Axitinib in combination with pembrolizumab in patients with advanced renal cell cancer: a non-randomised, open-label, dose-finding, and dose-expansion phase 1b trial.

BACKGROUND: Previous studies combining PD-1 checkpoint inhibitors with tyrosine kinase inhibitors of the VEGF pathway have been characterised by excess toxicity, precluding further development. We hypothesised that axitinib, a more selective VEGF inhibitor than others previously tested, could be combined safely with pembrolizumab (anti-PD-1) and yield antitumour activity in patients with treatment-naive advanced renal cell carcinoma. METHODS: In this ongoing, open-label, phase 1b study, which was done at ten centres in the USA, we enrolled patients aged 18 years or older who had advanced renal cell carcinoma (predominantly clear cell subtype) with their primary tumour resected, and at least one measureable lesion, Eastern Cooperative Oncology Group performance status 0-1, controlled hypertension, and no previous systemic therapy for renal cell carcinoma. Eligible patients received axitinib plus pembrolizumab in a dose-finding phase to estimate the maximum tolerated dose, and additional patients were enrolled into a dose-expansion phase to further establish safety and determine preliminary efficacy. Axitinib 5 mg was administered orally twice per day with pembrolizumab 2 mg/kg given intravenously every 3 weeks. We assessed safety in all patients who received at least one dose of axitinib or pembrolizumab; antitumour activity was assessed in all patients who received study treatment and had an adequate baseline tumour assessment. The primary endpoint was investigator-assessed dose-limiting toxicity during the first two cycles (6 weeks) to estimate the maximum tolerated dose and recommended phase 2 dose. This study is registered with ClinicalTrials.gov, number NCT02133742. FINDINGS: Between Sept 23, 2014, and March 25, 2015, we enrolled 11 patients with previously untreated advanced renal cell carcinoma to the dose-finding phase and between June 3, 2015, and Oct 13, 2015, we enrolled 41 patients to the dose-expansion phase. All 52 patients were analysed together. No unexpected toxicities were observed. Three dose-limiting toxicities were reported in the 11 patients treated during the 6-week observation period (dose-finding phase): one patient had a transient ischaemic attack and two patients were only able to complete less than 75% of the planned axitinib dose because of treatment-related toxicity. At the data cutoff date (March 31, 2017), 25 (48%) patients were still receiving study treatment. Grade 3 or worse treatment-related adverse events occurred in 34 (65%) patients; the most common included hypertension (n=12 [23%]), diarrhoea (n=5 [10%]), fatigue (n=5 [10%]), and increased alanine aminotransferase concentration (n=4 [8%]). The most common potentially immune-related adverse events (probably related to pembrolizumab) included diarrhoea (n=15 [29%]), increased alanine aminotransferase concentration (n=9 [17%]) or aspartate aminotransferase concentration (n=7 [13%]), hypothyroidism (n=7 [13%]), and fatigue (n=6 [12%]). 28 (54%) patients had treatment-related serious adverse events. At data cutoff, 38 (73%; 95% CI 59·0-84·4) patients achieved an objective response (complete or partial response). INTERPRETATION: The treatment combination of axitinib plus pembrolizumab is tolerable and shows promising antitumour activity in patients with treatment-naive advanced renal cell carcinoma. Whether or not the combination works better than a sequence of VEGF pathway inhibition followed by an anti-PD-1 therapy awaits the completion of a phase 3 trial comparing axitinib plus pembrolizumab with sunitinib monotherapy (NCT02853331). FUNDING: Pfizer Inc.

Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours.

