Anticancer Treatment Regimens Research Articles

Improving the predictive accuracy of efficacy evaluation using tumor orthotopic transplant and resection model.

Preclinical efficacy evaluation and tumor drug sensitivity analysis are two main applications of efficacy evaluation. Preclinical efficacy evaluation is to predict whether candidate drugs or therapies may improve patient outcomes in clinical trials. Tumor drug sensitivity analysis is an approach for the personalized evaluation and optimization of approved anti-cancer drugs and treatment regimens. Overall survival (OS) is the gold standard to evaluate the outcome of drugs or therapies in both clinical trials and clinical treatment. Many efficacy evaluation models, such as cell model, tumor cell-line transplant model, patient-derived tumor xenograft model, tumor organoid model, have been developed to assess the inhibitory effect of tested drugs or therapies on tumor growth. In fact, many treatments may also lead to malignant progression of tumors, such as chemotherapy, which can lead to metastasis. Therefore, tumor growth inhibition does not necessarily predict OS benefit. Whether it can prevent or inhibit tumor recurrence and metastasis is the key to whether drugs and therapies can improve patient outcomes. In this perspective, we summarize the current understanding of the pathological progression of tumor recurrence and metastasis, point out the shortcomings of existing tumor transplant models for simulating the clinical scenario of malignant progression of tumors, and propose five improved indicators for comprehensive efficacy evaluation to predict OS benefit using tumor orthotopic transplant and resection model. Improvement in the accuracy of efficacy evaluation will accelerate the development process of anti-cancer drugs or therapies, optimize treatment regimens to improve OS benefit, and reduce drug development and cancer treatment costs.

A trinuclear Zn (II) schiff base dicyanamide complex attenuates bacterial biofilm formation by ROS generation and membrane damage and exhibits anticancer activity

A trinuclear Zn (II) complex, [(ZnL{N(CN)2})2Zn], termed complex 1 has been synthesized by the reaction of an aqueous solution of sodium dicyanamide to the methanolic solution of Zn (CH3COO)2, 2H2O and corresponding Schiff base (H2L) which is derived from 1:2 condensation of 1, 4 butane diamine with 3-ethoxy salicylaldehyde. Complex 1 is characterized by elemental analysis, IR, UV and Single X-ray diffraction study. Drug resistance is a growing global public health concern that has prompted researchers to look into advanced alternative treatment modalities. In this context, complex 1 has shown promising antibacterial and antibiofilm efficacy against gram-positive Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus strains. Complex 1 attenuated Staphylococcal biofilm formation by reducing several virulence factors including the formation of extracellular polysaccharide matrix, slime, haemolysin, staphyloxanthin, auto-aggregation, cell surface hydrophobicity, and motility. Notably, complex 1 mechanistically potentiated Reactive Oxygen Species (ROS) generation within the bacterial cells, leading to the damage of bacterial cell membrane followed by DNA leakage and thereby impeding the growth of Staphylococcus aureus. Furthermore, complex 1 significantly exhibited anticancer activity by reducing the growth of prostate adenocarcinoma cells. It obstructed the migration of cancer cells by potentiating apoptosis and arresting the cell cycle at the G2/M phase. In summary, complex 1 could act as a potent candidate for the generation of novel antibacterial, antibiofilm as well as anticancer treatment regimens for the management of drug-resistant biofilm-mediated Staphylococcus aureus infection and lethal prostate malignancy.

Refinement of safety and efficacy of anti-cancer chemotherapeutics by tailoring their site-specific intracellular bioavailability through transporter modulation.

