Optimal Place In Therapy Research Articles

Targeted Therapies for Previously "Undruggable" KRAS-Mutated Non-Small Cell Lung Cancer: A Review of Sotorasib and Adagrasib.

To evaluate the safety and efficacy of the novel KRAS-targeting agents, sotorasib and adagrasib, in treating KRAS G12C-mutated non-small cell lung cancer (NSCLC). A comprehensive English-based literature search of PubMed and Clinicaltrials.gov between January 2000 and July 2023 was conducted using the terms sotorasib, Lumakras, AMG 510, adagrasib, Krazati, and MRTX849. Relevant prescribing information, clinical trials, and treatment guidelines were evaluated. Sotorasib and adagrasib received accelerated US Food and Drug Administration (FDA) approval following pivotal phase I/II clinical trials. Sotorasib, a first-in-class KRAS inhibitor, demonstrated an overall response rate (ORR) of 41% and a progression-free survival (PFS) of 6.3 months. In a phase III confirmatory trial, sotorasib showed significantly longer PFS compared with docetaxel (5.6 vs. 4.5 months; P = 0.0017). Adagrasib produced an ORR of 42.9% and a PFS of 6.5 months. Both drugs present unique safety profiles, with common toxicities, including diarrhea, musculoskeletal pain, fatigue, and hepatotoxicity. With KRAS mutations being among the most common oncogenic alterations in NSCLC, sotorasib and adagrasib offer new therapeutic avenues for this previously "undruggable" target. Current treatment guidelines list sotorasib and adagrasib as second-line options in patients with confirmed KRAS G12C-mutated NSCLC. Additional studies are required to further differentiate the safety and efficacy profiles of these 2 agents and identify their optimal place in therapy. Sotorasib and adagrasib demonstrated promising outcomes in targeting the constitutively active KRAS G12C oncogenic driver, underscoring the need for further research to optimize their therapeutic application in this high-risk population.

Place in Therapy of Cyclin-Dependent Kinase 4/6 Inhibitors in Breast Cancer: A Targeted Literature Review.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are the preferred regimen for patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced or metastatic breast cancer. However, the optimal treatment sequencing for CDK4/6i with other available therapeutic options is unclear. We conducted a targeted literature review to identify the current evidence on CDK4/6i treatment patterns in patients with breast cancer. The search was initially conducted in October 2021 and subsequently updated in October 2022. Biomedical databases and gray literature were searched, and bibliographies of included reviews were screened for relevant studies. The search identified ten reviews published since 2021 and 87 clinical trials or observational studies published since 2015. The included reviews discussed CDK4/6i usage with or without endocrine therapy (ET) in first-line and second-line treatment for patients with HR+/HER2- advanced or metastatic breast cancer, followed by ET, chemotherapy, or targeted therapy with ET. Clinical studies reported similar treatment sequences consisting of ET, chemotherapy, or targeted therapy with ET prior to CDK4/6i with ET, followed by ET monotherapy, chemotherapy, targeted therapy with ET, or continued CDK4/6i with ET. Current evidence suggests CDK4/6i are effective for HR+/HER2- advanced or metastatic breast cancer in earlier lines of therapy. Efficacy of CDK4/6i as measured by progression-free survival and overall survival was similar within a line of therapy regardless of the type of prior therapy. Survival on different post-CDK4/6i treatments was also similar within the same line of therapy. Additional research is needed to investigate the optimal place in therapy of CDK4/6i and the sequencing of treatments following progression on CDK4/6i.

