Pembrolizumab plus chemotherapy for first-line treatment of advanced triple-negative breast cancer.

Aim: A systematic review and network meta-analysis (NMA) was performed to evaluate the efficacy of first-line treatments for locally recurrent unresectable or metastatic triple-negative breast cancer (TNBC) patients. Materials & methods: Databases were searched for randomized controlled trials evaluating first-line treatments for locally recurrent unresectable or metastatic TNBC patients. NMA was performed to estimate relative treatment effects on overall and progression-free survival between pembrolizumab + chemotherapy and other interventions. Results: NMA including eight trials showed that the relative efficacy of pembrolizumab + chemotherapy was statistically superior to that of other immunotherapy- or chemotherapy-based treatment regimens. Conclusion: Pembrolizumab + chemotherapy confers benefits in survival outcomes versus alternative interventions for the first-line treatment of locally recurrent unresectable or metastatic TNBC patients.

Clinical value of initial treatments for patients with advanced triple-negative breast cancerWhat is this article about? Around 15% of breast cancer patients have the triple-negative breast cancer (TNBC) subtype, which has the worst prognosis. Treatments targeting the immune system, such as pembrolizumab, were recently found to improve the outcomes of patients with cancer that is at an advanced stage or resistant to standard therapies. However, clinical trials evaluating the efficacy of cancer treatments typically compare only two alternative treatments. Therefore, we conducted this study to understand the relative efficacy of several commonly used initial treatments for advanced TNBC by indirectly comparing the results of all available clinical trials that were sufficiently similar. We identified trials by systematically searching the medical literature and analyzed the results of several clinical trials together to estimate the efficacy of pembrolizumab + chemotherapy compared with several other initial treatment regimens for patients with advanced TNBC.What were the results? We identified eight randomized controlled trials evaluating treatment regimens containing chemotherapeutic or immunotherapeutic agents in patients with previously untreated advanced TNBC. Considering all these trials together, pembrolizumab + chemotherapy was found to prolong patient survival to a greater extent than several other treatment regimens including carboplatin, docetaxel, paclitaxel, nab-paclitaxel/paclitaxel, bevacizumab + paclitaxel, ixabepilone + paclitaxel and ixabepilone + bevacizumab depending on the specific set of trials analyzed.What do the results of the study mean? These results indicate that pembrolizumab + chemotherapy has beneficial effects on patient survival compared with other initial treatment regimens for patients with advanced TNBC.

Systematic literature review of treatments used for refractory or unexplained chronic cough in adults.

BACKGROUND: Refractory or unexplained chronic cough (RCC or UCC) is difficult to manage and is usually treated by the off-label use of drugs approved for other indications. OBJECTIVE: The objectives of this systematic literature review (SLR) were to identify and characterize the current published body of evidence for the efficacy and safety of treatments for RCC or UCC. METHODS: The SLR was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The SLRs pre-defined population included patients ≥18 years of age who were diagnosed with chronic cough. The review was not restricted to any intervention type or study comparator, nor by timeframe. RESULTS: A total of 20 eligible publications from 19 unique trials were included. Seventeen of these trials were randomized controlled trials and most (14/17) were placebo-controlled. There was considerable variability between trials in the definition of RCC or UCC, participant exclusion and inclusion criteria, outcome measurement timepoints, and the safety and efficacy outcomes assessed. Several trials identified significant improvements in cough frequency, severity, or health-related quality of life measures while participants were on treatment, although these improvements did not persist in any of the studies that included a post-treatment follow-up timepoint. CONCLUSIONS: In the absence of an approved therapy, placebo remains the most common comparator in trials of potential RCC or UCC treatments. The between-study comparability of the published evidence is limited by heterogeneity of study design, study populations, and outcomes measures, as well as by concerns regarding study size and risk of bias.

Clinical outcomes for previously treated patients with advanced biliary tract cancer: a meta-analysis.