Low intracellular bioavailability, off-site toxicities, and multi drug resistance (MDR) are the major constraints involved in cancer chemotherapy. Many anticancer molecules fail to become a good lead in drug discovery because of their poor site-specific bioavailability. Concentration of a molecule at target sites is largely varied because of the wavering expression of transporters. Recent anticancer drug discovery strategies are paying high attention to enhance target site bioavailability by modulating drug transporters. The level of genetic expression of transporters is an important determinant to understand their ability to facilitate drug transport across the cellular membrane. Solid carrier (SLC) transporters are the major influx transporters involved in the transportation of most anti-cancer drugs. In contrast, ATP-binding cassette (ABC) superfamily is the most studied class of efflux transporters concerning cancer and is significantly involved in efflux of chemotherapeutics resulting in MDR. Balancing SLC and ABC transporters is essential to avoid therapeutic failure and minimize MDR in chemotherapy. Unfortunately, comprehensive literature on the possible approaches of tailoring site-specific bioavailability of anticancer drugs through transporter modulation is not available till date. This review critically discussed the role of different specific transporter proteins in deciding the intracellular bioavailability of anticancer molecules. Different strategies for reversal of MDR in chemotherapy by incorporation of chemosensitizers have been proposed in this review. Targeted strategies for administration of the chemotherapeutics to the intracellular site of action through clinically relevant transporters employing newer nanotechnology-based formulation platforms have been explained. The discussion embedded in this review is timely considering the current need of addressing the ambiguity observed in pharmacokinetic and clinical outcomes of the chemotherapeutics in anti-cancer treatment regimens.

Risk of Lymphedema and Death after Lymph Node Dissection with Neoadjuvant and Adjuvant Treatments in Patients with Breast Cancer: An Eight-Year Nationwide Cohort Study.

Knowledge on the impact of neoadjuvant and adjuvant treatments on post-surgery lymphedema (LE) in patients with breast cancer is limited due to methodological limitations and an insufficient sample size. We investigated the risk of LE in patients going through long-term anticancer treatment regimens using a national cohort from the Korean National Health Insurance Service database from 2011-2013. Incidence rate ratio, Kaplan-Meier analysis, and Cox proportional regression analysis were performed. A total of 39,791 patients were included. While minimal lymph node dissection (SLNB) reduced the risk of LE (hazard ratio [HR] 0.51) as expected, neoadjuvant chemotherapy (NAC) followed by SLNB did not reduce the risk. Adjusting for adjuvant chemotherapy (AC) as time-varying exposure decreased the risk of LE in the SLNB group (HR 0.51), but not the mortality risk (HR 0.861). A longer duration of NAC, especially taxane-based, combined with SLNB reversed the effect and increased risk of LE. The findings highlight the importance of not only early surveillance before and after surgery, but also long-term surveillance during adjuvant treatment by surgeons and oncologists in order to reduce the risk of LE.

Cardiovascular Complications of Pan-Cancer Therapies: The Need for Cardio-Oncology.

It is more likely that a long-term survivor will have both cardiovascular disease and cancer on account of the progress in cancer therapy. Cardiotoxicity is a well-recognized and highly concerning adverse effect of cancer therapies. This side effect can manifest in a proportion of cancer patients and may lead to the discontinuation of potentially life-saving anticancer treatment regimens. Consequently, this discontinuation may adversely affect the patient's survival prognosis. There are various underlying mechanisms by which each anticancer treatment affects the cardiovascular system. Similarly, the incidence of cardiovascular events varies with different protocols for malignant tumors. In the future, comprehensive cardiovascular risk assessment and clinical monitoring should be considered for cancer treatments. Baseline cardiovascular evaluation risk should be emphasized prior to initiating clinical therapy in patients. Additionally, we highlight that there is a need for cardio-oncology to avoid or prevent cardiovascular side effects. Cardio-oncology service is based on identifying cardiotoxicity, developing strategies to reduce these toxicities, and minimizing long-term cardiotoxic effects.

A disease registry study to prospectively observe treatment patterns and outcomes in patients with HER2+ unresectable locally advanced or metastatic breast cancer (aBC): Interim results of the ESTHER study (NCT02393924).