BACKGROUND: In a phase III study, sunitinib led to a significant increase in progression-free survival (PFS) versus placebo in patients with pancreatic neuroendocrine tumours (panNETs). This study was a post-marketing commitment to support the phase III data. METHODS: In this ongoing, open-label, phase IV trial (NCT01525550), patients with progressive, advanced unresectable/metastatic, well-differentiated panNETs received continuous sunitinib 37.5 mg once daily. Eligibility criteria were similar to those of the phase III study. The primary endpoint was investigator-assessed PFS per Response Evaluation Criteria in Solid Tumours v1.0 (RECIST). Other endpoints included PFS per Choi criteria, overall survival (OS), objective response rate (ORR), and adverse events (AEs). RESULTS: Sixty-one treatment-naive and 45 previously treated patients received sunitinib. By March 19, 2016, 82 (77%) patients had discontinued treatment, mainly due to disease progression. Median treatment duration was 11.7 months. Investigator-assessed median PFS per RECIST (95% confidence interval [CI]) was 13.2 months (10.9-16.7): 13.2 (7.4-16.8) and 13.0 (9.2-20.4) in treatment-naive and previously treated patients, respectively. ORR (95% CI) per RECIST was 24.5% (16.7-33.8) in the total population: 21.3% (11.9-33.7) in treatment-naive and 28.9% (16.4-44.3) in previously treated patients. Median OS, although not yet mature, was 37.8 months (95% CI, 33.0-not estimable). The most common treatment-related AEs were neutropenia (53.8%), diarrhoea (46.2%), and leukopenia (43.4%). CONCLUSIONS: This phase IV trial confirms sunitinib as an efficacious and safe treatment option in patients with advanced/metastatic, well-differentiated, unresectable panNETs, and supports the phase III study outcomes. AEs were consistent with the known safety profile of sunitinib.

Axitinib plus pembrolizumab in patients with advanced renal-cell carcinoma: Long-term efficacy and safety from a phase Ib trial.

BACKGROUND: Axitinib plus pembrolizumab showed superior overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) versus sunitinib in a randomised phase III trial in patients with advanced renal-cell carcinoma (RCC). We report long-term efficacy and safety of the axitinib/pembrolizumab from the phase I trial (NCT02133742), after 46-55 months from study initiation (data cut-off date, 23rd July 2019). METHODS: Fifty-two treatment-naïve patients with advanced RCC were treated with oral axitinib 5 mg twice daily and intravenous pembrolizumab 2 mg/kg every 3 weeks. PFS, duration of response (DoR) and OS were summarised using the Kaplan-Meier method. RESULTS: At a median follow-up of 42.7 months (95% confidence interval [CI]: 41.1-44.1), median OS was not reached; 38 (73.1%) patients were alive. The probability of being alive at 4 years was 66.8% (95% CI: 49.1-79.5). Median PFS in the overall population was 23.5 months (95% CI: 15.4-30.4). ORR was 73.1%; five patients had complete response. Median DoR was 22.1 months (95% CI: 15.1-34.5). Grade III/IV adverse events (AEs) were reported in 38 (73.1%) patients and 20 (38.5%) discontinued treatment because of AEs: 17 (32.7%) discontinued axitinib, 13 (25.0%) discontinued pembrolizumab, and 10 (19.2%) discontinued both drugs. Common AEs included diarrhoea (84.6%), fatigue (80.8%), hypertension (53.8%), cough (48.1%) and dysphonia (48.1%). There were no new AE terms reported and no treatment-related deaths. CONCLUSIONS: In patients with advanced RCC with ~4 years of follow-up, combination axitinib/pembrolizumab continued to demonstrate clinical benefit, with no new safety signals.

Measuring attractiveness for abuse of prescription opioids.

OBJECTIVE: Prescription opioids are the second most misused/abused drug in the United States behind only marijuana. Recreational prescription opioid users appear to prefer some products over others; however, the extent to which attributes of any particular formulation account for such preferences has yet to be determined. The Opioid Attractiveness Technology Scaling was developed to identify the particular features of a prescription opioid that are relevant to its attractiveness for recreational use, and to use these features to model attractiveness for recreational use of particular prescription opioid formulations. DESIGN: Four hundred and ninety-one self-reported recreational prescription opioid users identified 43 product features as being relevant to determining whether a product is "attractive" or "unattractive" for recreational use. Average ratings were used to determine appropriate weights to be applied to the features. A factor analysis yielded 10, highly differentiated factors. Five hundred and sixty-four prescription opioid abusers were then asked to rate the extent to which the 43 features identified in Study 1 were relevant to specific prescription opioid products they had used. RESULTS: Respondents provided an overall preference rating of these products and a model was created. A random intercept model yielded a significant pseudo R(2) of 0.14 (chi-square = 310.02, degrees of freedom [df] = 10, P < 0.001). The model fit least well, albeit significantly, for abusers who preferred to swallow the drug (pseudo R(2) = 0.06; chi-square = 55.52, df = 10, P < 0.001) and best for those who preferred to inject (pseudo R(2) = 0.37; chi-square = 199.34, df = 10, P < 0.001). CONCLUSIONS: The relevance of the model is discussed along with possible modifications that might allow prediction of "attractiveness" of "abuse deterrent" formulations that have not yet been marketed.