Aim: A systematic review and meta-analysis were performed to evaluate the efficacy of treatments for previously treated advanced biliary tract cancer (BTC) patients. Materials & methods: Databases were searched for studies evaluating treatments for advanced (unresectable and/or metastatic) BTC patients who progressed on prior therapy. Pooled estimates of objective response rate (ORR), median overall survival (OS) and median progression-free survival (PFS) were calculated using random effects meta-analysis. Results: Across 31 studies evaluating chemotherapy or targeted treatment regimens in an unselected advanced BTC patient population, pooled ORR was 6.9%, median OS was 6.6 months and median PFS was 3.2 months. Conclusion: The efficacy of conventional treatments for previously treated advanced BTC patients is poor and could be improved by novel therapies.

What is this article about? Most patients with biliary tract cancer are identified with advanced disease, and almost all go through a worsening of the disease after their first treatment. For patients who go on to receive their next treatment, current guidelines are unclear regarding the best treatment choice. Therefore, we examined the available medical literature and performed an analysis of multiple studies to calculate overall estimates of the clinical value of standard treatments for these patients. Our goal was to develop a benchmark against which to compare the clinical value of new treatments that are currently being assessed in clinical trials. What were the results? We identified 31 studies assessing standard treatments (involving chemotherapy or molecularly targeted treatments) in previously treated advanced biliary tract cancer patients. Across these studies, the objective tumor response rate was 6.9%, median overall survival was 6.6 months and median progression-free survival was 3.2 months. What do the results of the study mean? These results indicate that there is limited clinical value of standard treatments for patients with advanced biliary tract cancer whose disease worsened after first treatment. This medical need could potentially be met by new treatments, such as immunotherapies that restore the immune system's ability to attack cancer cells and thereby prolong patient survival.

Clinical Outcomes of PD-1/PD-L1 Inhibitors Among Patients With Advanced or Metastatic Non-Small Cell Lung Cancer With BRAF, ERBB2/HER2, MET , or RET Alterations: A Systematic Literature Review.

The therapeutic landscape for patients with advanced or metastatic non-small cell lung cancer (NSCLC) is rapidly evolving due to advances in molecular testing and the development of new targeted therapies and immunotherapies. However, the efficacy of programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors in advanced or metastatic patients with NSCLC whose tumors harbor BRAF V600E mutation, HER2/ERBB2 alteration, MET exon 14 skipping mutation, or RET rearrangement is not completely understood. A systematic literature review was performed to summarize evidence from clinical trials and observational studies on objective response rate, progression-free survival, and overall survival in patients whose tumors express these biomarkers and who were treated with PD-1/PD-L1 inhibitors. Searches of Embase, MEDLINE, conference abstracts, and a clinical trial registry identified a total of 12 unique studies: 4 studies included patients with BRAF V600E mutation, 6 studies included patients with HER2/ERBB2 alteration, 7 studies included patients with MET exon 14 skipping mutation, and 5 studies included patients with RET rearrangement. Across studies, there was heterogeneity in treatment and patient characteristics and a lack of reporting on many important predictive and prognostic factors, including treatment regimens, patients' line of therapy, and tumor PD-L1 expression, which may explain the wide variation in objective response rate, progression-free survival, and overall survival across studies. Therefore, additional studies prospectively evaluating clinical outcomes of PD-1/PD-L1 inhibitors among patients with advanced or metastatic NSCLC whose tumors harbor emerging predictive or prognostic biomarkers are needed to determine whether this class of immunotherapy can provide additional survival benefits for these patients.

Chronic cough: more than just a persistent cough: a systematic literature review to understand the impact of chronic cough on quality of life.