500. Impact of an iron chelator on in vitro and in vivo growth of A. baumannii

Abstract Background Acinetobacter baumannii (AB) has become multidrug-resistant in recent years and currently there is no consensus on the optimal treatment for these infections. To combat this urgent threat, novel treatment options are needed to minimize spread and lower mortality rates. Nutrient metals (e.g., iron) are essential to the metabolic functions of AB. If the bioavailability of essential nutrients is restricted, this can cause a bacterial stress response and alter their ability to multiply. Methods The objective of the study was to examine the impact of iron chelation on the growth of AB in vitro and in vivo. MDR AB bloodstream isolates (n=4) were recovered from unique patients between 2011 and 2018. Clonal diversity was ascertained by Fourier Transform Infrared Spectroscopy. In vitro bacterial densities were measured longitudinally over 20-hours to determine the growth profile. Isolates were started at a baseline concentration of approximately 5.5 log CFU/mL in tryptic soy broth. Variable amounts of an iron chelating agent (deferiprone, 0.2-2mM) were added to create a concentration gradient. Galleria mellonella larvae (100-150mg) were inoculated with approximately 5 log CFU of an isolate, with and without deferiprone (10mM). Quantitative culture was used to ascertain the bacterial burden of aggregate larvae (n=10) immediately and 4h post infection. Additional infected larvae (n=20 in each group) were incubated at 35°C and monitored hourly for 24h. Results Time to mortality was compared using Kaplan-Meier survival analysis and log-rank test. Increasing concentrations of the chelating agent caused a transient and concentration-dependent hindrance of in vitro bacterial growth, compared to the no-treatment group. Bacterial burden immediately post-infection of the control and treatment group were comparable at 6.4 log CFU/g. After 4 hours the bacterial burden was much higher in the control group than the treatment group, 8.7 and 6.7 log CFU/g respectively. A trend of delayed mortality was shown in the iron chelator group (median survival 6.5 vs 10 hours, p=0.15). Conclusion These results support that micro-nutrient limitation has the potential to be a novel approach for treating high-risk infections due to MDR AB. Future studies are warranted to further define its optimal place in therapy. Disclosures All Authors: No reported disclosures.

A Review of Tisotumab Vedotin-tftv in Recurrent or Metastatic Cervical Cancer.

To evaluate the safety and efficacy of tisotumab vedotin-tftv (TV), a first-in-class vectorized anti-tissue factor (TF) antibody-drug conjugate (ADC), for the treatment of recurrent or metastatic cervical cancer. A literature search of ClinicalTrials.gov, Embase, and PubMed was conducted using the terms tisotumab vedotin AND cervical cancer from inception to June 30, 2022. All applicable publications, package inserts, meeting abstracts, and clinical trials involving TV in the treatment of cervical cancer were reviewed. TV is a fully human TF-specific monoclonal antibody conjugated to monomethyl auristatin E, which serves as a highly potent cytotoxic payload. In the pivotal phase II InnovaTV 204 clinical trial, TV demonstrated an objective response rate of 24% (95% confidence interval [CI], 16%-33%). The mean duration of response was 8.3 months. Common toxicities included abdominal pain, alopecia, conjunctivitis, constipation, decreased appetite, diarrhea, dry eye, epistaxis, nausea/vomiting, and peripheral neuropathy. Unique and/or serious adverse events warranting careful monitoring include ocular complications, hemorrhaging, peripheral neuropathies, fetal-embryo toxicity, pneumonitis, and immunogenicity. Recurrent or metastatic cervical cancer remains a high-risk disease with limited treatment options. Using ADCs to target tumors with aberrant expression of TF appears to be a viable treatment strategy. TV is the first Food and Drug Administration-approved TF-directed ADC. With a manageable safety profile and promising anticancer activity, TV warrants consideration as a novel targeted agent for the treatment of recurrent or metastatic cervical cancer. Further studies are required to determine the optimal place in therapy for TV.

Oncology stewardship in acute myeloid leukemia.

In recent years, an explosion of novel agents has shifted the treatment paradigm for patients with acute myeloid leukemia. The optimal place in therapy for many of these novel agents remains unknown due to limited guidance from national guidelines and the way these agents were studied prior to entering the market. A critical evaluation of the literature and incorporation of oncology stewardship principles can be helpful in determining an optimal place for these agents while being mindful of the overall cost that is associated with therapies. The purpose of this review is to critically evaluate the efficacy and safety data for five controversial agents and provide examples of the use of stewardship practices in determining their place in the treatment of acute myeloid leukemia.

Evaluation of Inhaled Alprostadil in Hospitalized Adult Patients.

