Use Of Targeted Agents Research Articles

1798. Impact and Sustainability of Antibiotic Prescribing Feedback with Peer Comparison to Hospitalists in a Community Hospital

Abstract Background Antibiotic prescribing feedback with peer comparison has been shown to reduce antibiotic prescription rates in the outpatient setting, but data regarding its impact in community hospitals are lacking. We previously developed novel denominator metrics to control for differences between physician practices such as patient volume or workload. Using these metrics, we provided regular antibiotic prescribing feedback with peer comparison to hospitalists in a community hospital over four years and evaluated its impact on targeted antibiotic prescribing. Methods Antibiotic days of therapy (DOT) for all antibacterials and targeted agents (aztreonam, antipseudomonal beta-lactams, vancomycin, and the fluoroquinolones (FQ)) were obtained from electronic medication administration records and linked to the ordering hospitalist. Physician-specific shifts worked data by month were calculated from local administrative datasets. De-identified data were presented in DOT/shifts worked, and trends in facility-wide and hospitalist-specific antibiotic prescribing were evaluated. Results A total of 37,938 antibiotic DOTs were prescribed by hospitalists from January 2018 to March 2022. De-identified feedback was shared in-person (4/2018, 4/2019, 3/2020, 11/2021) or virtually (9/2020) in small group sessions, and education, including local antibiogram data and recommended alternatives, was provided for targeted agents. Of the 31 hospitalists that received feedback, trends in FQ use for 7 hospitalists with longitudinal data are shown (Figure 1). In the month following feedback sessions, hospitalist antibiotic use data demonstrated substantial reductions in FQ prescribing, and similar trends were observed among all targeted agents. A single hospitalist’s prescribing trend for targeted agents is shown in Figure 2. Facility-wide, targeted agent use decreased 31% from 2017 to 2021 and was primarily driven by reductions in use by hospitalists. Conclusion Regular antibiotic prescribing feedback with peer comparison and education was associated with a reduction in targeted agent prescribing by hospitalists at a community hospital. Disclosures All Authors: No reported disclosures.

Ibrutinib Combined with Obinutuzumab and CHOP (I-OCHOP) for Richter Transformation

