for FiH trials enrolling at least 100 patients. We identified 1786 early-phase trials enrolling 57 559 adult patients. Fifty-one of the trials (2.9%) investigated 50 investigational new drugs, were seamless, and accounted for 14.6% of the total patients. The seamless trials included a median of 3 (range = 1-13) expansion cohorts. The overall risk of clinically significant treatment-related adverse events (grade 3-4) was 49.1% (range = 0.0-100%), and seven studies reported at least one toxic death. Rapid expansion of FiH trials may lead to earlier drug approval and corresponding widespread patient access to active therapeutics. Nevertheless, seamless designs must adhere to established ethical, scientific, and statistical standards. Protocols should include prospectively planned analyses of efficacy in disease- or biomarker-defined cohorts of sufficient rigor to support accelerated approval. [ABSTRACT FROM AUTHOR]

To study the contribution of T‐cell receptors (TCR) to resulting T‐cell responses, we studied three different human αβ TCRs, reactive to the same gp100‐derived peptide presented in the context of HLA‐A*0201. When expressed in primary CD8 T cells, all receptors elicited classic antigen‐induced IFN‐γ responses, which correlated with TCR affinity for peptide–MHC in the order T4H2 > R6C12 > SILv44. However, SILv44 elicited superior IL‐17A release. Importantly, in vivo, SILv44‐transgenic T cells mediated superior antitumor responses to 888‐A2 + human melanoma tumor cells upon adoptive transfer into tumor‐challenged mice while maintaining IL‐17 expression. Modeling of the TCR ternary complexes suggested architectural differences between SILv44 and the other complexes, providing a potential structural basis for the observed differences. Overall, the data reveal a more prominent role for the T‐cell receptor in defining host T‐cell physiology than traditionally assumed, while parameters beyond IFN‐γ secretion and TCR affinity ultimately determine the reactivity of tumor‐reactive T cells. [ABSTRACT FROM AUTHOR]

Background: The gene desert on human chromosomal band 8q24 harbors multiple genetic variants associated with common cancers, including breast cancer. The locus, including the gene desert and its flanking genes, MYC, PVT1 and FAM84B, is also frequently amplified in human breast cancer. We generated a megadeletion (MD) mouse model lacking 430-Kb of sequence orthologous to the breast cancer-associated region in the gene desert. The goals were to examine the effect of the deletion on mammary cancer development and on transcript level regulation of the candidate genes within the locus.Methods: The MD allele was engineered using the MICER system in embryonic stem cells and bred onto 3 well-characterized transgenic models for breast cancer, namely MMTV-PyVT, MMTV-neu and C3(1)-TAg. Mammary tumor growth, latency, multiplicity and metastasis were compared between homozygous MD and wild type mice carrying the transgenes. A reciprocal mammary gland transplantation assay was conducted to distinguish mammary cell-autonomous from non-mammary cell-autonomous anti-cancer effects. Gene expression analysis was done using quantitative real-time PCR. Chromatin interactions were evaluated by 3C. Gene-specific patient outcome data were analysed using the METABRIC and TCGA data sets through the cBioPortal website.Results: Mice homozygous for the MD allele are viable, fertile, lactate sufficiently to nourish their pups, but maintain a 10% lower body weight mainly due to decreased adiposity. The deletion interferes with mammary tumorigenesis in mouse models for luminal and basal breast cancer. In the MMTV-PyVT model the mammary cancer-reducing effects of the allele are mammary cell-autonomous. We found organ-specific effects on transcript level regulation, with Myc and Fam84b being downregulated in mammary gland, prostate and mammary tumor samples. Through analysis using the METABRIC and TCGA datasets, we provide evidence that MYC and FAM84B are frequently co-amplified in breast cancer, but in contrast with MYC, FAM84B is frequently overexpressed in the luminal subtype, whereas MYC activity affect basal breast cancer outcomes.Conclusion: Deletion of a breast cancer-associated non-protein coding region affects mammary cancer development in 3 transgenic mouse models. We propose Myc as a candidate susceptibility gene, regulated by the gene desert locus, and a potential role for Fam84b in modifying breast cancer development. [ABSTRACT FROM AUTHOR]