e13039 Background: Over the last decade the standard-of-care treatment for patients with HER2+ aBC has included anti-HER2 therapies often combined with chemotherapy. These approaches have shown efficacy in clinical trials which have recruited patients in restricted populations defined by lines of therapy and previous treatments. There are few data regarding the long-term outcomes of patients treated with these regimens, including those with brain metastases. We conducted a prospective, multicentre non-interventional study to observe anti-cancer treatment regimens and clinical outcomes in patients with HER2 positive aBC. Methods: Adult patients diagnosed with HER2-positive aBC within the last 6 months were included. No specific treatment approach or course was mandated by the protocol. Source data was taken from the patient’s chart and other medical records, then reported by means of an electronic data collection system. Data regarding treatment received, efficacy (progression-free and overall survival (PFS), response rates (RR) and development of CNS metastases) and safety (including cardiac toxicity) were captured. Results: Between February 2015 and April 2018, 311 eligible patients were recruited with median age 57 years (24-96). At diagnosis of aBC the most common distant metastatic sites were bone (n = 145;47%), liver (n=117;38%), lung (n=100;32%) and brain (n=21;7%). First line treatment was with pertuzumab (P)/trastuzumab(T)/chemotherapy (n=212;68%), T/chemotherapy (n=45;14%), other T combinations without P (n=19;6%), Trastuzumab Emtansine regimens without T or P (n=16;5%) (19; 5% other combinations). Patients’ status as of cut-off date for this analysis (28th Feb 2022, median follow-up 44.1 months) is shown. The median PFS of patients treated in the 1st, 2nd and 3rd lines was 26.7 months, 10.7 months and 8.6 months. At the time of this analysis an additional 60 patients (19%) had developed brain metastases during first line. The number of patients starting 2nd, 3rd and 4th line treatment with brain metastases were 28 (22%), 17 (40%), 7 (37%) respectively. Conclusions: In routine clinical practice, as reflected by this registry, at least 40% of patients who initiate first line therapy for advanced breast cancer do not proceed to 3rd line therapy, and brain metastases become increasingly common. These findings have implications for selection of optimal 2nd and 3rd line treatment. Clinical trial information: ISRCTN02393924 . [Table: see text]

Doxorubicin-An Agent with Multiple Mechanisms of Anticancer Activity.

Doxorubicin (DOX) constitutes the major constituent of anti-cancer treatment regimens currently in clinical use. However, the precise mechanisms of DOX's action are not fully understood. Emerging evidence points to the pleiotropic anticancer activity of DOX, including its contribution to DNA damage, reactive oxygen species (ROS) production, apoptosis, senescence, autophagy, ferroptosis, and pyroptosis induction, as well as its immunomodulatory role. This review aims to collect information on the anticancer mechanisms of DOX as well as its influence on anti-tumor immune response, providing a rationale behind the importance of DOX in modern cancer therapy.

Multi-analyte liquid biopsies for molecular pathway guided personalized treatment selection in advanced refractory cancers: A clinical utility pilot study.

The selection of safe and efficacious anticancer regimens for treatment of patients with broadly refractory metastatic cancers remains a clinical challenge. Such patients are often fatigued by toxicities of prior failed treatments and may have no further viable standard of care treatment options. Liquid Biopsy-based multi-analyte profiling in peripheral blood can identify a majority of drug targets that can guide the selection of efficacious combination regimens. LIQUID IMPACT was a pilot clinical study where patients with advanced refractory cancers received combination anticancer treatment regimens based on multi-analyte liquid biopsy (MLB) profiling of circulating tumor biomarkers; this study design was based on the findings of prior feasibility analysis to determine the abundance of targetable variants in blood specimens from 1299 real-world cases of advanced refractory cancers. Among the 29 patients in the intent to treat (ITT) cohort of the trial, 26 were finally evaluable as per study criteria out of whom 12 patients showed Partial Response (PR) indicating an Objective Response Rate (ORR) of 46.2% and 11 patients showed Stable Disease (SD) indicating the Disease Control Rate (DCR) to be 88.5%. The median Progression-Free Survival (mPFS) and median Overall Survival (mOS) were 4.3 months (95% CI: 3.0 - 5.6 months) and 8.8 months (95% CI: 7.0 - 10.7 months), respectively. Toxicities were manageable and there were no treatment-related deaths. The study findings suggest that MLB could be used to assist treatment selection in heavily pretreated patients with advanced refractory cancers.