PURPOSE: Chronic cough (CC), defined as a cough persisting ≥ 8 weeks, can have a substantial negative impact on health-related quality of life (HRQoL). This is exacerbated by challenges with timely diagnosis and a lack of approved therapies. A systematic literature review (SLR) was conducted to identify evidence on HRQoL and health state utility values associated with refractory CC or unexplained CC. METHODS: Electronic database searches were supplemented with searches of conference proceedings and health technology assessment body websites. Two independent reviewers assessed all citations for inclusion based on predefined inclusion/exclusion criteria. Key inclusion criteria were patient populations with CC and reporting of patient-reported outcomes or utilities using generic or disease-specific measures. RESULTS: Following screening, 65 studies were identified for inclusion in the SLR. Of these, 23 studies assessed HRQoL among patients with CC who were not treated or treated with unspecified interventions, and 42 studies in patients who were treated with specified interventions. The studies indicated a substantial decrement to HRQoL as a result of CC, characterized by generic and disease-specific patient-reported outcome measures. HRQoL was impacted across multiple domains, including physical, psychological, and social functioning. The studies also demonstrated the potential for treatments to have a significant positive impact on HRQoL. CONCLUSIONS: CC can substantially affect HRQoL in patients, across physical, psychological, and social domains. Although treatments can improve HRQoL in these patients, the available evidence is limited. There remains an unmet need for approved pharmacological treatments to alleviate CC and improve HRQoL for these patients.

Understanding the economic burden of chronic cough: a systematic literature review.

Chronic cough (CC) is associated with high healthcare resource utilization (HCRU) due to challenges in diagnosis and treatment and is anticipated to have a substantial economic impact. This systematic literature review (SLR) sought to identify evidence on the cost-effectiveness of treatments and the economic burden associated with CC. Electronic database searches were supplemented with searches of conference proceedings and health technology assessment body websites. Two independent reviewers assessed all citations for inclusion based on predefined inclusion/exclusion criteria. Key inclusion criteria were patient population with CC, and outcomes related to cost-effectiveness and HCRU and costs. After screening, one cost-effectiveness analysis was identified, alongside eight studies reporting HCRU and costs related to CC. Though evidence was limited, studies suggest that patients with CC incur higher costs and use more resources than those with acute cough. Types of resource use reported included healthcare contacts and prescriptions, diagnostic tests, referrals and specialist evaluations, and treatment use. There is a paucity of literature on HCRU and costs in CC, and very limited cost-effectiveness analyses. The economic burden appears higher in these patients however, without direct comparison to the general population it is difficult to determine the total impact. The increased burden is expected to be a result of the challenges with diagnosis and lack of approved treatments. However, limited conclusions can be drawn in the absence of further data. Future studies should endeavor to quantify the HCRU and cost attributable to patients with CC.

Neoadjuvant immunotherapy and chemotherapy regimens for the treatment of high-risk, early-stage triple-negative breast cancer: a systematic review and network meta-analysis.

BACKGROUND: Patients with triple-negative breast cancer (TNBC) are generally younger and more likely to experience disease recurrence and have the shortest survival among all breast cancer patients. Recently, neoadjuvant delivery of the programmed cell death protein-1 inhibitor pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab was approved for patients with high-risk, early-stage TNBC, but this treatment regimen has not been evaluated in head-to-head trials with other neoadjuvant treatment regimens. Therefore, the objective of this study was to estimate the relative efficacy of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab versus other neoadjuvant treatments for early-stage TNBC through a systematic review and network meta-analysis (NMA). METHODS: EMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, conference abstracts, and clinical trial registries were searched for randomized controlled trials evaluating neoadjuvant treatments for early-stage TNBC. NMA was performed to estimate relative treatment effects among evaluated interventions. RESULTS: Five trials met the inclusion criteria and were included in the NMA. The relative efficacy of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab was favorable to paclitaxel followed by anthracycline + cyclophosphamide in terms of pathologic complete response (pCR), event-free survival (EFS), and overall survival; paclitaxel + carboplatin followed by anthracycline + cyclophosphamide in terms of pCR and EFS; paclitaxel + bevacizumab followed by anthracycline + cyclophosphamide + bevacizumab in terms of pCR; and paclitaxel + carboplatin + veliparib followed by anthracycline + cyclophosphamide in terms of EFS. CONCLUSIONS: Neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab confers benefits in response and survival outcomes versus alternative neoadjuvant treatments for early-stage TNBC.

Clinical Outcomes for Previously Treated Patients with Advanced Gastric or Gastroesophageal Junction Cancer: A Systematic Literature Review and Meta-Analysis.