Angiogenic and Immune-Related Biomarkers and Outcomes Following Axitinib/Pembrolizumab Treatment in Patients with Advanced Renal Cell Carcinoma.

PURPOSE: Combined axitinib/pembrolizumab is approved for advanced renal cell carcinoma (aRCC). This exploratory analysis examined associations between angiogenic and immune-related biomarkers and outcomes following axitinib/pembrolizumab treatment. PATIENTS AND METHODS: Prospectively defined retrospective correlative exploratory analyses tested biospecimens from 52 treatment-naïve patients receiving axitinib and pembrolizumab (starting doses 5 mg twice daily and 2 mg/kg respectively, every 3 weeks). Tumor tissue, serum, and whole blood samples were collected at baseline, at cycle 2 day 1 (C2D1), and end of treatment (EOT) for blood-based samples. Clinical outcomes were objective response rate (ORR) and progression-free survival (PFS). RESULTS: Higher baseline tumor levels of CD8 showed a trend toward longer PFS (HR 0.4; P = 0.091). Higher baseline serum levels of CXCL10 (P = 0.0197) and CEACAM1 (P = 0.085) showed a trend toward better ORR and longer PFS, respectively. Patients for whom IL6 was not detected at baseline had longer PFS versus patients for whom it was detected (HR 0.4; P = 0.028). At C2D1 and/or EOT, mainly immune-related biomarkers showed any association with better outcomes. The genes CA9 (P = 0.084), HIF1A (P = 0.064), and IFNG (P = 0.073) showed trending associations with ORR, and AKT3 (P = 0.0145), DDX58 (P = 0.0726), GZMA (P = 0.0666), LCN2 (NGAL; P = 0.0267), and PTPN11 (P = 0.0287) with PFS. CONCLUSIONS: With combined axitinib/pembrolizumab treatment in patients with aRCC, mostly immune-related biomarkers are associated with better treatment outcomes. This exploratory analysis has identified some candidate biomarkers to consider in future prospective testing.

Update on prescription monitoring in clinical practice: a survey study of prescription monitoring program administrators.

OBJECTIVE: Prescription drug abuse and undertreatment of pain are public health priorities in the United States. Few options to manage these problems are balanced, in simultaneously supporting pain relief and deterring prescription drug abuse. Prescription monitoring programs (PMPs) potentially offer a balanced approach; however, the medical/scientific communities are not well informed about their current status and potential risks/benefits. The purpose of this study was to provide a benchmark of the current status of PMPs for healthcare providers upon which to engage PMP administrators. DESIGN: A Web survey of current PMP directors with a telephone follow-up conducted in June-July 2006 regarding goals, data captured, data sharing procedures, healthcare provider training, and evaluation efforts. RESULTS: Eighteen of 23 states with operating PMPs at that time participated. Eleven programs allowed physician access to PMP data. Data were delivered by mail (N = 6), fax (N = 8), e-mail (N = 1), and Websites (N = 8). Eight programs provided data to providers within 1 hour. Three states have developed provider PMP usage guidelines. Eight states developed or are developing educational programs. Two states completed or are conducting evaluations of the public health impact of PMP implementation. Five states have begun utilizing PMP data as an epidemiological tool. CONCLUSIONS: Initial public safety orientation of PMPs is evolving to include improving public health and patient care. Beginning with efforts to engage healthcare providers through data sharing and education, and progressively including program evaluation on public health and patient care, our results suggest a rapid movement in the direction of utilization of PMPs to improve health care.