Reactivaion of immune-related colitis during targeted therapy in a patient with metastatic cutaneous melanoma

Background. The development of unique immune-related adverse events (irAEs) is a known hallmark of immunotherapy. Generally, such complications occur during the first 3–6 months of immunotherapy, however, the experience with immune checkpoint inhibitors (ICIs) shows that irAEs can also occur after completion of ICI therapy, as well as during other anticancer treatment regimens. Description of the clinical case. We present a clinical case of a patient with metastatic cutaneous melanoma, who had recurrent events of grade 2 immune-mediated diarrhea during the 2ndline of therapy. After completion of the course of immunosuppressive therapy with systemic glucocorticoids, irAE resumed, and mesalazine and budesonide (local steroid) with subsequent dose reduction were prescribed. Maintenance anti-inflammatory therapy and re-induction of targeted therapy with BRAF- and MEK-inhibitors due to the progression of the disease resulted in the reactivation of immune-mediated colitis. The complication was successfully managed by increasing dose of local steroid to full dose. Anticancer therapy was continued at the same regime without recurrent episodes of irAEs. Conclusion. When changing the anticancer treatment regimen, the recurrence of irAEs dictates careful monitoring of toxicity and the importance of timely selection of the optimal treatment algorithm to improve the quality and longevity of cancer patients.

91 (PB081) - A Ph-Ib study of TRK-950 combined with anti-cancer treatment regimens in patients with advanced solid tumors

Background: TRK-950 is a first-in-class humanized antibody raised against CAPRIN-1 which we have identified as a novel and universal target for cancer therapies. TRK-950 strongly and specifically binds to various cancer cells and shows anti-tumor effects via engagement of immune cells. A series of pre-clinical studies demonstrates its potency and safety. In the phase I study of TRK-950 monotherapy (NCT02990481), it appears safe and well tolerated. No DLT was observed and MTD was not reached at doses of 3–30 mg/kg IV weekly.

New anticancer drug adjustment guidelines for kidney disease attempt to filter out mess

New anticancer drug adjustment guidelines for kidney disease attempt to filter out mess

Pertuzumab study in the neoadjuvant setting for HER2-positive nonmetastatic breast cancer in Australia (PeRSIA).

The pertuzumab study in the neoadjuvant setting for HER2+ nonmetastatic breast cancer in Australia (PeRSIA-ML39622) is an analysis of safety and effectiveness data from the pertuzumab patient registry. Although the prognosis of patients with early stage HER2+ breast cancer has been greatly improved by advances in chemotherapy approximately 25% to 30% of patients develop recurrent disease. Our study aimed to examine the effectiveness of neoadjuvant pertuzumab on surgical outcomes, describe the medium-term effectiveness outcomes of patients treated with pertuzumab, and describe the planned and actual anticancer treatment regimens that patients received. Deidentified data were collected from the patients' medical records and entered into REDCap, between March 2018 and July 2019 (n=95). The adverse events (AEs) reported most frequently were diarrhea (20; 21.1%), rash (4; 4.2%), and LVSD (4; 4.2%; two patients during neoadjuvant treatment and two patients during adjuvant treatment). AEs, ≥Grade 3 were diarrhea (2; 2.1%) and LVSD (1; 1.1%). Following surgery, a breast pathological complete response (bpCR) was achieved in 65 patients (70.7%; 95% CI: 60.2%-79.7%) and total pathological complete response (tpCR) in 59 patients (64.1%; 95% CI: 53.4%-73.9%). All patients who did not achieve a tpCR obtained a partial response (33/92, 35.9%). Our study is the first to capture real-world data on the use of pertuzumab in the neoadjuvant setting in Australia. The effectiveness and safety data are consistent with those reported in clinical trials of pertuzumab in patients with HER2+ breast cancer, with no new safety concerns.