PURPOSE: Although second-line treatments improve survival compared to best supportive care in patients with advanced gastric cancer with disease progression on first-line therapy, prognosis remains poor. A systematic review and meta-analysis were conducted to quantify the efficacy of second-or-later line systemic therapies in this target population. METHODS: A systematic literature review (January 1, 2000 to July 6, 2021) of Embase, MEDLINE, and CENTRAL with additional searches of 2019-2021 annual ASCO and ESMO conferences was conducted to identify studies in the target population. A random-effects meta-analysis was performed among studies involving chemotherapies and targeted therapies relevant in treatment guidelines and HTA activities. Outcomes of interest were objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) presented as Kaplan-Meier data. Randomized controlled trials reporting any of the outcomes of interest were included. For OS and PFS, individual patient-level data were reconstructed from published Kaplan-Meier curves. RESULTS: Forty-four trials were eligible for the analysis. Pooled ORR (42 trials; 77 treatment arms; 7256 participants) was 15.0% (95% confidence interval (CI) 12.7-17.5%). Median OS from the pooled analysis (34 trials; 64 treatment arms; 60,350 person-months) was 7.9 months (95% CI 7.4-8.5). Median PFS from the pooled analysis (32 trials; 61 treatment arms; 28,860 person-months) was 3.5 months (95% CI 3.2-3.7). CONCLUSION: Our study confirms poor prognosis among patients with advanced gastric cancer, following disease progression on first-line therapy. Despite the approved, recommended, and experimental systemic treatments available, there is still an unmet need for novel interventions for this indication.

Efficacy and safety of treatments for advanced thymic carcinoma after failure of first-line platinum-based chemotherapy: A systematic literature review and meta-analysis.

Thymic carcinoma (TC) is a rare cancer and patients failing initial chemotherapy (relapse/refractory) face limited therapeutic options given no approved options or consensus standard of care. This study aimed to identify and summarize clinical outcomes of all regimens evaluated in clinical trials of relapsed or refractory patients. Interventional trials enrolling advanced TC patients who failed first-line chemotherapy and reported outcomes in this group were eligible for inclusion in our systemic literature review (SLR). Between-study heterogeneity was assessed to determine the feasibility of pooling specific studies and treatments. Objective response rate (ORR), overall survival (OS), progression-free survival (PFS), and duration of response (DOR) endpoints were of interest for meta-analysis. Nineteen trials were identified in the SLR. Three trials with one or two TC patients were removed from our assessment to reduce publication bias. Response rates among studies with at least ten TC patients varied from 9 % to 38 %. Pooled ORRs in patients receiving S-1 (46 patients), sunitinib (46 patients), or pembrolizumab (66 patients) were 28 %, 24 %, and 21 %, respectively. Prolonged duration of response with pembrolizumab was observed with a pooled median of 23.8 months (95 % confidence interval [CI]: 12, not reached). Median PFS of five months or greater was reported in patients treated with sunitinib, lenvatinib, pembrolizumab, capecitabine + gemcitabine, everolimus, or S-1. Median OS of 20 months or greater was reported in trials evaluating S-1 or pembrolizumab; this endpoint was not reached in trials evaluating lenvatinib, regorafenib, or sunitinib. Generalizability of treatment effects is challenging in the research of rare diseases and meta-analysis of clinical outcomes may help to increase precision and relevance of results to the larger TC population. Our study found limited treatment options upon relapse, demonstrating a need for further investigations into novel therapeutics and well-powered clinical trials to better inform on optimal treatments.

Clinical outcomes of chemotherapy-based therapies for previously treated advanced colorectal cancer: a systematic literature review and meta-analysis.

