Targeting the Liver with Nucleic Acid Therapeutics for the Treatment of Systemic Diseases of Liver Origin.

Systemic diseases of liver origin (SDLO) are complex diseases in multiple organ systems, such as cardiovascular, musculoskeletal, endocrine, renal, respiratory, and sensory organ systems, caused by irregular liver metabolism and production of functional factors. Examples of such diseases discussed in this article include primary hyperoxaluria, familial hypercholesterolemia, acute hepatic porphyria, hereditary transthyretin amyloidosis, hemophilia, atherosclerotic cardiovascular diseases, α-1 antitrypsin deficiency-associated liver disease, and complement-mediated diseases. Nucleic acid therapeutics use nucleic acids and related compounds as therapeutic agents to alter gene expression for therapeutic purposes. The two most promising, fastest-growing classes of nucleic acid therapeutics are antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs). For each listed SDLO disease, this article discusses epidemiology, symptoms, genetic causes, current treatment options, and advantages and disadvantages of nucleic acid therapeutics by either ASO or siRNA drugs approved or under development. Furthermore, challenges and future perspectives on adverse drug reactions and toxicity of ASO and siRNA drugs for the treatment of SDLO diseases are also discussed. In summary, this review article will highlight the clinical advantages of nucleic acid therapeutics in targeting the liver for the treatment of SDLO diseases. SIGNIFICANCE STATEMENT: Systemic diseases of liver origin (SDLO) contain rare and common complex diseases caused by irregular functions of the liver. Nucleic acid therapeutics have shown promising clinical advantages to treat SDLO. This article aims to provide the most updated information on targeting the liver with antisense oligonucleotides and small interfering RNA drugs. The generated knowledge may stimulate further investigations in this growing field of new therapeutic entities for the treatment of SDLO, which currently have no or limited options for treatment.

Phase 4 Multinational Multicenter Retrospective and Prospective Real-World Study of Nivolumab in Recurrent and Metastatic Squamous Cell Carcinoma of the Head and Neck.

This study examined the real-world use of nivolumab in patients with recurrent/metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). This was a multinational retrospective study (VOLUME) assessing treatment effectiveness and safety outcomes and a prospective study (VOLUME-PRO) assessing HRQoL and patient-reported symptoms. There were 447 and 51 patients in VOLUME and VOLUME-PRO, respectively. Across both studies, the median age was 64.0 years, 80.9% were male, and 52.6% were former smokers. Clinical outcomes of interest included real-world overall survival (rwOS) and real-world progression-free survival (rwPFS). The median rwOS was 9.2 months. Among patients with at least one assessment, 21.7% reported their best response as 'partial response', with 3.9% reporting 'complete response'. The median duration of response (DoR) and median rwPFS were 11.0 months and 3.9 months, respectively. At baseline, VOLUME-PRO patients reported difficulties relating to fatigue, physical and sexual functioning, dyspnea, nausea, sticky saliva, dry mouth, pain/discomfort, mobility, and financial difficulties. There were improvements in social functioning and financial difficulties throughout the study; however, no other clinically meaningful changes were noted. No new safety concerns were identified. This real-world, multinational, multicenter, retrospective and prospective study supports the effectiveness and safety of nivolumab for R/M SCCHN patients.

Correlation between pathologic complete response, event-free survival/disease-free survival and overall survival in neoadjuvant and/or adjuvant HR+/HER2-breast cancer.