Tackling healthcare inequities through a social media-based platform to connect solid tumor patients with COVID-19 to clinical trials.

e18560 Background: COVID-19 has contributed to healthcare inequity amongst minorities and lower socioeconomic populations, while complicating present anti-cancer treatment regimens. Due to their immunocompromised status, cancer patients are at an increased risk of severe SARS-CoV-2 infection. While sentiment analysis via SM has seen vast growth among healthcare professional, deeper connection and management has been lacking. Given the higher usage of SM impressions and the increase in healthcare disparities especially at the intersection of oncology and COVID-19, the aim of this study was to develop a platform that can: (1) show that the relationships highlighted within these tweets can be realized in biomolecular interactions—specifically within the interaction between solid tumors and COVID-19; (2) use SM data to connect patients with clinical trials. Methods: To determine this relationship, ontologies, which are groupings of terms and related identifiers, such as genes, were created for general search terms, utilizing the Human Phenotype Ontology. They were then combined with “COVID-19” and used as search terms in Twitter’s Standard Search tool. The keywords with the most matches were then queried through clinicaltrials.gov and European Bioinformatics Institute’s (EBI) Protein Search Tool to find relevant clinical trials and proteins. Finally, the proteins found by the EBI protein search were run through the SwissModel Tool to find relevant protein structures before being used in binding using Polar+’s Binding Platform from Iff Technologies, which provides K values related to 50% inhibition for each medication or immunotherapy. This produced a set of disease-specific keywords that are related to top tweets, clinical trials, protein structures, and binding concentration values in relevant biomolecular pathways for the keyword set “Tumor COVID-19”. Results: The example shown in Table is produced via our platform, with keywords with tweet numbers greater than 95% of all tweets with connected keywords used. Conclusions: By utilizing SM with highly relevant keywords, this platform can combat healthcare inequity by connecting patients and their tweets to clinical trials and enhance literacy about their medical conditions, while providing a greater understanding of the biomolecular pathways involved.[Table: see text]

Non-coding RNAs as Novel Biomarkers in Cancer Drug Resistance.

Chemotherapy is often the primary and most effective anticancer treatment; however, drug resistance remains a major obstacle to it being curative. Recent studies have demonstrated that non-coding RNAs (ncRNAs), especially microRNAs and long non-coding RNAs, are involved in drug resistance of tumor cells in many ways, such as modulation of apoptosis, drug efflux and metabolism, epithelial-to-mesenchymal transition, DNA repair, and cell cycle progression. Exploring the relationships between ncRNAs and drug resistance will not only contribute to our understanding of the mechanisms of drug resistance and provide ncRNA biomarkers of chemoresistance, but will also help realize personalized anticancer treatment regimens. Due to the high cost and low efficiency of biological experimentation, many researchers have opted to use computational methods to identify ncRNA biomarkers associated with drug resistance. In this review, we summarize recent discoveries related to ncRNA-mediated drug resistance and highlight the computational methods and resources available for ncRNA biomarkers involved in chemoresistance.

Anti-cancer Therapy Leads to Increased Cardiovascular Susceptibility to COVID-19.

Anti-cancer treatment regimens can lead to both acute- and long-term myocardial injury due to off-target effects. Besides, cancer patients and survivors are severely immunocompromised due to the harsh effect of anti-cancer therapy targeting the bone marrow cells. Cancer patients and survivors can therefore be potentially extremely clinically vulnerable and at risk from infectious diseases. The recent global outbreak of the novel coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its infection called coronavirus disease 2019 (COVID-19) has rapidly become a worldwide health emergency, and on March 11, 2020, COVID-19 was declared a global pandemic by the World Health Organization (WHO). A high fatality rate has been reported in COVID-19 patients suffering from underlying cardiovascular diseases. This highlights the critical and crucial aspect of monitoring cancer patients and survivors for potential cardiovascular complications during this unprecedented health crisis involving the progressive worldwide spread of COVID-19. COVID-19 is primarily a respiratory disease; however, COVID-19 has shown cardiac injury symptoms similar to the cardiotoxicity associated with anti-cancer therapy, including arrhythmia, myocardial injury and infarction, and heart failure. Due to the significant prevalence of micro- and macro-emboli and damaged vessels, clinicians worldwide have begun to consider whether COVID-19 may in fact be as much a vascular disease as a respiratory disease. However, the underlying mechanisms and pathways facilitating the COVID-19-induced cardiac injury in cancer and non-cancer patients remain unclear. Investigations into whether COVID-19 cardiac injury and anti-cancer drug-induced cardiac injury in cancer patients and survivors might synergistically increase the cardiovascular complications and comorbidity risk through a “two-hit” model are needed. Identification of cardiac injury mechanisms and pathways associated with COVID-19 development overlapping with anti-cancer therapy could help clinicians to allow a more optimized prognosis and treatment of cancer survivors suffering from COVID-19. The following review will focus on summarizing the harmful cardiovascular risk of COVID-19 in cancer patients and survivors treated with an anti-cancer drug. This review will improve the knowledge of COVID-19 impact in the field of cardio-oncology and potentially improve the outcome of patients.