PURPOSE: The purpose of this study was to evaluate clinical outcomes of standard therapies in previously treated, advanced colorectal cancer (CRC) patients. METHODS: A systematic literature review was conducted in Embase, MEDLINE, and CENTRAL databases (January 2000-July 2021), annual oncology conferences (2019-2021), and clinicaltrials.gov to identify studies evaluating the use of licensed interventions in second-line or later settings. The primary outcome of interest was objective response rate (ORR) and secondary outcomes included progression-free survival (PFS) and overall survival (OS). ORR was pooled using the Freeman-Tukey double arcsine transformation. For survival outcomes, published Kaplan-Meier curves for OS and PFS were digitized to re-construct individual patient-level data and pooled following the methodology described by Combescure et al. (2014). RESULTS: Twenty-three trials evaluating standard chemotherapies with or without targeted therapies across 4,791 advanced CRC patients contributed to our meta-analysis. In the second-line setting, the random effects pooled estimate of ORR was 22.4% (95% confidence interval (CI): 18.0, 27.1), median PFS was 7.0 months (95% CI: 6.4, 7.4), and median OS was 14.9 months (95% CI: 13.6, 16.1). In the third-line or later setting, the random effects pooled estimate of ORR was 1.7% (95% CI: 0.8, 2.7), median PFS was 2.3 months (95% CI: 2.0, 2.8), and median OS was 8.2 months (95% CI: 7.1, 9.1). CONCLUSION: Standard treatments have limited efficacy in the second-line or later setting with worsening outcomes in later lines. Given the global burden of CRC, further research into novel and emerging therapeutic options following treatment failure is needed.

Resistance to anti-PD1 therapies in patients with advanced melanoma: systematic literature review and application of the Society for Immunotherapy of Cancer Immunotherapy Resistance Taskforce anti-PD1 resistance definitions.

Nearly half of advanced melanoma patients do not achieve a clinical response with anti-programmed cell death 1 protein (PD1) therapy (i.e. primary resistance) or initially achieve a clinical response but eventually progress during or following further treatment (i.e. secondary resistance). A consensus definition for tumor resistance to anti-PD1 monotherapy was published by Society for Immunotherapy of Cancer Immunotherapy Resistance Taskforce (SITC) in 2020. A systematic literature review (SLR) of clinical trials and observational studies was conducted to characterize the proportions of advanced melanoma patients who have progressed on anti-PD1 therapies. The SLR included 55 unique studies and the SITC definition of primary resistance was applied to 37 studies that specified disease progression by best overall response. Median and range of patients with primary resistance in studies that specified first-line and second-line or higher anti-PD1 monotherapy was 35.50% (21.19-39.13%; n = 4 studies) and 41.54% (30.00-56.41%, n = 3 studies); median and range of patients with primary resistance in studies that specified first-line and second-line or higher combination therapy was 30.23% (15.79-33.33%; n = 6 studies), and 70.00% (61.10-73.33%; n = 3 studies). Primary resistance to anti-PD1 monotherapies and when in combination with ipilimumab are higher in patients receiving second-line or higher therapies, in patients with acral, mucosal, and uveal melanoma, and in patients with active brain metastases. The percentage of patients with primary resistance was generally consistent across clinical trials, with variability in resistance noted for observational studies. Limitations include applying the SITC definitions to combination therapies, where consensus definitions are not yet available. Future studies should highly consider utilizing the SITC definitions to harmonize how resistance is classified and facilitate meaningful context for clinical activity.

Economic and Humanistic Burden of Triple-Negative Breast Cancer: A Systematic Literature Review.