Background: The development of Richter Transformation (RT) in patients (pts) with chronic lymphocytic leukemia (CLL) while on targeted agents has been reported to have a median survival of 2.3-3.5 months (mo). Treatment is usually anthracycline-based combination regimens, though responses are short-lived. Phase 2 trial of combined venetoclax-REPOCH achieved a median progression free survival (PFS) of 16 mo. We studied the use of ibrutinib in combination with obinutuzumab, cyclophosphamide, doxorubicin, vincristine, and prednisone (I-OCHOP) JUN2017-SEP2018 (ClinicalTrials.gov: NCT03145480). During the conduct of the study, ibrutinib plus RCHOP in untreated diffuse large B cell lymphoma (NCT01855750) reported more treatment-emergent serious adverse events when compared to RCHOP, leading to higher rates of treatment discontinuation with toxicity more prominent in elderly pts. Since the majority of pts with CLL are elderly, enrollment was stopped. We report the outcomes of 3 participants.Methods: Informed consent was provided through IRB-approved protocol. Subjects were enrolled in an open-label phase II trial combining ibrutinib with O-CHOP. Ibrutinib 560mg was taken daily starting cycle 1 day 1 (C1D1) continuously until progression or start of new anticancer treatment. Obinutuzumab was given per prescription insert starting on C1D1 with CHOP for up to 6 cycles. Pts were allowed to discontinue study drugs to pursue allogeneic stem cell transplant (allo-SCT). Pts aged 18-80 years old with adequate organ function, Eastern Cooperative Oncology Group performance status ≤ 2, and histologically confirmed evidence of RT from CLL were eligible to participate. Prior targeted agent use was allowed until 24 hours prior to dosing. Chemo- or immuno-therapy was not allowed within 21 and 10 days of C1D1 respectively.The primary endpoint was investigator-assessed overall response rate (ORR) per revised response criteria for malignant lymphoma. Secondary outcomes included hematological improvement, PFS, overall survival (OS), and quality of life. Pts were allowed to pursue allo-SCT after achieving a response and were followed for PFS/OS. Descriptive analyses were utilized, and PFS/OS was calculated from initial treatment to death or last follow-up.Results: Three pts consented and started therapy: two women and one man with a median [range] age of 53 [36-73] years, all had high-risk disease (Figure 1). Median Cumulative Illness Rating Scale at baseline 2 [0-4]. No large cell lymphoma involved the bone marrow. All pts developed RT while on a novel agent (ibrutinib, acalabrutinib, or venetoclax monotherapy respectively). All enrolled immediately after RT diagnosis and received I-OCHOP. Participants had overall good adherence to ibrutinib therapy (mean missed doses per 28-day treatment cycle was 0.88 doses) while on trial. Two pts developed neutropenia (n=1, grade 3 and n=1, grade 4; neither febrile) that resolved by time of withdrawal from study. 2 pts had anemia (grade 1 and 2), and one participant had thrombocytopenia (grade 2), neither requiring transfusion support. All 3 pts reported fatigue (all grade 2 or less) that on average improved during treatment as assessed by FACIT questionnaire (mean Δ from baseline to end of treatment: -5). Figure 1 lists other adverse events.Of 3 enrolled pts, 2 pts achieved remission (1 complete, 1 partial) and undetectable minimal residual disease (detection sensitivity 0.01%) in the bone marrow post 4 cycles I-OCHOP and underwent allo-SCT and were followed for progression. Figures 2 and 3 show the PET responses after 2 cycles of I-OCHOP in 2 participants with bulky lymphadenopathy. Time to allo-SCT for the 2 pts was 3.7 and 3.9 mo from C1D1. After transplant, one pt relapsed with RT in the central nervous system after 20 mo and died from pneumonia 5 mo later; the other pt is alive 49.5 mo later with no evidence of disease. The third pt had rapid progression and came off study. Median PFS for the 3 pts was 23.5 mo [1.9-NR] and OS 29.1 mo [6.7-NR] as of datacut July 30, 2021.Conclusions: Despite historically poor outcomes reported after RT while on a targeted agent, ibrutinib addition to anthracycline-based regimen seemed well tolerated. Two patients achieved a rapid and deep responses irrespective of prior BTK inhibitor use and were able to pursue allo-SCT which correlated with durable PFS/OS. [Display omitted] DisclosuresRhodes: Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support; AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant.

Trends in Cancer Treatment for Oral Cavity, Oropharynx, and Larynx in 2016 Versus 2009: SEER Patterns of Care Studies.

To determine if there was a higher percentage of patients treated surgically and with advanced radiotherapy in 2016 (N = 897) versus 2009 (N = 1136), the patient and tumor characteristics associated with surgical care and advanced radiotherapy, and if chemotherapy or targeted agent use varied over time for squamous cell carcinoma of the head and neck. We utilized Surveillance Epidemiology and End Results Patterns of Care datasets. Rao-Scott Chi-square tests and logistic regressions were applied to determine differences in surgery, advanced radiotherapy (RT), and chemotherapy by year. There was a lower prevalence of surgery only treatment in 2016 versus 2009 with exception of oral cavity stages IVB/IVC and unknown, and larynx stage unknown. Advanced RT was more common in 2016 for patients receiving definitive RT among all sites, excluding stages I/II glottic larynx. Among each site (oral cavity, oropharynx, and larynx) lower stage was associated with increased odds of surgery. Among each site, advanced RT was more common in patients receiving definitive versus postoperative RT. For the larynx site, 2016 versus 2009 was associated with greater odds of advanced RT. Systemic treatment with fluorouracil, taxanes, or cetuximab was less prevalent in 2016. In 2016 versus 2009, there was largely not a higher percentage of patients treated surgically. There was a higher prevalence of advanced RT for definitive care. Further investigations of these patterns are needed, including trend analysis.

Barriers to Prescribing Targeted Therapies for Patients With NSCLC With Highly Actionable Gene Variants in the Veterans Affairs National Precision Oncology Program.

