Characterizing Opioid Prescribing Trends of Medical Oncologists From 2013 to 2019: Analysis From the Centers for Medicare & Medicaid Services Medicare Part D Prescribers Database.

PURPOSE: Opioid prescribing trends in medical oncology are poorly defined past 2017, the year after the CDC updated opioid prescription guidelines in noncancer settings. We aim to characterize pain management by medical oncologists by analyzing opioid and gabapentin prescribing trends from 2013 to 2019, identify physician-related factors associated with prescribing patterns, and assess whether CDC guidelines for nononcologic settings changed prescribing patterns. METHODS: The Centers for Medicare & Medicaid Services (CMS) Medicare Part D Prescribers-by Provider, CMS Medicare Part D Prescribers-by Provider and Drug, and CMS Medicare Physician National Downloadable files from 2013 to 2019 were merged by National Provider Identification. The database included physicians' sex, years of practice, regions, and practice settings. Multivariable binary logistic regression identified significant predictors of total opioid, long-acting opioid, and gabapentin prescriptions. RESULTS: Binary logistic regression modeling revealed no significant difference in mean daily total opioid prescriptions from 2013 to 2017. Daily opioid prescriptions by medical oncologists decreased significantly after 2017 (P < .001). Increased opioid prescribing was associated with physician male sex (P < .001), practicing over 10 years (P < .001), and practice in nonurban areas (P < .001). Opioid prescribing was greatest in the South and Midwest United States (P < .001). The same patterns were observed with total long-acting opioid prescriptions, whereas gabapentin prescribing increased from 2013 to 2019 (P < .001). CONCLUSION: Opioid prescriptions by medical oncologists decreased significantly from 2013 to 2019, but this decrease was most substantial from 2017 to 2019. These results may imply that the 2016 CDC guidelines influenced medical oncologists, particularly more junior physicians in urban settings, to manage chronic cancer pain with alternative therapies.

Treatment of ALK-rearranged non-small-cell lung cancer with brigatinib as second or later lines: real-world observations from a single institution.

The second-generation ALK tyrosine kinase inhibitor brigatinib has recently been approved in the European Union for use after crizotinib treatment in patients with EML4-ALK-rearranged lung cancer. In the current study, brigatinib was investigated as second-line or later-line treatment in 35 patients who had developed resistance to crizotinib, ceritinib, or alectinib. Most patients (68.6%) received brigatinib as second or third line (range: second to 12th line). In the total cohort, complete and partial responses were obtained for 9.1 and 75.8%, respectively. Overall median progression-free survival was 9.9 months, whereas the largest treatment cohort (brigatinib after crizotinib failure) showed a median progression-free survival of 8.4 months. Fifty-four percent of patients with baseline brain metastases responded to brigatinib treatment. Brigatinib was highly effective after crizotinib and ceritinib failure. Six patients had received alectinib as monotherapy, second-line, or third line before brigatinib; of these, four experienced partial responses and two progressed responses. Brigatinib treatment was well tolerated.

Comparison of RECIST, iRECIST, and PERCIST for the Evaluation of Response to PD-1/PD-L1 Blockade Therapy in Patients With Non-Small Cell Lung Cancer.

PURPOSE: The aim of this study was to compare the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1, the immune RECIST (iRECIST) criteria, and the Positron Emission Tomography Response Criteria in Solid Tumors (PERCIST) 1.0 in patients with advanced non-small cell lung cancer treated with programmed cell death protein 1 (PD-1)/programmed cell death protein 1 ligand (PD-L1) inhibitors. METHODS: This prospective study of 42 patients treated with a PD-1/PD-L1 inhibitor was approved by our institutional review board, and all patients gave written, informed consent. Tumor burden dynamics were assessed on F-FDG PET/CT before and after treatment initiation. Immunotherapeutic responses were evaluated according to RECIST 1.1, iRECIST, and PERCIST 1.0 for the dichotomous groups, responders versus nonresponders. Cohen κ and Wilcoxon signed rank tests were used to evaluate concordance among these criteria. We assessed progression-free survival and overall survival using the Kaplan-Meier estimator. RESULTS: The RECIST 1.1 and PERCIST 1.0 response classifications were discordant in 6 patients (14.2%; κ = 0.581). RECIST 1.1 and iRECIST were discordant in 2 patients, who evidenced pseudoprogression after treatment initiation. Median progression-free survival, as well as overall survival, was significantly longer for responders compared with nonresponders for all criteria (P < 0.001), with no significant difference between the 3 criteria (P > 0.05). CONCLUSIONS: RECIST 1.1 and PERCIST 1.0 show only moderate agreement, but both can predict treatment response to PD-1/PD-L1 inhibitor therapy. In case of pseudoprogression, metabolic tumor activity may help to correctly classify treatment response.