BACKGROUND: Triple-negative breast cancer (TNBC) accounts for 10-20% of all breast cancers (BCs). It is more commonly diagnosed in younger women and often has a less favorable prognosis compared with other BC subtypes. OBJECTIVE: The objective of this study was to provide a literature-based extensive overview of the economic and humanistic burden of TNBC to assist medical decisions for healthcare payers, providers, and patients. METHODS: A systematic literature review was performed using multiple databases, including EMBASE, MEDLINE, Econlit, the Cochrane Central Register of Controlled Trials, and the Cochrane Database of Systematic Reviews, from database inception to 16 May 2021. In addition, a targeted search was performed in the Northern Light Life Sciences Conference Abstracts database from 2016 through June 2021. The bibliographies of included articles were reviewed to identify other potentially relevant publications. Quality assessment of the included studies was conducted. RESULTS: The review identified 19 studies assessing the economic burden and 10 studies assessing the humanistic burden of TNBC. Studies varied widely in study design, settings, patient populations, and time horizons. The estimates of mean per-patient annual direct medical costs ranged from around $20,000 to over $100,000 in stage I-III TNBC and from $100,000 to $300,000 in stage IV TNBC. Healthcare costs and resource utilization increased significantly with disease recurrence, progression, and increased cancer stage or line of therapy. Compared with the costs of systemic anticancer therapy, cancer management costs comprised a larger portion of total direct costs. The estimates of indirect costs due to productivity loss ranged from $207 to $1573 per patient per month (all costs presented above were adjusted to 2021 US dollars). Cancer recurrence led to significantly reduced productivity and greater rates of leaving the workforce. A rapid deterioration of health utility associated with disease progression was observed in TNBC patients. Treatment with pembrolizumab or talazoparib showed significantly greater improvements in health-related quality of life (HRQoL) compared with chemotherapy, as measured by EORTC QLQ-C30, QLQ-BR23, and FACT-B. CONCLUSION: TNBC is associated with a substantial economic burden on healthcare systems and societies and considerably reduced productivity and HRQoL for patients. This study synthesized the published literature on the economic and humanistic burden of TNBC and highlighted the need for continued research due to the rapidly changing landscape of TNBC care.

Indirect comparison of pembrolizumab monotherapy versus nivolumab + ipilimumab in first-line metastatic lung cancer.

Aim: This study indirectly compared the effectiveness of pembrolizumab monotherapy versus nivolumab + ipilimumab in metastatic non-small-cell lung cancer. Materials and methods: A matching-adjusted indirect comparison was conducted using pooled individual patient data from KEYNOTE-024 and KEYNOTE-042 and published aggregate data from CheckMate 227 Part 1A, with platinum doublet chemotherapy as the anchor. Results: After matching, estimated hazard ratios (95% CI) of pembrolizumab monotherapy versus nivolumab + ipilimumab for overall survival and progression-free survival were 1.07 (0.82, 1.39) and 1.16 (0.93, 1.45), respectively. For objective response rate, the estimated risk ratio (95% CI) was 0.93 (0.71, 1.22) and the risk difference (95% CI) was -2.86%(-11.38, 5.67). Conclusion: Matching-adjusted indirect comparison results demonstrated comparable effectiveness between pembrolizumab monotherapy and nivolumab + ipilimumab as first-line therapies for metastatic non-small-cell lung cancer with PD-L1 tumor-proportion score ≥1%.

Pembrolizumab+chemotherapy versus atezolizumab+chemotherapy+/-bevacizumab for the first-line treatment of non-squamous NSCLC: A matching-adjusted indirect comparison.