Next-generation sequencing (NGS) gene panels are frequently completed for patients with advanced non-small-cell lung cancer (NSCLC). Patients with highly actionable gene variants have improved outcomes and reduced toxicities with the use of corresponding targeted agents. We sought to identify barriers to targeted agent use within the Veterans Health Affairs' National Precision Oncology Program (NPOP). A retrospective evaluation of patients with NSCLC who underwent NGS multigene panels through NPOP between July 2015 and February 2019 was conducted. Patients who were assigned level 1 or 2A evidence for oncogenic gene variants by an artificial intelligence offering (IBM Watson for Genomics [WfG]) and NPOP staff were selected. Antineoplastic drug prescriptions and provider notes were reviewed. Reasons for withholding targeted treatments were categorized. Of 1,749 patients with NSCLC who successfully underwent NGS gene panel testing, 112 (6.4%) patients were assigned level 1 and/or 2A evidence for available targeted treatments by WfG and NPOP staff. All highly actionable gene variants were within ALK, BRAF, EGFR, ERBB2, MET, RET, and ROS1. Of these, 36 (32.1%) patients were not prescribed targeted agents. The three most common reasons were (1) patient did not carry a diagnosis of metastatic disease (33.3%), (2) treating provider did not comment on the NGS results (25.0%), and (3) provider felt that patient could not tolerate therapy (19.4%). No patients were denied access to level 1 or 2A targeted drugs because of rejection of a nonformulary drug request. A substantial minority of patients with NSCLC bearing highly actionable gene variants are not prescribed targeted agents. Further provider- and pathologist-directed educational efforts and implementation of health informatics systems to provide real-time decision support for test ordering and interpretation are needed.

Barriers to prescribing targeted therapies for NSCLC patients with highly actionable gene variants in the VA National Precision Oncology Program.

2005 Background: Next-Generation Sequencing (NGS) gene panels are often completed to guide therapeutic decisions for patients with advanced stage non-small cell lung cancer (NSCLC). Patients with highly-actionable gene variants may experience improved therapeutic treatments and reduced toxicities with use of targeted agents. Ensuring appropriate prescription of targeted therapies is therefore of high importance. We sought to identify barriers to targeted agent use within the Veterans Health Affairs’ (VHA) National Precision Oncology Program (NPOP). Methods: A retrospective evaluation examined the cohort of NSCLC patients who underwent NGS multi-gene panels through NPOP between July 2015 and February 2019. A level of evidence for drug actionability was assigned to each observed oncogenic gene variant using an artificial intelligence offering (IBM Watson for Genomics: WfG). WfG level 1 and 2A evidence was reviewed by NPOP staff to exclude gene variants that did not conform to NPOP level 1 and 2A definitions. Anti-neoplastic drug prescriptions and oncology provider notes were obtained for all included patients from the VHA Corporate Data Warehouse. Review of clinical notes of patients who did not receive targeted agents was performed to categorize the reason(s). Results: Of 1764 NSCLC patients who successfully underwent NGS gene panel testing, 156 (8.9%) received therapeutic level 1 (7.3%) or 2A (1.6%) options for targeted agents based on WfG evidence analysis. In total, 117 (6.6%) patients had NPOP level 1 and 2A gene variants, all within ALK, BRAF, EGFR, ERBB2, MET, and RET. Of these, 49 (41.2%) patients were not prescribed available targeted agents. The three most common reasons were: (1) treating provider did not comment on NGS results (30.7%), (2) patient did not carry a diagnosis of advanced stage disease (18.4%), and (3) patient had begun an alternative systemic therapy prior to completion of sequencing (16.3%). No patient was denied access to a level 1 or 2A targeted drug due to utilization-management review. Conclusions: A substantial minority of patients with advanced NSCLC bearing highly-actionable gene variants are not prescribed available targeted agents. Further provider- and pathologist-directed educational effort are needed, as well as implementation of health informatics systems to provide near real-time decision support for test ordering and interpretation.