Development and validation of an Opioid Attractiveness Scale: a novel measure of the attractiveness of opioid products to potential abusers.

BACKGROUND: The growing trends in opioid abuse, assessment of the abuse liability of prescription opioid products, and growing efforts by the pharmaceutical industry to develop 'abuse-resistant' formulations highlight a need to understand the features that make one product more 'attractive' than another to potential abusers. We developed a scale to measure the 'attractiveness' of prescription opioids to potential abusers, and used the scale to measure the relative attractiveness of 14 opioid analgesic products. METHODS: First, the concept of attractiveness was empirically defined with a group of prescription opioid abusers and experts in opioid abuse using a process called Concept Mapping. Abuse liability consisted of two components: factors intrinsic to the drug formulation (e.g., speed of onset, duration) and factors extrinsic to drug formulation (e.g., availability, availability of alternatives, cost). A 17-item Opioid Attractiveness Scale (OAS) was constructed, focusing on factors intrinsic to the drug product. RESULTS: A total of 144 individuals participated in tests of validity and reliability. Internal consistency was excellent (Cronbach's alpha = 0.85-0.94). Drug rankings based on OAS scores achieved good inter-rater agreement (Kendall's W 0.37, p < 0.001). Agreement on drug OAS scores between the developmental sample and a confirmation sample was good (IntraClass Correlations [ICC] of 0.65-0.69). Global ratings of overall attractiveness of the 14 selected opioid products by substance abuse counselors corresponded with the rankings based on OAS ratings of the abuser group. Finally, substance abuse counselors completed the OAS, yielding a high level of correspondence with ratings by the abuser group (ICC = 0.83, p = 0.002). The OAS differentiated attractiveness among 14 selected pharmaceutical opioid products. OxyContin, Dilaudid, and Percocet were ranked highest (most attractive); Talwin NX and Duragesic were ranked lowest (least attractive). CONCLUSION: An initial examination of the psychometric properties of the OAS suggests that it is a valid and reliable scale. The OAS may be useful in providing important guidance on product features that are attractive to potential abusers.

Validation of the Spanish Addiction Severity Index Multimedia Version (S-ASI-MV).

This study aimed to develop and test the reliability and validity of a Spanish adaptation of the ASI-MV, a computer administered version of the Addiction Severity Index, called the S-ASI-MV. Participants were 185 native Spanish-speaking adult clients from substance abuse treatment facilities serving Spanish-speaking clients in Florida, New Mexico, California, and Puerto Rico. Participants were administered the S-ASI-MV as well as Spanish versions of the general health subscale of the SF-36, the work and family unit subscales of the Social Adjustment Scale Self-Report, the Michigan Alcohol Screening Test, the alcohol and drug subscales of the Personality Assessment Inventory, and the Hopkins Symptom Checklist-90. Three-to-five-day test-retest reliability was examined along with criterion validity, convergent/discriminant validity, and factorial validity. Measurement invariance between the English and Spanish versions of the ASI-MV was also examined. The S-ASI-MV demonstrated good test-retest reliability (ICCs for composite scores between .59 and .93), criterion validity (rs for composite scores between .66 and .87), and convergent/discriminant validity. Factorial validity and measurement invariance were demonstrated. These results compared favorably with those reported for the original interviewer version of the ASI and the English version of the ASI-MV.

Cross-Validation of a Screener to Predict Opioid Misuse in Chronic Pain Patients (SOAPP-R).