PURPOSE: Advanced practice providers (APPs, which include nurse practitioners [NPs] and physician assistants [PAs]) are integral members of oncology teams. This study aims to identify all oncology APPs and to understand personal and practice characteristics (including compensation) of those APPs. METHODS: We identified APPs who practice oncology from membership and claims data. We surveyed 3,055 APPs about their roles in clinical care. RESULTS: We identified at least 5,350 APPs in oncology and an additional 5,400 who might practice oncology. Survey respondents totaled 577, which provided a 19% response rate. Results focused on 540 NPs and PAs. Greater than 90% reported satisfaction with career choice. Respondents identified predominately as White (89%) and female (94%). NPs and PAs spent the majority (80%) of time in direct patient care. The top four patient care activities were patient counseling (NPs = 94%; PAs = 98%), prescribing (NPs = 93%; PAs = 97%), treatment management (NPs = 89%; PAs = 93%), and follow-up visits (NPs = 81%; PAs = 86%). A majority of all APPs reported both independent and shared visits (65% hematology/oncology/ survivorship/prevention/pediatric hematology/oncology; 85% surgical/gynecologic oncology; 78% radiation oncology). A minority of APPs reported that they conducted only shared visits. Average annual compensation was between $113,000 and $115,000, which is approximately $10,000 higher than average pay for nononcology APPs. CONCLUSION: We identified 5,350 oncology APPs and conclude that number may be as high as 7,000. Results suggest that practices that incorporate APPs routinely rely on them for patient care. Given the increasing number of patients with and survivors of cancer, APPs are important to ensure access to quality cancer care. [ABSTRACT FROM AUTHOR]

Purpose: Case reports and small prospective trials suggest that administering targeted therapies to patients with advanced cancer and an identified genomic target may be associated with clinical benefit. The Targeted Agent and Profiling Utilization Registry (TAPUR) study, a phase II prospective, nonrandomized, multibasket pragmatic clinical trial, aims to identify signals of drug activity when US Food and Drug Administration–approved drugs are matched to prespecified genomic targets in patients with advanced cancer, outside of approved indications. Methods: Patients eligible to participate in TAPUR are age ≥ 12 years and have advanced measurable or evaluable solid tumors, multiple myeloma, or B-cell non-Hodgkin lymphoma. Eligible participants are matched to any of the 16 US Food and Drug Administration–approved study drugs based on protocol-specified genomic inclusion and exclusion criteria. Genomic profiling from any Clinical Laboratory Improvement Amendments–certified, College of American Pathologists–accredited laboratory is acceptable. The treating physician selects the treatment from the available study therapies or consults with the TAPUR Molecular Tumor Board. Participants are placed into multiple parallel cohorts defined by tumor type, genomic alteration, and drug. The primary study end point within each cohort is objective response or stable disease of at least 16 weeks duration. Secondary end points include safety, progression-free survival, and overall survival. Results: More than 1,000 participants have thus far been registered, and more than 800 have been treated with a TAPUR study drug. Two study cohorts have permanently closed to enrollment because of lack of antitumor activity, and 12 have expanded to the second stage of enrollment after promising preliminary activity. Conclusion: The TAPUR study will describe the efficacy and toxicity of the targeted drugs used outside of their approved indications when matched to a somatic genomic variant. [ABSTRACT FROM AUTHOR]

Purpose: Advanced practice providers (APPs, which include nurse practitioners [NPs] and physician assistants [PAs]) are integral members of oncology teams. This study aims first to identify all oncology APPs and, second, to understand personal and practice characteristics (including compensation) of those APPs. Methods: We identified APPs who practice oncology from membership and claims data. We surveyed 3,055 APPs about their roles in clinical care. Results: We identified at least 5,350 APPs in oncology and an additional 5,400 who might practice oncology. Survey respondents totaled 577, which provided a 19% response rate. Results focused on 540 NPs and PAs. Greater than 90% reported satisfaction with career choice. Respondents identified predominately as white (89%) and female (94%). NPs and PAs spent the majority (80%) of time in direct patient care. The top four patient care activities were patient counseling (NPs, 94%; PAs, 98%), prescribing (NPs, 93%; PAs, 97%), treatment management (NPs, 89%; PAs, 93%), and follow-up visits (NPs, 81%; PAs, 86%). A majority of all APPs reported both independent and shared visits (65% hematology/oncology/survivorship/prevention/pediatric hematology/oncology; 85% surgical/gynecologic oncology; 78% radiation oncology). A minority of APPs reported that they conducted only shared visits. Average annual compensation was between $113,000 and $115,000, which is approximately $10,000 higher than average pay for nononcology APPs. Conclusion: We identified 5,350 oncology APPs and conclude that number may be as high as 7,000. Survey results suggest that practices that incorporate APPs routinely rely on them for patient care. Given the increasing number of patients with and survivors of cancer, APPs are important to ensure access to quality cancer care now and in the future. [ABSTRACT FROM AUTHOR]