Extending the Duration of Efficacy of Targeted Therapies with Radiation to Oligoprogressive Disease (OPD) in Oncogene-Driven Metastatic Non-Small Cell Lung Cancer (NSCLC)

We evaluated the role of local ablative radiotherapy (LAR) to sites of OPD in extending the duration of efficacy of the targeted therapies for patients with oncogene-driven metastatic NSCLC. From January 2015 to February 2019 we identified 81 patients with metastatic NSCLC EGFR, ALK, ROS1, and BRAF (n = 50, 20, 7, and 4, respectively) driver mutations on targeted therapies with OPD of ≤ 5 sites per LAR course treated at our center. Progression free survival-1 (PSF1) on targeted therapy was defined as time from targeted agent use to the LAR course for OPD. PFS2 was defined as start of LAR to change of systemic therapy. If more than 1 LAR course was administered on the same targeted therapy, PFS2 included the total time interval until change of system therapy. CNS and regional lymph node regions were each considered a single site of disease. Overall survival and PFS were estimated using the Kaplan-Meier method and analyzed using the log-rank test. Median PFS1 on targeted therapy was 8.7 months for all patients. Median PFS2 after LAR course(s) was an additional 7.6 months. The median PFS2 for CNS only OPD was 8.0 months whereas the median PFS2 for extracranial only OPD was 6.8 months (log-rank p=0.236). The resulting median overall time on the same targeted therapy was 17.3 months in patients who received LAR for OPD which was statically significant compared to PSF1 of 8.7 months (log-rank p<0.0001). Overall, there were 133 courses of LAR among the 81 patients, with mean, median, and range of 1.6, 1, and 1-5 courses per patient, respectively. The number of sites treated per LAR course had a mean, median, and range of 1.4, 1, and 1-5 sites per course, respectively. Median overall survival in the cohort was 62.0 months. In patients with oncogene-driven NSCLC, one or more courses of LAR to sites of OPD significantly increased the duration of efficacy of targeted therapies by 7.6 months and nearly doubled the time on a given targeted agent. LAR to OPD in oncogene-driven NSCLC represents a highly effective strategy to maximize the duration of access to targeted therapies.

Outcomes of stent insertion and mortality in obstructive stage IV colorectal cancer patients through 10 year duration

Colorectal stents are frequently used in patients with stage IV colorectal cancer with obstruction. However, there are only few studies on changes in outcomes of these patients and on the effect of stents on outcome over a long period of time with ongoing changes in therapeutic strategy, including chemotherapy. We retrospectively evaluated 353 patients with bowel obstruction in stage IV colorectal cancer who underwent colonic stenting between years 2005 and 2014. The study population was divided into three groups based on time periods: 2005-2008, 2009-2011, and 2012-2014. The frequency of colorectal stent insertion procedure increased over the time periods (13.8%, 18.3%, and 20.8%, respectively). There were no changes in success rate and total complication rate. However, the early complication rate in the 3rd period was significantly lower than in the other periods (15.4% vs. 17.1% vs. 7.2%; P = 0.039). In the multivariate analysis, carcinomatosis (hazard ratio, 1.478; 95% confidence interval, 1.016-2.149; P = 0.041) and covered or partial-covered stent (hazard ratio, 1.733; 95% confidence interval, 1.144-2.624; P = 0.009; hazard ratio, 1.988; 95% confidence interval, 1.132-3.493; P = 0.017, respectively) were associated with increased complication rate. Stent-related perforation was an independent risk factor related with increased mortality. Although survival duration increased over time (P = 0.042), the mortality rate was unchanged across the three time periods. Over 10 years, the targeted agent use and survival duration increased, and early complication rate was decreased, without change in late complication rate or mortality rate during the three time periods in patients with obstructive stage IV colorectal cancer and stent insertion.

The Impact of Skin Problems on the Quality of Life in Patients Treated with Anticancer Agents: A Cross-Sectional Study.