OBJECTIVES: The Screener and Opioid Assessment for Patients with Pain - Revised (SOAPP-R) is a self-report questionnaire designed to predict aberrant medication-related behaviors among persons with chronic pain. This measure was developed to complement current risk assessment practices and to improve a clinician's ability to assess a patient's risk for opioid misuse. The aim of this study was to cross-validate the SOAPP-R with a new sample of chronic, non-cancer pain patients. METHODS: Three hundred and two participants (N=302) prescribed opioids for pain were recruited from five pain management centers in the U.S. Subjects completed a series of self-report measures and were followed for five months. Patients were rated by their treating physician, had a urine toxicology screen, and were classified on the Aberrant Drug Behavior index. RESULTS: Seventy-three percent (73.2%) of the subjects (N= 221) were followed and 66 participants repeated the SOAPP-R after one week for test-retest reliability. The reliability and predictive validity, as measured by the area under the curve (AUC), were found to be highly significant (test-retest reliability = .91; coefficient alpha = .86; AUC = .74) and were sufficiently similar to values found with the initial sample. A cut-off score of 18 revealed a sensitivity of .80 and specificity of .52. CONCLUSIONS: Results of this cross-validation study suggest that the psychometric parameters of the SOAPP-R are not based solely on the unique characteristics of the initial validation sample. The SOAPP-R is found to be a reliable and valid screening tool for risk of aberrant drug-related behavior among chronic pain patients.

A pilot study of an online workplace nutrition program: the value of participant input in program development.

OBJECTIVE: Tailored nutrition Web programs constitute an emerging trend in obesity prevention. Initial investment in innovative technology necessitates that the target population be well understood. This pilot study's purpose was to determine the feasibility of a workplace nutrition Web program. DESIGN: Formative research was conducted with gaming industry employees and benefits managers to develop a consensus on workplace-specific nutrition needs. A demonstration Web program was piloted with stakeholders to determine feasibility. SETTING: Indiana, Mississippi, Nevada, and New Jersey gaming establishments. PARTICIPANTS: 86 employees, 18 benefits managers. INTERVENTION: Prototype Web program. MAIN OUTCOME MEASURES: Concept mapping; 16-item nutrition knowledge test; satisfaction. ANALYSIS: Concept mapping was used to aggregate importance ratings on programmatic content, which informed Web program curriculum. Chi-square tests were performed postintervention to determine knowledge improvement. RESULTS: (1) Employees and benefits managers exhibited moderate agreement about content priorities for the program (r = 0.48). (2) There was a significant increase in employees' nutrition knowledge scores postintervention (t = 7.16, df = 36, P < .001); those with less knowledge exhibited the greatest gains in knowledge scores (r = -0.647, P < .001). CONCLUSIONS AND IMPLICATIONS: Employees and benefit managers do not necessarily agree on the priority of nutrition-related content, suggesting a need for programs to appeal to various stakeholders. Computer-based approaches can address various stakeholder health concerns via tailored, customized programming.

Development and validation of the Current Opioid Misuse Measure.

Clinicians recognize the importance of monitoring aberrant medication-related behaviors of chronic pain patients while being prescribed opioid therapy. The purpose of this study was to develop and validate the Current Opioid Misuse Measure (COMM) for those pain patients already on long-term opioid therapy. An initial pool of 177 items was developed with input from 26 pain management and addiction specialists. Concept mapping identified six primary concepts underlying medication misuse, which were used to develop an initial item pool. Twenty-two pain and addiction specialists rated the items on importance and relevance, resulting in selection of a 40-item alpha COMM. Final item selection was based on empirical evaluation of items with patients taking opioids for chronic, noncancer pain (N=227). One-week test-retest reliability was examined with 55 participants. All participants were administered the alpha version of the COMM, the Prescription Drug Use Questionnaire (PDUQ) interview, and submitted a urine sample for toxicology screening. Physician ratings of patient aberrant behaviors were also obtained. Of the 40 items, 17 items appeared to adequately measure aberrant behavior, demonstrating excellent internal consistency and test-retest reliability. Cutoff scores were examined using ROC curve analysis and reasonable sensitivity and specificity were established. To evaluate the COMM's ability to capture change in patient status, it was tested on a subset of patients (N=86) that were followed and reassessed three months later. The COMM was found to have promise as a brief, self-report measure of current aberrant drug-related behavior. Further cross-validation and replication of these preliminary results is pending.