Intermittent inhaled alprostadil (iPGE1) may be a viable alternative to inhaled nitric oxide or epoprostenol for management of right ventricular failure, pulmonary hypertension (pHTN) or acute respiratory distress syndrome (ARDS). However, limited evidence exists regarding iPGE1 use in adults, ideal dosing strategies, or optimal use cases. To describe the clinical characteristics of patients receiving iPGE1 and identify specific sub-populations warranting further research. This was a single-center, retrospective, descriptive analysis of inpatients who received at least one dose of iPGE1. The primary outcome was to describe patient characteristics and alprostadil dosing strategies. Secondary outcomes included changes in respiratory support requirements, hemodynamics, and inotropic/vasoactive use. Outcomes were stratified and compared based on primary therapeutic indication (cardiac or pulmonary). Fifty-four patients received iPGE1 40 (75%) for pulmonary (pHTN or ARDS) and 14 (25%) for cardiac indications. There was no difference between indications in the number of patients de-escalated from level of respiratory (53% vs 57%, P = 0.76), inotropic (70% vs 57%, P = 0.39), or vasopressor support (78% vs 57%, P = 0.17). Furthermore, there was no significant improvement in cardiopulmonary parameters at multiple time intervals after iPGE1 initiation. This is the largest study to date on the use of intermittent iPGE1 in adults. Alprostadil was safely utilized in novel populations; however, efficacy as evaluated by clinical or surrogate endpoints could not be demonstrated and further investigation is needed to determine its potential and optimal place in therapy.

Risk factors for nephrotoxicity associated with polymyxin B therapy in Chinese patients.

Background The widespread application of Polymyxin B, an active agent against multidrug resistance and extensive drug resistance Gram-negative bacteria, is majorly impeded by nephrotoxicity. Studies on the safety of polymyxin B in Chinese patients have not been widely reported. Objective This study aimed to explore the risk factors for polymyxin B-associated nephrotoxicity and guide its optimal place in therapy. Setting A tertiary care hospital located in eastern China. Methods This being a retrospective cohort study, we evaluated adult patients who received ≥ 72h of polymyxin B therapy from January 2018 to December 2019. However, patients who received polymyxin B therapy for less than 3 days or received renal replacement therapy at baseline were excluded. Pertinent information was retrieved from medical records. All statistical analysis was performed in SPSS version 22.0. Main outcome measure(s) The main outcome measures included the proportion of patients who developed nephrotoxicity when subjected to polymyxin B treatment and the independent risk factors for nephrotoxicity. Results A total of 119 patients received polymyxin and met the overall inclusion criterion. Of the 119, 46 patients (38.7%) developed nephrotoxicity. Through multiple logistic regression analysis, we found three variables as independent risk factors for nephrotoxicity, including co-morbidities of malignancy (OR 4.55; 95% CI 1.44-14.41; P = 0.010), co-infection with other microorganisms (OR 4.15; 95% CI 1.48-11.63; P = 0.007), and polymyxin B daily dose (OR 1.02; 95% CI 1.00-1.03; P = 0.026). Conclusion This retrospective cohort study identified three risk factors for polymyxin B-associated nephrotoxicity therapy in Chinese patients. These include malignancy, co-infection with other microorganisms, and polymyxin B daily dose.

Doravirine: A Return of the NNRTI Class?

Objective: To compare and contrast doravirine (DOR) with other agents in the nonnucleoside reverse transcriptase inhibitor (NNRTI) class, review safety and efficacy data from both completed and ongoing clinical trials, and outline the potential place in therapy of DOR. Data Sources: A literature search using the PubMed database (inception to June 2019) was conducted using the search terms HIV, doravirine, non-nucleoside reverse transcriptase inhibitor, NNRTI, and MK-1439. Study Selection and Data Extraction: Clinical data were limited to those published in the English language from phase 2 or 3 clinical trials. Ongoing trials were identified through ClinicalTrials.gov. Data Synthesis: DOR was approved by the US Food and Drug Administration on the strength of 2 phase 3 randomized, double-blind, noninferiority clinical trials with additional studies currently underway examining its utility in other clinical scenarios. Relevance to Patient Care and Clinical Practice: The role of NNRTIs as part of antiretroviral (ARV) therapy has diminished in recent years given the introduction of more tolerable individual ARV agents and regimens. Despite this, new agents are still needed in the therapeutic arena because treatment failure as well as intolerance can still occur with many first-line therapies. The optimal place in therapy of DOR remains to be defined. Conclusions: DOR is a new NNRTI that represents a potential treatment option for treatment-naïve patients, without many of the previously described untoward effects of the NNRTI class.

Role of angiotensin II in treatment of refractory distributive shock.