PurposePatients treated with anticancer agents often experience a variety of treatment-related skin problems, which can impair their quality of life.Materials and MethodsIn this cross-sectional study, Dermatology Life Quality Index (DLQI) and clinical information were evaluated in patients under active anticancer treatment using a questionnaire survey and their medical records review.ResultsOf 375 evaluated subjects with anticancer therapy, 136 (36.27%) and 114 (30.40%) were treated for breast cancer and colorectal cancer, respectively. We found that women, breast cancer, targeted agent use, and longer duration of anticancer therapy were associated with higher dermatology-specific quality of life distraction. In addition, itching, dry skin, easy bruising, pigmentation, papulopustules on face, periungual inflammation, nail changes, and palmoplantar lesions were associated with significantly higher DLQI scores. Periungual inflammation and palmoplantar lesions scored the highest DLQI.ConclusionWe believe our findings can be helpful to clinicians in counseling and managing the patients undergoing anticancer therapy.

Impact of systemic targeted agents on the clinical outcomes of patients with brain metastases

To determine the clinical benefits of systemic targeted agents across multiple histologies after stereotactic radiosurgery (SRS) for brain metastases. Between 2000 and 2013, 737 patients underwent upfront SRS for brain metastases. Patients were stratified by whether or not they received targeted agents with SRS. 167 (23%) received targeted agents compared to 570 (77%) that received other available treatment options. Time to event data were summarized using Kaplan-Meier plots, and the log rank test was used to determine statistical differences between groups. Patients who received SRS with targeted agents vs those that did not had improved overall survival (65% vs. 30% at 12 months, p < 0.0001), improved freedom from local failure (94% vs 90% at 12 months, p = 0.06), improved distant failure-free survival (32% vs. 18% at 12 months, p = 0.0001) and improved freedom from whole brain radiation (88% vs. 77% at 12 months, p = 0.03). Improvement in freedom from local failure was driven by improvements seen in breast cancer (100% vs 92% at 12 months, p < 0.01), and renal cell cancer (100% vs 88%, p = 0.04). Multivariate analysis revealed that use of targeted agents improved all cause mortality (HR = 0.6, p < 0.0001). Targeted agent use with SRS appears to improve survival and intracranial outcomes.

Targeted Agent Use in Cancer Patients at the End of Life

ContextThe use of targeted therapy at the end of life has not been well characterized. ObjectivesTo determine the frequency and predictors of targeted therapy use in the last days of life. MethodsAll adult patients residing in the Houston area who died of advanced cancer between September 1, 2009 and February 28, 2010 and had contact with our institution within the last three months of life were included. We collected baseline demographics and data on chemotherapy and targeted agents. ResultsEight hundred sixteen patients were included: average age 62 years (range 21–97), female 48% and white 61%. The median interval between the last treatment and death was 47 (interquartile range [IQR] 21–97) days for targeted agents and 57 (IQR 26–118) days for chemotherapeutic agents. Within the last 30 days of life, 116 (14%) patients received targeted agents and 147 (18%) received chemotherapy. Regimens given in the last 30 days of life included a median of one (IQR 1–2) chemotherapeutic or targeted agent and 43 (5%) patients receiving targeted agents had concurrent chemotherapy. The most common targeted agents in the last 30 days of life were erlotinib (n = 25), bevacizumab (n = 20), rituximab (n = 11), gemtuzumab (n = 8), and temsirolimus (n = 8). On multivariate analysis, younger age (odds ratio [OR] 0.98 per year, P = 0.01), hematologic malignancy (OR = 6.1, P < 0.001), and lung malignancy (OR = 2.6, P = 0.05) were associated with increased targeted agent use in the last 30 days of life. ConclusionTargeted agents were used as often as chemotherapy at the end of life, particularly among younger patients and those with hematologic malignancies. Guidelines on targeted therapy use at the end of life are needed.

Targeted agent use in patients with cancer at the end of life.