EGFR Mutations in Cell-free Plasma DNA from Patients with Advanced Lung Adenocarcinoma: Improved Detection by Droplet Digital PCR.

BACKGROUND: Analysis of cell-free DNA from blood could provide an alternative method for identifying genomic changes in the tumors of patients with advanced lung adenocarcinoma. OBJECTIVE: We compared the performance of droplet digital PCR (ddPCR) and Cobas® EGFR Mutation Test v2 (Cobas) for detecting EGFR mutations in cell-free plasma DNA. PATIENTS AND METHODS: Plasma samples from patients with advanced EGFR-mutated lung adenocarcinoma were analyzed for EGFR T790M, exon 19 deletions, and L858R mutations by both ddPCR and Cobas. RESULTS: T790M testing was performed in 354 plasma samples collected from 129 patients. The concordance rate between ddPCR and Cobas for T790M, sensitivity, and specificity were 86, 100, and 85%, respectively. Exon 19 deletions were analyzed in 196 plasma samples obtained from 71 of the 129 patients using both platforms. The concordance rate between ddPCR and Cobas for exon 19 deletions, sensitivity, and specificity were 90, 92, and 89%, respectively. L858R mutations were studied in 124 plasma samples obtained from 44 of the 129 patients using both assays. The concordance rate between ddPCR and Cobas for L858R, sensitivity, and specificity were 90, 91, and 89%, respectively. In patients who progressed under treatment with an EGFR TKI (n = 50), the T790M positivity rate was 66% using ddPCR, but only 24% using Cobas. CONCLUSIONS: We observed a high concordance between ddPCR and Cobas in detecting EGFR mutations in plasma samples of patients with advanced EGFR-mutated lung adenocarcinoma, but ddPCR was more sensitive than Cobas.

Liquid-Biopsy-Based Identification of EGFR T790M Mutation-Mediated Resistance to Afatinib Treatment in Patients with Advanced EGFR Mutation-Positive NSCLC, and Subsequent Response to Osimertinib.

BACKGROUND: Acquired epidermal growth factor receptor (EGFR) T790M mutation is the primary resistance mechanism to first-generation EGFR tyrosine kinase inhibitors (TKIs) used in advanced, EGFR mutation-positive non-small-cell lung cancer (NSCLC). Available data, predominantly in Asian patients, suggest that this mutation is also the major cause of resistance to the irreversible ErbB family blocker, afatinib. For EGFR T790M-positive patients who progress on EGFR TKI therapy, osimertinib is an effective treatment option. However, data on osimertinib use after afatinib are, to date, scarce. OBJECTIVE: To identify the prevalence of EGFR T790M mutations in predominantly Caucasian patients with stage IV EGFR mutation-positive NSCLC who progressed on afatinib, and to investigate the subsequent response to osimertinib. PATIENTS AND METHODS: In this single-center, retrospective analysis, EGFR T790M mutation status after afatinib failure was assessed using liquid biopsy and tissue rebiopsy. EGFR T790M-positive patients subsequently received osimertinib. RESULTS: Sixty-seven patients received afatinib in the first-, second-, or third-line (80.6%, 14.9%, and 4.5%, respectively). After afatinib failure, the T790M mutation was identified in 49 patients (73.1%). Liquid biopsy and tissue rebiopsy were concordant in 79.4% of cases. All patients with T790M-positive tumors received osimertinib (73.5% after first-line afatinib); 37 (75.5%) of these had an objective response (complete response: 22.4%; partial response: 53.1%). Response rate was independent of T790M copy number. CONCLUSION: EGFR T790M mutation is a major mechanism of acquired resistance to afatinib. Osimertinib confers high response rates after afatinib failure in EGFR T790M-positive patients and its use in sequence potentially allows extended chemotherapy-free treatment.

Cell-Free Plasma DNA-Guided Treatment With Osimertinib in Patients With Advanced EGFR-Mutated NSCLC.