Clinical data and gaps in knowledge regarding angiotensin II (AT2), which was approved by the Food and Drug Administration in December 2017 via priority review for treatment of septic and other vasodilatory shock, is discussed. AT2 is an endogenous peptide that raises blood pressure via vasoconstriction and increased aldosterone release. It was previously available but withdrawn from the US market; previous low-quality research describes increases in mean arterial pressure (MAP). The recent approval of AT2 was based on data from a Phase III randomized trial comparing i.v. AT2 (n = 163) with placebo use (n = 158) in patients with vasodilatory shock receiving high doses of other vasopressors. AT2 significantly increased achievement of the primary endpoint, MAP response at 3 hours after the start of infusion, relative to placebo use (69.9% [n = 114] versus 23.4% [n = 37], p < 0.0001). Serious adverse events occurred in 60.7% (n = 99) and 67.1% (n = 106) of patients treated with AT2 and placebo recipients, respectively, including venous and arterial thromboembolic events (12.9% [n = 21] and 5.1% [n = 8], respectively). No significant effects of AT2 on 7- or 28-day mortality were seen among all patients in the ATHOS-3 trial. However, post hoc analyses suggested that AT2 may reduce mortality in patients with low baseline AT2 levels, exaggerated response to AT2, and acute kidney injury receiving concomitant renal replacement therapy. Overall, due to shortcomings of the ATHOS-3 trial data and the absence of confirmatory studies, the optimal place in therapy of AT2 for vasodilatory shock cannot be determined with confidence. Intravenous AT2 represents a novel treatment strategy for refractory septic or other vasodilatory shock, although findings of safety and efficacy have not been replicated and the drug's optimal place in therapy is uncertain.

Treatment of adult acute lymphoblastic leukemia with inotuzumab ozogamicin.

Treatment of adult acute lymphoblastic leukemia (ALL) has largely relied on cytotoxic chemotherapy agents borrowed from successful treatment regimens of pediatric ALL. However, the high cure rates seen in pediatric ALL have not been replicated in adults. In recent years, the development of monoclonal antibodies targeting cell surface antigens, such as CD19 and CD20, have significantly improved outcomes when used alone or in combination with cytotoxic chemotherapy. With these novel agents come challenges in managing adverse events, understanding mechanisms of resistance and determining their optimal place in therapy alongside conventional chemotherapy and allogeneic stem cell transplant. Herein we discuss the above challenges with the next addition to the armamentarium of antileukemic agents, inotuzumab ozogamicin, an antibody-drug conjugate against CD22.

Rational use of rasburicase for the treatment and management of tumor lysis syndrome

Purpose There is a lack of high-level evidence identifying meaningful outcomes and the optimal place in therapy of rasburicase in patients with, or at high risk for tumor lysis syndrome. The primary objective of this study was to evaluate and characterize outcomes resulting from an institution-specific guideline emphasizing supportive care, xanthine oxidase inhibitors, and lower doses of rasburicase. Methods In this retrospective chart review, we compared conservative rasburicase dosing, in accordance with newly developed UMHS tumor lysis syndrome guidelines, with aggressive rasburicase in adult patients (≥ 18 years of age) with hematological or solid tumor malignancies, and a uric acid level between 8 and 15 mg/dL. The primary efficacy outcome assessed the difference in the proportion of patients achieving a uric acid level <8 mg/dL within 48 h using a one-sided noninferiority test. The principle safety outcomes analyzed included incidence of acute kidney injury and hemodialysis requirement. Results One hundred sixty-one patients met inclusion criteria and were included in the study. Within 48 h of an elevated uric acid level, treatment was successful in 97.03% of patients in the conservative group, as compared with 98.33% in the aggressive group (difference, 1.3 percentage points; 95% confidence interval [CI], -3.33 to 5.93). Furthermore, there was no difference in the proportion of patients requiring hemodialysis (2.97% vs. 10.0%, p-value 0.079), or incidence of acute kidney injury (4.0% vs. 12.5%, p-value 1.00) between the treatment group and control group, respectively. Conclusions Conservative rasburicase use was noninferior to aggressive rasburicase use in patients with or at high risk for tumor lysis syndrome.

Blinatumomab: A First-in-Class Bispecific T-Cell Engager for Precursor B-Cell Acute Lymphoblastic Leukemia.