OBJECTIVES: Multiple immunotherapy and chemotherapy combinations are approved for the management of advanced NSCLC which have not been directly compared in randomized clinical trials. This study indirectly compared the effectiveness of pembrolizumab + chemotherapy versus atezolizumab + chemotherapy+/-bevacizumab for previously untreated non-squamous NSCLC patients without EGFR/ALK aberrations. MATERIALS AND METHODS: A matching-adjusted indirect comparison (MAIC) was conducted using individual patient data (IPD) from KEYNOTE-021 Cohort G (KN021 G) (pembrolizumab + carboplatin + pemetrexed; N = 59) and KEYNOTE-189 (KN189) (pembrolizumab + pemetrexed + platinum chemotherapy; N = 410) and published aggregate data from IMpower 130 (atezolizumab + carboplatin + nab-paclitaxel; N = 451) and IMpower 150 (atezolizumab + carboplatin + paclitaxel + bevacizumab; N = 356). To adjust for cross-trial differences in baseline characteristics, data from patients randomized to pembrolizumab + chemotherapy in KN021 G/KN189 were reweighted to match the baseline characteristics of patients randomized to atezolizumab + chemotherapy from IMpower 130 or atezolizumab + chemotherapy + bevacizumab from IMpower 150. Outcomes included overall survival (OS), blinded independent review-assessed progression-free survival (PFS) and objective response rate (ORR). OS and PFS follow-up were truncated to the trial with shorter follow-up. Sensitivity analyses were conducted without truncation of follow-up of OS and PFS. RESULTS: After matching for cross-trial differences, the effective sample size of pembrolizumab + chemotherapy was 428 and 389 for the IMpower 130 and IMpower 150 comparisons, respectively. The estimated HRs (95 % CIs) of pembrolizumab + chemotherapy versus atezolizumab + chemotherapy were 0.80 (0.67,0.95) and 0.79 (0.67,0.93) with regard to OS and PFS, respectively. For pembrolizumab + chemotherapy versus atezolizumab + chemotherapy + bevacizumab, the estimated HR (95 % CIs) was 0.86 (0.72,1.03) for OS and 0.81 (0.68,0.96) for PFS. For ORR, the estimated risk ratio (95 % CI) and the risk difference (95 % CI) was 0.9 (0.8,1.1) and -3.5 % (-10.0,3.1) for pembrolizumab + chemotherapy versus atezolizumab + chemotherapy, respectively, and 0.8 (0.7,0.9) and -12.2 % (-19.6,-4.8) for pembrolizumab + chemotherapy versus atezolizumab + chemotherapy + bevacizumab, respectively. Findings were consistent across sensitivity analyses for both outcomes. CONCLUSION: MAIC results showed a significantly better OS and PFS for pembrolizumab + chemotherapy compared with atezolizumab + chemotherapy and a significantly better PFS for pembrolizumab + chemotherapy compared with atezolizumab + chemotherapy + bevacizumab.

A Matching-Adjusted Indirect Comparison of Pembrolizumab + Chemotherapy vs. Nivolumab + Ipilimumab as First-Line Therapies in Patients with PD-L1 TPS ≥1% Metastatic NSCLC.

BACKGROUND: In the absence of head-to-head trials, this study indirectly compared the effectiveness of pembrolizumab + chemotherapy vs nivolumab + ipilimumab for the first-line treatment of metastatic stage IV NSCLC patients with PD-L1 tumor proportion score (TPS) ≥1%. METHODS: An anchored matching-adjusted indirect comparison (MAIC) was conducted using pooled individual patient data (IPD) from the ITT population in KEYNOTE-021G, KEYNOTE-189 and KEYNOTE-407 (n = 816) and published aggregate data of nivolumab + ipilimumab from CheckMate 227 Part 1A (n = 793). To adjust for cross-trial differences in baseline characteristics, data from KEYNOTE-021G/KEYNOTE-189/KEYNOTE-407 were re-weighted to match the baseline characteristics of CheckMate 227 Part 1A. Outcomes included OS, PFS and ORR. Base case analyses were restricted to patients with PD-L1 TPS ≥1%, with sub-group analyses in PD-L1 TPS ≥50% and 1-49%. RESULTS: The estimated HR (95% CI) of pembrolizumab + chemotherapy vs nivolumab + ipilimumab was 0.80 (0.59,1.09) and 0.53 (0.41,0.68) for OS and PFS, respectively. For ORR, the estimated risk ratio was 1.8 (1.3,2.4) for pembrolizumab + chemotherapy vs nivolumab + ipilimumab and the risk difference was 25.5% (15.0,36.0). PD-L1 TPS ≥50% and 1-49% sub-groups showed an OS HR of 0.89 (0.58,1.36) and 0.68 (0.46,1.01), respectively. CONCLUSION: These MAIC results suggest that pembrolizumab + chemotherapy leads to a greater clinical benefit vs nivolumab + ipilimumab in patients with PD-L1 TPS ≥1% across multiple endpoints.

Prostaglandin E2 and Its Receptor EP2 Modulate Macrophage Activation and Fusion in Vitro.