215 Background: Chemotherapy use at the end of life is considered an indicator of poor quality of care. The use of targeted agent has not been well characterized. In this study, we determined the frequency and predictors of targeted therapy use in the last 30 days of life. Methods: All adult patients residing in the Houston area who died of advanced cancer between September 1, 2009 and February 28, 2010 and had contact with our institution within the last three months of life were included. We collected baseline demographics and data on chemotherapy and targeted agents. Results: 816 patients were included: average age 62 (range 21 to 97), female 48% and White 61%. The median interval between the last treatment and death was 47 (interquartile range 21 to 97) days for targeted agents and 57 (26 to 118) days for chemotherapeutic agents. 116 (14%) patients received targeted agents and 147 (18%) received chemotherapy within the last 30 days of life. 43 (5%) patients received targeted agents had concurrent chemotherapy. The most common targeted agents in the last 30 days of life were erlotinib (n=25), bevacizumab (n=20) and rituximab (n=11). In multivariate analysis, younger age, hematologic, and lung malignancies were associated with increased targeted agent use in the last 30 days of life (Table). Conclusions: Targeted agents were used as often as chemotherapy at the end of life, particularly among younger patients and those with hematologic malignancies. Guidelines on targeted therapy use at the end of life are needed. [Table: see text]

Update on novel therapies for pancreatic neuroendocrine tumors.

Neuroendocrine tumors (NETs) describe a heterogeneous group of tumors with a wide range of morphologic, functional, and behavioral characteristics. Pancreatic neuroendocrine tumors (pNET) are a subset of NETs which are increasing in incidence and prevalence. These tumors are generally slow growing and behave in an indolent fashion. However, when these tumors spread they can be life threatening and difficult to treat with current modalities. In 2011, the landscape of treatment for pNET was changed with the approval of two targeted agents, sunitinib and everolimus, the first new therapies for this disease in over 20 years. Data from these clinical trials and extensive preclinical work into the underlying molecular pathways in neuroendocrine tumors has generated intense interest in the quest to identify additional effective agents in this challenging disease. At the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, several researchers presented updated data regarding the use of targeted agents, alternative chemotherapeutic agents and combinations of these in the treatment of pNET. Corrie et al. (Abstract #4121) reported data from a chemotherapy clinical trial replacing 5-FU with capecitabine and evaluating the addition of cisplatin in NETs. Several authors reviewed the addition of the anti VEGF monoclonal antibody bevacizumab into combination therapy. Ducreux et al (Abstract #4036) presented results from a trial of chemotherapy plus bevacizumab while Firdaus et al. (Abstract #4127) reported the results of combination therapy with octreotide, bevacizumab, and pertuzumab. Hobday et al. (Abstract #4048) reported positive results of an interim analysis of combination therapy with an mTOR inhibitor and bevacizumab. Kulke et al (Abstract #4125) reported the results of a clinical trial utilizing an antibody targeting the insulin growth factor receptor. Finally, Vinik et al. (Abstract #4118) provided updated survival data form the seminal phase III trial that led to approval of sunitinib in the treatment of pNET. The authors review and summarize these abstracts in this article.

Combination Targeted Therapy for Patients with Advanced Renal Cancer

Novel therapies that target vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways have transformed that manner in which patients with advanced renal cancer are managed; but because these agents are not curative, disease progression eventually ensues. Data on optimal sequential use of these therapies are lacking, and efforts to explore combined use of targeted agents have been hampered by intolerable toxicities. Evidence …

Use of Targeting Agents to Increase Uptake and Localization of Drugs to the Intestinal Epithelium

Despite early successes in oral drug delivery of small molecules such as antibiotics, cephalosporins and vitamins, little success has been achieved with more recent pharmaceuticals such as peptides and proteins. This lack of success is primarily due to the impenetrable nature of the gastro-intestinal epithelial cell layers. Despite this, many bacteria, viruses and toxins are readily taken up from the intestine and thereby gain entry into the circulation. This review focuses on the use of various surface molecules from these organisms as well as toxin binding subunits as carriers for oral delivery of other molecules. It also describes the subversion of the natural uptake mechanisms for various vitamins and iron to allow for oral delivery of pharmaceuticals. These mechanisms provide exciting solutions to overcome the problems in oral delivery of peptides and proteins, which has been the nemesis of pharmaceutical scientists for many decades.