Ways of medicinal prevention and treatment of doxorubicin-induced cardiomyopathy in oncological patients

The high incidence of malignant tumors is currently supported by the general ageing of the world population and unfavorable environmental factors. In 2018, 18.1 million new cases of cancer and 9.6 million deaths from them were registered in the world. At the same time, a significant increase in the life expectancy of these patients after the treatment noted over the past 20 years highlights the problem of side effects of the anticancer therapy. One of the most serious side effects is the development of doxorubicin-induced cardiomyopathy (DRIC). In all three distinct clinical forms (acute, early and late) DRIC can develop in 58 % of patients after using anticancer treatment regimens with the inclusion of doxorubicin. The review provides a detailed analysis of medicinal treatment regimens and preparations (ACE inhibitors, beta-blockers, statins, etc.) currently used, and evaluates their effectiveness and expected results. Currently, several therapeutic strategies have been proposed for the prevention and treatment of DRIC, each of them has certain positive results. At the same time, some therapeutic methods used in the clinic have some disadvantages. Conclusions. The limitations of the results of DRIC prevention achieved by the existing therapeutic regimens, as well as the possibilities for their prediction, have been stated. The need for further research to improve the effectiveness of medicinal prevention and treatment of DRIC is emphasized.

Early Loss of Fat Mass During Chemoradiotherapy Predicts Overall Survival in Locally Advanced Squamous Cell Carcinoma of the Lung, but Not in Locally Advanced Squamous Cell Carcinoma of the Head and Neck.

Background: Cancer cachexia is highly prevalent in advanced non-small cell lung cancer (NSCLC) and locally advanced head and neck squamous cell carcinoma (LAHNSCC), and compromises treatment tolerance and overall survival (OS). NSCLC and LAHNSCC patients share similar risk factors, and receive comparable anti-cancer treatment regimens. The aim of this study was to determine the predictive value of body composition assessed by bioelectrical impedance analysis (BIA) and handgrip strength (HGS) (baseline and early changes during therapy) on OS in NSCLC and LAHNSCC patients treated with platinum-based chemoradiotherapy (CRT) or cetuximab-based bioradiotherapy (BRT). To elucidate potential underlying determinants of early changes in body composition and HGS, specific (fat and fat free) mass loss patterns of squamous NSCLC (sNSCLC) were compared to human papilloma virus negative (HPV–) LAHNSCC patients treated with CRT.Methods: Between 2013 and 2016, BIA and HGS were performed at baseline and after 3 weeks of CRT/BRT in LAHNSCC and NSCLC patients treated with curative intent.Results: Two hundred thirty-three patients were included for baseline measurements. Fat free mass index (FFMI) and HGS<10th percentile of reference values at baseline were both prognostic for poor OS in NSCLC and LAHNSCC [HR 1.64 [95%CI 1.13–2.39], p = 0.01 and HR 2.30 [95%CI 1.33–3.97], p = 0.003, respectively], independent of Charlson Comorbidity Index, cancer site, and gross tumor volume. Early fat mass (FM) loss during CRT was predictive for poor OS in sNSCLC (n = 64) [HR 3.80 [95%CI 1.79–8.06] p ≤ 0.001] but not in HPV– LAHNSCC (n = 61). In patients with significant weight loss (>2%) in the first 3 weeks of CRT (sNSCLC n = 24, HPV– LAHNSCC n = 23), the FM change was −1.4 ± 14.5% and −8.7 ± 9.0% in sNSCLC and HPV– LAHNSCC patients, respectively (p < 0.05). Fat fee mass change was −5.6 ± 6.3% and −4.0 ± 4.3% for sNSCLC and HPV– LAHNSCC, respectively (p = 0.31).Conclusion: FFMI and HGS<10th percentile at baseline are independent prognostic factors for poor OS in NSCLC and LAHNSCC patients treated with CRT/BRT. The specific composition of mass loss during first 3 weeks of CRT significantly differs between sNSCLC and HPV– LAHNSCC patients. Early FM loss was prognostic in sNSCLC only.