Purpose: The study's purpose was to evaluate the correlation between overall survival (OS) and its potential surrogate endpoints: pathologic complete response (pCR) and event-free survival (EFS)/disease-free survival (DFS) in neoadjuvant and/or adjuvant HR+/HER2- breast cancer. Methods: Systematic search was performed in MEDLINE, EMBASE, Cochrane Library databases and other relevant sources to identify literature that have reported outcomes of interest in the target setting. The strength of correlation of EFS/DFS with OS, pCR with OS, and pCR with EFS/DFS was measured using Pearson's correlation coefficient (r) based on weighted regression analysis. For Surrogate Endpoint-True Endpoint pairs where correlation was found to be moderate, surrogate threshold effect (STE) was estimated using a mixed-effects model. Sensitivity analyses were conducted on the scale and weights used and removing outlier data. Results: Moderate correlation was observed of relative measures [log(HR)] of EFS/DFS and OS (r = 0.91; 95% CI: 0.83, 0.96, p < 0.0001). STE for HREFS/DFS was estimated to be 0.73. Association between EFS/DFS at 1, 2 and 3 years with OS at 4- and 5-year landmarks was moderate. Relative treatment effects of pCR and EFS/DFS were not strongly associated (r: 0.24; 95% CI: -0.63, 0.84, p = 0.6028). Correlation between pCR and OS was either not evaluated due to inadequate sample size (relative outcomes) or weak (absolute outcomes). Results obtained in the sensitivity analyses were similar to base scenario. Conclusion: EFS/DFS were moderately correlated with OS in this trial-level analysis. They may be considered as valid surrogates for OS in HR+/HER2- breast cancer.

Neoadjuvant treatment and survival outcomes by pathologic complete response in HER2-negative early breast cancers.

Background: The benefit of pathologic complete response (pCR) in early breast cancer (eBC) is not well described in the real-world setting. This study used the nationwide Flatiron Health electronic health record-derived deidentified database to describe treatment patterns and survival outcomes by pCR status after neoadjuvant therapy (NAT) in women with triple-negative or HR+/HER2- eBC. Materials & methods: Observational cohort study analyzing women with eBC who started NAT between 2011 and 2018. Results: 496 women were included in the study; of those, 16.1% achieved pCR, of which 35.7% were triple-negative and 6.1% were HR+/HER2- eBC. More women with triple-negative eBC (95.2%) were exclusively treated with chemotherapy-based NAT versus HR+/HER2- eBC (56.1%). In multivariate analyses from NAT start, not achieving pCR was associated with increased risk of death and progression. Conclusion: pCR status may be a reliable prognostic indicator for survival in these eBC subtypes in the real-world setting.

Response to treatment before surgery indicates better outcomes in breast cancer patients. To understand how well cancer treatments work, patients are compared on their overall survival. This measures the number of people in a study or treatment group who are still alive after a certain amount of time from when they were diagnosed or started treatment. Overall survival shows how well patients are doing in their cancer journey, but it takes time to understand how good treatments are when using this measure. In women with early-stage breast cancer, a quicker way to understand how well patients react to their treatment is called pathologic complete response (pCR). Some people have whole-body treatments such as chemotherapy before surgery (known as neoadjuvant treatment). For these patients, pCR may occur after neoadjuvant treatment, meaning all signs of cancer are gone when they have surgery. In real-life clinical settings, little research has been done to understand how pCR can measure breast cancer survival. In this study, the authors investigate whether women who had a pCR were more or less likely to have their cancer become worse or experience death than those who did not achieve pCR. The health records of 496 women diagnosed with early breast cancer over an eight-year period were assessed. The results show that women who did not have a pCR were more likely to have their cancer become worse or die. This means that pCR could be a better way than overall survival to identify which treatments work well in early breast cancer, and importantly, change the course of a patient's journey.

Cost-Effectiveness of Pharmacologic Treatment Options for Women With Endocrine-Refractory or Triple-Negative Metastatic Breast Cancer.