To review the clinical pharmacology, efficacy, and safety of blinatumomab for the treatment of pediatric and adult precursor B-cell acute lymphoblastic leukemia (B-ALL). A literature search of EMBASE (1947 to April 2015), Medline (1946 to April 2015), PubMed (1996 to April 2015), the U.S. National Institutes of Health Clinicaltrials.gov, the Food and Drug Administration, and relevant meeting abstracts was conducted using the terms blinatumomab, BiTE, bispecific T-cell engager, MT103, MEDI-538, and Blincyto. Human and animal studies describing the pharmacology, pharmacokinetics and pharmacodynamics, efficacy, and safety of blinatumomab for precursor B-ALL were identified. Blinatumomab is a first-in-class bispecific T-cell engager (BiTE) antibody derived from a B-lineage specific antitumor mouse monoclonal antibody that binds to both CD19 of B-cells and CD3 of T-cells. A pivotal phase II trial demonstrated that response rates were high in a refractory or relapsed patient population, with 43% achieving complete remission (CR). Median relapse-free survival was 5.9 months for those with CR or CR with incomplete hematological recovery. Median overall survival was 6.1 months, and 60% of patients achieved minimal residual disease (MRD) negativity. The most common adverse events included pyrexia, neurological events, headache, febrile neutropenia, peripheral edema, nausea, hypokalemia, constipation, and anemia. Blinatumomab is a novel BiTE therapeutic monoclonal antibody that has shown promising results in patients with relapsed or refractory ALL or those achieving a CR with persistent MRD. Phase III clinical trials should define the optimal place in therapy of blinatumomab.

Serotonin-Norepinephrine Reuptake Inhibitors for the Management of Chemotherapy-Induced Peripheral Neuropathy

To review the literature evaluating serotonin-norepinephrine reuptake inhibitors (SNRIs) for chemotherapy-induced peripheral neuropathy (CIPN). A PubMed search (1966-January 2014) was performed using the key terms serotonin-norepinephrine reuptake inhibitor, desvenlafaxine, duloxetine, milnacipran, venlafaxine, chemotherapy, and peripheral neuropathy. Bibliographies of select articles were examined for additional references and abstracts. Case reports and clinical trials published in English and conducted in humans were identified. All reports and trials evaluating a SNRI for the treatment of CIPN were included; 4 case reports, 1 open-label study, and 2 randomized controlled trials were identified for review. At present, no medications are approved for the treatment for CIPN. Emerging evidence suggests that venlafaxine and duloxetine may be effective for treating CIPN. Results of select trials report that these medications not only decrease pain but also relieve symptoms of numbness and tingling and improve the functional status and quality of life of patients suffering from CIPN. Evidence to support venlafaxine and duloxetine for the treatment of CIPN from oxaliplatin- or paclitaxel-based regimens is promising. Unfortunately, direct comparisons between venlafaxine and duloxetine do not exist, so definitive conclusions about which agent is preferred cannot be made. However, the breadth of data with duloxetine is larger, suggesting that it may be prudent to consider duloxetine first when choosing a SNRI for CIPN treatment. More robust trials are needed to establish their optimal place in therapy with regard to patient population, timing of therapy, dosing, and treatment duration.

Clinical and Economic Outcomes of Coronary Angioplasty Alone or in Combination with Stents in Academic Health Centers: A Retrospective Database Analysis

Objectives Indications for the use of stents are evolving and their optimal place in therapy remains to be defined. The objective was to compare the 1-year clinical and economic outcomes of percutaneous transluminal coronary agioplasty (PTCA) with and without the use of stents. Methods This retrospective database analysis was conducted using data from 60 US academic medical centers in 1996 and 1997. Outcomes of interest included in-hospital mortality (both on sentinel and readmission visits), readmission rates, revascularization procedures, length of stay, and the cost of sentinel and readmission hospitalization. Results A total of 27,020 patients either did (n = 13,254) or did not (n = 13,766) receive coronary stents in conjunction with PTCA. The median cost of hospitalization for the stent group was about $1,409 higher (mean, $1,200) than the no-stent group and the length of stay was similar (4.3 days vs. 4.5 days, respectively, P = .2628). Mortality rates on readmission (0.9% stent vs. 0.8% no-stent, P = NS) did not differ. However, patients in the stent group had better mortality rates compared to the no-stent group during the sentinel visit (1.7% vs. 2.7%, P < .001). Stent use was not associated with a significantly lower risk of a revascularization procedure on readmission to the same institution (OR 0.95, 95% CI 0.87–1.04, P = .28). Conclusion Stents were associated with a 1% decrease of inpatient mortality during the sentinel visit without impacting length of stay or readmission rates. This advantage was associated with a $1,409 higher median cost of hospitalization in the stent group.