Preliminary Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Subcutaneously (SC) Administered PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Preliminary Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Subcutaneously (SC) Administered PF-06863135, a B-Cell Maturation Antigen (BCMA)-CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)

Concordance of provider treatment patterns with NCCN oncology treatment guidelines (NCCN Guidelines) for metastatic non-small cell lung cancer (mNSCLC).

e21574 Background: mNSCLC clinical treatment guidelines are rapidly evolving, however, their influence on prescriber use of anti-cancer treatment regimens is not known. This retrospective study evaluated whether US patients with mNSCLC received first line (1LOT), second (2LOT), or third (3LOT) line treatment regimens that were concordant with NCCN Category 1-2A recommendations. Methods: mNSCLC patients who initiated treatment between 2014-2017 were identified using medical and pharmacy claims from the 100% Medicare Fee-for-Service (FFS) Part A/B/D sample and multi-payer Inovalon MORE2 Registry. Claims-based algorithms identified mNSCLC and LOT following diagnosis; patients with other primary cancers or &lt; 6 months follow-up were excluded. Treatment regimens were compared to active NCCN Guidelines at time of treatment to determine if regimen was concordant with Category 1-2A recommendations. Genetic mutation/biomarker status was not available. Results: 6,523 patients with mNSCLC met criteria for analysis (FFS/Medicare Advantage:78.6%; commercial:14.0%, managed Medicaid:7.4%; mean age:69.3 [SD:9.2]). For 1LOT, 81% received platinum-based doublet regimens; most common monotherapy included erlotinib, nivolumab, and pembrolizumab; 18% of 1LOT patients received maintenance therapy. For 2LOT, approximately one-third received nivolumab monotherapy, one-third received platinum-based doublets, and remainder received other regimens. Most common 3LOT included monotherapy nivolumab, pemetrexed, paclitaxel, and docetaxel. NCCN Guidelines concordance varied: 1LOT (90.5%), 2LOT (58.5%), 3LOT (71.9%). Non-concordant regimens included nivolumab as 1LOT and early adoption of platinum agent+(pemetrexed or paclitaxel) in 2LOT, and chemotherapy as 2LOT in anaplastic lymphoma kinase rearrangement-positive or epidermal growth factor receptor mutation-positive disease. Conclusions: In Medicare and non-Medicare patients with mNSCLC, 1LOT closely followed NCCN Guidelines. Most variability was observed in 2LOT where 58.5% regimens were concordant with Category 1-2A recommendations. Non-concordance may be driven by lack of effective second-line regimens and early adoption of innovative therapies.

Multivariate Modulation of the Zr MOF UiO-66 for Defect-Controlled Combination Anticancer Drug Delivery.

Metal–organic frameworks (MOFs) are emerging as leading candidates for nanoscale drug delivery, as a consequence of their high drug capacities, ease of functionality, and the ability to carefully engineer key physical properties. Despite many anticancer treatment regimens consisting of a cocktail of different drugs, examples of delivery of multiple drugs from one MOF are rare, potentially hampered by difficulties in postsynthetic loading of more than one cargo molecule. Herein, we report a new strategy, multivariate modulation, which allows incorporation of up to three drugs in the Zr MOF UiO‐66 by defect‐loading. The drugs are added to one‐pot solvothermal synthesis and are distributed throughout the MOF at defect sites by coordination to the metal clusters. This tight binding comes with retention of crystallinity and porosity, allowing a fourth drug to be postsynthetically loaded into the MOFs to yield nanoparticles loaded with cocktails of drugs that show enhancements in selective anticancer cytotoxicity against MCF‐7 breast cancer cells in vitro. We believe that multivariate modulation is a significant advance in the application of MOFs in biomedicine, and anticipate the protocol will also be adopted in other areas of MOF chemistry, to easily produce defective MOFs with arrays of highly functionalised pores for potential application in gas separations and catalysis.