INTRODUCTION: Osimertinib is standard treatment for patients with advanced EGFR T790M-mutated non-small-cell lung cancer who have been pre-treated with EGFR-tyrosine kinase inhibitors (TKIs). We studied whether cell-free plasma DNA for T790M detection can be used to select patients for osimertinib treatment in the clinical routine. METHODS: From April 2015 to November 2016, we included 119 patients with advanced EGFR-mutated non-small-cell lung cancer who had progressed under treatment with an EGFR-TKI. The T790M mutation status was assessed in cell-free plasma DNA by droplet digital polymerase chain reaction in all patients and by tissue analyses in selected patients. RESULTS: T790M mutations were detected in 85 (93%) patients by analyses of cell-free plasma DNA and in 6 (7%) plasma-negative patients by tumor re-biopsy. Eighty-nine of 91 T790M-positive patients received osimertinib. Median progression-free survival (PFS) was 10.1 months (95% confidence interval [CI]: 8.1-12.1). Median survival was not reached and the 1-year survival was 64%. The response rate was 70% in T790M-positive patients (n = 91) in the intention-to-treat population. PFS trended to be shorter in patients with high T790M copy number (≥10 copies/mL) compared to those with low T790M copy number (<10 copies/mL) (hazard ratio for PFS = 1.72, 95% CI: 0.92-3.2, p = 0.09). A comparable trend was observed for overall survival (hazard ratio for overall survival = 2.16, 95% CI: 0.89-5.25, p = 0.09). No difference in response rate was observed based on T790M copy numbers. CONCLUSION: Plasma genotyping using digital polymerase chain reaction is clinically useful for the selection of patients who had progressed during first-line EGFR-TKI therapy for treatment with osimertinib.

Symptomatic pseudo-progression followed by significant treatment response in two lung cancer patients treated with immunotherapy.

In the setting of pseudo-progression in a cancer patient who receives immunotherapeutic treatment, discontinuation of therapy is recommended if the patient is symptomatic. Here, we present two patients with advanced adenocarcinoma of the lung who developed massive tumor growth after initiation of treatment with the anti-PD-1 antibody pembrolizumab. Even though clinical deterioration occurred in the form of severe dyspnea and weight loss, pembrolizumab therapy was continued, as the speed of tumor growth suggested pseudo-progression and the tumors showed marked PD-L1 expression. This approach was successful, and both patients experienced impressive treatment responses within a few weeks.

Complete remission of intrathecal metastases with lorlatinib therapy in a heavily pretreated ALK-positive lung cancer patient.

Patients with lung cancer who show EML4-ALK translocation are routinely treated with ALK tyrosine kinase inhibitors, although in the majority of cases, these patients develop resistance over time. The central nervous system is a common of site of recurrence in this population, which calls for next-generation drugs that can penetrate into the brain and achieve clinically meaningful central nervous system activity. Here, I report the case of a female patient diagnosed with adenocarcinoma of the lung in 2005, at the age of 46 years, who underwent lobectomy and then experienced a series of progression episodes 6 years later. Local recurrence was managed by chemotherapy and crizotinib after the patient was included in a named patient use programme in 2012. Over the following years, the patient repeatedly developed lesions at different sites in the brain and spinal cord. Partial remission was obtained twice with local irradiation. When the next-generation ALK tyrosine kinase inhibitors became available, her treatment was switched to brigatinib, which again induced partial remission. Another episode of intrathecal progression prompted the prescription of the third-generation ALK tyrosine kinase inhibitor lorlatinib. This treatment has resulted in complete remission in the patient.

Hypothalamic insulin responsiveness is associated with pancreatic insulin secretion in humans.

CONTEXT: Activity of the hypothalamus - the major brain area controlling peripheral metabolism - is specifically modulated by insulin. Research in animals suggests that brain insulin action influences pancreatic insulin secretion. OBJECTIVE: We investigated the association between hypothalamic insulin sensitivity and pancreatic insulin secretion in humans. DESIGN AND SETTING: This was a clinical-experimental trial in an university hospital setting. PARTICIPANTS: 48 healthy volunteers (21 women and 27 men) were included. MAIN OUTCOME MEASURES: Insulin sensitivity of the hypothalamus was quantified by cerebral blood flow (CBF) using MRI in combination with intranasal insulin administration. On a different day, a 75g oral glucose tolerance test with glucose, insulin, and C-peptide levels measured at five time points was performed. Three established insulin secretion indices (insulinogenic index [IGI], corrected insulin response [CIR], and AUCC-peptide0-30/AUCglucose0-30) were then analyzed for correlations with hypothalamic insulin sensitivity independent of whole-body insulin sensitivity. RESULTS: Hypothalamic insulin sensitivity showed a significant association with all three investigated insulin secretion indices (IGI p=0.0043; CIR p=0.06; AUCCpep0-30/AUCgluc0-30 p=0.0179). Participants with a strong hypothalamic insulin effect (i.e. decreased CBF after intranasal insulin administration) had lower insulin secretion during the OGTT, whereas participants with hypothalamic insulin resistance had substantially higher insulin secretion. No correlations with the occipital cortex, a control region, were detected. CONCLUSIONS: Our data suggest that hypothalamic insulin resistance might contribute to pancreatic insulin hypersecretion. Alternatively, common pathogenetic mechanisms could introduce both brain insulin resistance and beta cell hypersecretion.