PURPOSE: Treatments for endocrine-refractory or triple-negative metastatic breast cancer (mBC) are modestly effective at prolonging life and improving quality of life but can be extremely expensive. Given these tradeoffs in quality of life and cost, the optimal choice of treatment sequencing is unclear. Cost-effectiveness analysis can explicitly quantify such tradeoffs, enabling more informed decision making. Our objective was to estimate the societal cost-effectiveness of different therapeutic alternatives in the first- to third-line sequences of single-agent chemotherapy regimens among patients with endocrine-refractory or triple-negative mBC. METHODS: Using three dynamic microsimulation models of 10,000 patients each, three cohorts were simulated, based upon prior chemotherapy exposure: (1) unexposed to either taxane or anthracycline, (2) taxane- and anthracycline-exposed, and (3) taxane-exposed/anthracycline-naive. We focused on the following single-agent chemotherapy regimens as reasonable and commonly used options in the first three lines of therapy for each cohort, based upon feedback from oncologists treating endocrine-refractory or triple-negative mBC: (1) for taxane- and anthracycline-unexposed patients, paclitaxel, capecitabine (CAPE), or pegylated liposomal doxorubicin; (2) for taxane- and anthracycline-exposed patients, Eribulin, CAPE, or carboplatin; and (3) for taxane-exposed/anthracycline-naive patients, pegylated liposomal doxorubicin, CAPE, or Eribulin. RESULTS: In each cohort, accumulated quality-adjusted life-years were similar between regimens, but total societal costs varied considerably. Sequences beginning first-line treatment with paclitaxel, carboplatin, and CAPE, respectively, for cohorts 1, 2, and 3, had lower costs and similar or slightly better outcomes compared with alternative options. CONCLUSION: In this setting where multiple single-agent chemotherapy options are recommended by clinical guidelines and share similar survival and adverse event trajectories, treatment sequencing approaches that minimize costs early may improve the value of care.

Absorption, Distribution, Metabolism, and Excretion of US Food and Drug Administration-Approved Antisense Oligonucleotide Drugs.

Absorption, distribution, metabolism, and excretion (ADME) are the key biologic processes for determination of a drug's pharmacokinetic parameters, which have direct impacts on efficacy and adverse drug reactions (ADRs). The chemical structures, dosage forms, and sites and routes of administration are the principal determinants of ADME profiles and consequent impacts on their efficacy and ADRs. Newly developed large molecule biologic antisense oligonucleotide (ASO) drugs have completely unique ADME that is not fully defined. ASO-based drugs are single-stranded synthetic antisense nucleic acids with diverse modes of drug actions from induction of mRNA degradation, exon skipping and restoration, and interactions with proteins. ASO drugs have a great potential to treat certain human diseases that have remained untreatable with small molecule-based drugs. The ADME of ASO drugs contributes to their unique set of ADRs and toxicity. In this review, to better understand their ADME, the 10 US Food and Drug Administration (FDA)-approved ASO drugs were selected: fomivirsen, pegaptanib, mipomersen, nusinersen, inotersen, defibrotide, eteplirsen, golodirsen, viltolarsen, and casimersen. A meta-analysis was conducted on their formulation, dosage, sites of administration, local and systematic distribution, metabolism, degradation, and excretion. Membrane permeabilization through endocytosis and nucleolytic degradation by endonucleases and exonucleases are major ADME features of the ASO drugs that differ from small-molecule drugs. The information summarized here provides comprehensive ADME characteristics of FDA-approved ASO drugs, leading to a better understanding of their therapeutic efficacy and their potential ADRs and toxicity. Numerous knowledge gaps, particularly on cellular uptake and subcellular trafficking and distribution, are identified, and future perspectives and directions are discussed. SIGNIFICANCE STATEMENT: Through a systematic analysis of the existing information of absorption, distribution, metabolism, and excretion (ADME) parameters for 10 US Food and Drug Administration (FDA)-approved antisense oligonucleotide (ASO) drugs, this review provides an overall view of the unique ADME characteristics of ASO drugs, which are distinct from small chemical drug ADME. This knowledge is useful for discovery and development of new ASO drugs as well as clinical use of current FDA-approved ASO drugs.

Projecting the Prevalence and Costs of Metastatic Breast Cancer From 2015 through 2030.