Abstract Background Primary care is the most important point of healthcare contact for smokers. Brief physician advice to quit, based on the 5As/AAR model, offers some efficacy but is inconsistently administered and has limited population impact. Nicotine replacement therapy (NRT) sampling, defined as provision of a brief NRT starter kit, when added to the 5As/AAR, is well-suited to primary care because it is simple, brief, and can be provided to all smokers. This article describes the design and methods of an ongoing comparative effectiveness trial testing standard care vs. standard care + NRT sampling within primary care. Methods Smokers were recruited directly from primary care practices between July 2014 and December 2017 within an established network of South Carolina clinics. Interventions were delivered randomly by clinic personnel, and phone-based follow-ups were centrally coordinated by research staff to track outcomes through six months post-intervention. Primary study aims are to examine the impact of NRT sampling on smoking, inclusive of cessation, quit attempts, and uptake of evidence-based treatment. Results Twenty-two clinics were recruited. Across clinics, patient census ranged from 985 to 10,957 and number of providers ranged from 1 to 63. Average patient age across clinics was 52.9 years and smoking prevalence across ranged from 10.6% to 28.5%. Conclusion Improving the effectiveness and reach of brief interventions within primary care could have a considerable impact on population quit rates. We consider the advantages and disadvantages of key methodological decisions relevant to the design of future primary care-based cessation trials. [ABSTRACT FROM AUTHOR]

Purpose: Case reports and small prospective trials suggest that administering targeted therapies to patients with advanced cancer and an identified genomic target may be associated with clinical benefit. The Targeted Agent and Profiling Utilization Registry (TAPUR) study, a phase II prospective, nonrandomized, multibasket pragmatic clinical trial, aims to identify signals of drug activity when US Food and Drug Administration–approved drugs are matched to prespecified genomic targets in patients with advanced cancer, outside of approved indications. Methods: Patients eligible to participate in TAPUR are age ≥ 12 years and have advanced measurable or evaluable solid tumors, multiple myeloma, or B-cell non-Hodgkin lymphoma. Eligible participants are matched to any of the 16 US Food and Drug Administration–approved study drugs based on protocol-specified genomic inclusion and exclusion criteria. Genomic profiling from any Clinical Laboratory Improvement Amendments–certified, College of American Pathologists–accredited laboratory is acceptable. The treating physician selects the treatment from the available study therapies or consults with the TAPUR Molecular Tumor Board. Participants are placed into multiple parallel cohorts defined by tumor type, genomic alteration, and drug. The primary study end point within each cohort is objective response or stable disease of at least 16 weeks duration. Secondary end points include safety, progression-free survival, and overall survival. Results: More than 1,000 participants have thus far been registered, and more than 800 have been treated with a TAPUR study drug. Two study cohorts have permanently closed to enrollment because of lack of antitumor activity, and 12 have expanded to the second stage of enrollment after promising preliminary activity. Conclusion: The TAPUR study will describe the efficacy and toxicity of the targeted drugs used outside of their approved indications when matched to a somatic genomic variant. [ABSTRACT FROM AUTHOR]