Background: This study projected the number of metastatic breast cancer (mBC) cases and costs (medical and productivity) attributable to mBC through 2030 among 3 age groups: younger (aged 18-44 years), midlife (aged 45-64 years), and older women (aged 65 years and older). Methods: We developed a stock/flow model in which women enter the mBC population at initial diagnosis (de novo stage IV) or through progression of an earlier-stage cancer. Women exit the mBC population through death. Input parameters by age and phase of treatment came from the US Census, Surveillance, Epidemiology, and End Results and peer-reviewed literature. Results: In 2030, we estimated there would be 246 194 prevalent cases of mBC, an increase of 54.8% from the 2015 estimate of 158 997. We estimated total costs (medical and productivity) of mBC across all age groups and phases of care were $63.4 billion (95% sensitivity range = $59.4-$67.4 billion) in 2015 and would increase to $152.4 billion (95% sensitivity range = $111.6-$220.4 billion) in 2030, an increase of 140%. Trends in estimated costs were higher for younger and midlife women than for older women. Conclusions: The cost of mBC could increase substantially in the coming decade, especially among younger and midlife women. Although accounting for trends in incidence, progression, and survival, our model did not attempt to forecast structural changes such as technological innovations in breast cancer treatment and health-care delivery reforms. These findings can motivate early detection activities, direct value-driven mBC treatment, and provide a useful baseline against which to measure the effect of prevention and treatment efforts.

Treatment patterns and outcomes for patients with newly diagnosed glioblastoma multiforme: a retrospective cohort study.

Aim: Investigate real-world outcomes and healthcare utilization of patients with glioblastoma multiforme (GBM) related to O6-methylguanine DNA methyltransferase (MGMT) promoter testing and methylation. Patients & methods: US Oncology Network data were analyzed for patients receiving first-line (1L) treatment for GBM. Results: Most patients received 1L radiation with temozolomide. Unadjusted median overall survival (OS) was higher in tested versus untested (median:18.1 vs 11.8 months) and in methylated versus unmethylated (median: 25.5 vs 12.4 months). Untested status, unmethylated MGMT and older age were associated with reduced OS and longer 1L treatment with increased OS. Similar findings were observed for progression-free survival. Utilization was similar between cohorts. Conclusion: In community oncology practices, MGMT methylation and testing were predictive of better survival in GBM.

Lay abstract We studied the characteristics and survival of patients with newly diagnosed glioblastoma multiforme (GBM) in community-based oncology practices. These patients had received temozolomide and radiotherapy with surgery, which is the standard of care for GBM. We were interested in how patient survival was related to methylation of the O⁶-methylguanine DNA methyltransferase (MGMT) promoter. The study showed that patients with methylated versus unmethylated MGMT GBM survived longer. However, patients who were tested for methylation, whether MGMT was methylated or not, also survived longer. This may be because patients who get tested also get better care in general.

Medical costs associated with metastatic breast cancer in younger, midlife, and older women.

PURPOSE: We estimated average medical costs due to metastatic breast cancer (mBC) among younger (aged 18-44), midlife (aged 45-64), and older women (aged 65 and older) by phase of care: initial, continuing, and terminal. METHODS: We used 2003-2014 North Carolina cancer registry data linked with administrative claims from public and private payers. We developed a claims-based algorithm to identify breast cancer patients who progressed to metastatic disease. We matched breast cancer patients (mBC and earlier stage) to non-cancer patients on age group, county of residence, and insurance plan. Outcomes were average monthly medical expenditures and expected medical expenditures by phase. We used regression to estimate excess costs attributed to mBC as the difference in mean payments between patients with mBC (N = 4806) and patients with each earlier-stage breast cancer (stage 1, stage 2, stage 3, and unknown stage; N = 21,772) and non-cancer controls (N = 109,631) by treatment phase and age group. RESULTS: Adjusted monthly costs for women with mBC were significantly higher than for women with earlier-stage breast cancer and non-cancer controls for all age groups and treatment phases except the initial treatment among women with stage 3 breast cancer at diagnosis. The largest expected total costs were for women aged 18-44 with mBC during the continuing phase ($209,961 95% Confidence Interval $165,736-254,186). CONCLUSIONS: We found substantial excess costs for mBC among younger women and during the continuing and terminal phases of survivorship. It is important to assess whether this care is high value for these women.