Purpose: To describe the US hematology and medical oncology practice landscape and to report findings of the sixth annual ASCO Oncology Practice Census survey. Participants and Methods: ASCO used Medicare Physician Compare data to characterize oncology practices in the United States. Practice size, number of care sites, and geographic distribution were determined. Trends in the number and size of practices from 2013 to 2017 were examined. All US oncology practices were targeted for the survey; survey responses were linked to the practices identified from Physician Compare to augment results and assess generalizability. Results: More than 2,200 hematology/oncology practices provided care to adult patients in 2017. We observed annual decreases in the number of practices and annual increases in practice size. Of the 2017 practices, 394 (18%) completed the survey and accounted for 58% of the US hematologist/oncologist workforce (n = 7,203). Respondents tended to be larger and encompass more sites of care than nonrespondents. Surveyed practices cited payers (58%), competition (38%), and staffing (37%) as primary sources of strain. Prior authorization was dominant among payer pressures (78%). Electronic health records remained a burden on practices, with only 15% reporting full interoperability. Conclusion: The results of ASCO’s 2017 survey indicate that oncology practices are challenged by day-to-day operations, often related to payment, reimbursement, and competition. Our findings likely represent conservative estimates of such burdens because they are driven by responses from midsized to large-sized organizations, which have lower relative administrative burden, greater market influence, and potentially better ability to adapt in a changing health care environment. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rβγ pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC.Methods: In this non-randomised, open-label, phase 1b trial, we enrolled patients (aged ≥18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 μg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing.Findings: Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT-803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 μg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks.Interpretation: ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC.Funding: Altor BioScience (a NantWorks company), National Institutes of Health, and Medical University of South Carolina Hollings Cancer Center. [ABSTRACT FROM AUTHOR]

Therapeutic outcomes for adoptive cell transfer (ACT) therapy are constrained by the quality of the infused T cells. The rapid expansion necessary to obtain large numbers of cells results in a more terminally differentiated phenotype with decreased durability and functionality. N-acetyl cysteine (NAC) protects against activation-induced cell death (AICD) and improves anti-tumor efficacy of Pmel-1 T cells in vivo. Here, we show that these benefits of NAC can be extended to engineered T cells and significantly increases T-cell survival within the tumor microenvironment. The addition of NAC to the expansion protocol of human TIL13838I TCR-transduced T cells that are under evaluation in a Phase I clinical trial, demonstrated that findings in murine cells extend to human cells. Expansion of TIL13838I TCR-transduced T cells in NAC also increased their ability to kill target cells in vitro. Interestingly, NAC did not affect memory subsets, but diminished up-regulation of senescence (CD57) and exhaustion (PD-1) markers and significantly decreased expression of the transcription factors EOMES and Foxo1. Pharmacological inhibition of the PI3K/Akt pathway ablates the decrease in Foxo1 induced by NAC treatment of activated T cells. This suggests a model in which NAC through PI3K/Akt activation suppresses Foxo1 expression, thereby impacting its transcriptional targets EOMES, PD-1, and granzyme B. Taken together, our results indicate that NAC exerts pleiotropic effects that impact the quality of TCR-transduced T cells and suggest that the addition of NAC to current clinical protocols should be considered. [ABSTRACT FROM AUTHOR]

Malignant melanoma incidence has been increasing for over 30 years, and despite promising new therapies, metastatic disease remains difficult to treat. We describe preliminary results from a Phase I clinical trial (NCT01586403) of adoptive cell therapy in which three patients received autologous CD4+ and CD8+ T cells transduced with a lentivirus carrying a tyrosinase-specific TCR and a marker protein, truncated CD34 (CD34t). This unusual MHC Class I-restricted TCR produces functional responses in both CD4+ and CD8+ T cells. Parameters monitored on transduced T cells included activation (CD25, CD69), inhibitory (PD-1, TIM-3, CTLA-4), costimulatory (OX40), and memory (CCR7) markers. For the clinical trial, T cells were activated, transduced, selected for CD34t+ cells, then re-activated, and expanded in IL-2 and IL-15. After lymphodepleting chemotherapy, patients were given transduced T cells and IL-2, and were followed for clinical and biological responses. Transduced T cells were detected in the circulation of three treated patients for the duration of observation (42, 523, and 255 days). Patient 1 tolerated the infusion well but died from progressive disease after 6 weeks. Patient 2 had a partial response by RECIST criteria then progressed. After progressing, Patient 2 was given high-dose IL-2 and subsequently achieved complete remission, coinciding with the development of vitiligo. Patient 3 had a mixed response that did not meet RECIST criteria for a clinical response and developed vitiligo. In two of these three patients, adoptive transfer of tyrosinase-reactive TCR-transduced T cells into metastatic melanoma patients had clinical and/or biological activity without serious adverse events. [ABSTRACT FROM AUTHOR]