An updated systematic review of the cost-effectiveness of therapies for metastatic breast cancer.

PURPOSE: The goal of this systematic review is to provide an update to the review by Pouwels et al. by conducting a systematic review and an assessment of the reporting quality of the economic analyses conducted since 2014. METHODS: This systematic review identified published articles focused on metastatic breast cancer treatment using the Medline/PubMed and Scopus databases and the following search criteria: (((cost effectiveness[MeSH Terms]) OR (cost effectiveness) OR (cost-effectiveness) OR (cost utility) OR (cost-utility) OR (economic evaluation)) AND (("metastatic breast cancer") OR ("advanced breast cancer"))). The reporting quality of the included articles was evaluated using the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: Of the 256 identified articles, 67 of the articles were published after October 2014 when the prior systematic review stopped its assessment (Pouwels et al. in Breast Cancer Res Treat 165:485-498, 2017). From the 67 articles, we narrowed down to include 17 original health economic analyses specific to metastatic or advanced breast cancer. These articles were diverse with respect to methods employed and interventions included. CONCLUSION: Although each of the articles contributed their own analytic strengths and limitations, the overall quality of the studies was moderate. The review demonstrated that the vast majority of the reported incremental cost-effectiveness ratios exceeded the typically employed willingness to pay thresholds used in each country of analysis. Only three of the reviewed articles studied chemotherapies rather than treatments targeting either HER2 or hormone receptors, demonstrating a gap in the literature.

Economic Analysis of Neoadjuvant Chemotherapy Versus Primary Debulking Surgery for Advanced Epithelial Ovarian Cancer Using an Aggressive Surgical Paradigm.

OBJECTIVES: Neoadjuvant chemotherapy (NACT) versus primary debulking surgery (PDS) for advanced epithelial ovarian cancer (AEOC) remains controversial in the United States. Generalizability of existing trial results has been criticized because of less aggressive debulking procedures than commonly used in the United States. As a result, economic evaluations using input data from these trials may not accurately reflect costs and outcomes associated with more aggressive primary surgery. Using data from an ongoing trial performing aggressive debulking, we investigated the cost-effectiveness and cost-utility of NACT versus PDS for AEOC. METHODS: A decision tree model was constructed to estimate differences in short-term outcomes and costs for a hypothetical cohort of 15,000 AEOC patients (US annual incidence of AEOC) treated with NACT versus PDS over a 1-year time horizon from a Medicare payer perspective. Outcomes included costs per cancer-related death averted, life-years and quality-adjusted life-years (QALYs) gained. Base-case probabilities, costs, and utilities were based on the Surgical Complications Related to Primary or Interval Debulking in Ovarian Neoplasms trial. Base-case analyses assumed equivalent survival; threshold analysis estimated the maximum survival difference that would result in NACT being cost-effective at $50,000/QALY and $100,000/QALY willingness-to-pay thresholds. Probabilistic sensitivity analysis was used to characterize model uncertainty. RESULTS: Compared with PDS, NACT was associated with $142 million in cost savings, 1098 fewer cancer-related deaths, and 1355 life-years and 1715 QALYs gained, making it the dominant treatment strategy for all outcomes. In sensitivity analysis, NACT remained dominant in 99.3% of simulations. Neoadjuvant chemotherapy remained cost-effective at $50,000/QALY and $100,000/QALY willingness-to-pay thresholds if survival differences were less than 2.7 and 1.4 months, respectively. CONCLUSIONS: In the short term, NACT is cost-saving with improved outcomes. However, if PDS provides a longer-term survival advantage, it may be cost-effective. Research is needed on the role of patient preferences in tradeoffs between survival and quality of life.