The foreign body response (FBR) has impaired progress of new implantable medical devices through its hallmark of chronic inflammation and foreign body giant cell (FBGC) formation leading to fibrous encapsulation. Macrophages are known to drive the FBR, but efforts to control macrophage polarization remain challenging. The goal for this study was to investigate whether prostaglandin E2 (PGE2), and specifically its receptors EP2 and/or EP4, attenuate classically activated (i.e., inflammatory) macrophages and macrophage fusion into FBGCs in vitro. Lipopolysaccharide (LPS)-stimulated macrophages exhibited a dose-dependent decrease in gene expression and protein production of tumor necrosis factor alpha (TNF-α) when treated with PGE2. This attenuation was primarily by the EP4 receptor, as the addition of the EP2 antagonist PF 04418948 to PGE2-treated LPS-stimulated cells did not recover TNF-α production while the EP4 antagonist ONO AE3 208 did. However, direct stimulation of EP2 with the agonist butaprost to LPS-stimulated macrophages resulted in a ∼60% decrease in TNF-α secretion after 4 h and corresponded with an increase in gene expression for Cebpb and Il10, suggesting a polarization shift toward alternative activation through EP2 alone. Further, fusion of macrophages into FBGCs induced by interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF) was inhibited by PGE2 via EP2 signaling and by an EP2 agonist, but not an EP4 agonist. The attenuation by PGE2 was confirmed to be primarily by the EP2 receptor. Mrc1, Dcstamp, and Retlna expressions increased upon IL-4/GM-CSF stimulation, but only Retnla expression with the EP2 agonist returned to levels that were not different from controls. This study identified that PGE2 attenuates classically activated macrophages and macrophage fusion through distinct EP receptors, while targeting EP2 is able to attenuate both. In summary, this study identified EP2 as a potential therapeutic target for reducing the FBR to biomaterials.

Pembrolizumab plus chemotherapy for first-line treatment of metastatic nonsquamous non-small-cell lung cancer: a network meta-analysis.

AIM: A systematic review and network meta-analysis were conducted to evaluate the efficacy of pembrolizumab + pemetrexed + platinum relative to other regimens in metastatic nonsquamous non-small-cell lung cancer (NSq-NSCLC). PATIENTS & METHODS: Eligible studies evaluated first-line regimens in NSq-NSCLC patients without known targetable mutations. Relative treatment effects were synthesized with random effects proportional hazards Bayesian network meta-analyses. RESULTS: The hazard ratio (HR) for overall survival (OS) for pembrolizumab + pemetrexed + platinum was statistically significant over all platinum-doublet (HR range: 0.42-0.61), platinum-doublet + bevacizumab (HR range: 0.44-0.53) and platinum-doublet + atezolizumab regimens (HR range: 0.56-0.62). Additionally, pembrolizumab + pemetrexed + platinum numerically improved OS over atezolizumab + paclitaxel + carboplatin + bevacizumab (HR: 0.65; 95% credible interval: 0.43, 1.01). Pembrolizumab + pemetrexed + platinum had 95.6% probability of being the best treatment regimen for OS. CONCLUSION: Pembrolizumab + pemetrexed + platinum is likely the most efficacious first-line regimen for metastatic NSq-NSCLC.

An investigation into quality of life improvement in patients undergoing microvascular decompression for hemifacial spasm.

OBJECTIVE Hemifacial spasm (HFS) is a movement disorder characterized by involuntary spasms of the facial muscles, and it can negatively impact quality of life (QOL). This retrospective study and systematic review with meta-analysis was conducted to investigate the QOL in patients with HFS following intervention with microvascular decompression (MVD) and botulinum toxin (BT). METHODS In the retrospective analysis, a QOL questionnaire was administered to all patients undergoing MVD performed by a single surgeon. The QOL questionnaire included unique questions developed based on the authors' experience with HFS patients in addition to the health-related QOL HFS-8 questionnaire. The authors also report on a systematic review of the English literature providing outcomes and complications in patients with HFS undergoing treatment with either MVD or BT. RESULTS Regarding the retrospective analysis, 242 of 331 patients completed the questionnaire. The mean score of the 10 QOL questions improved from 22.78 (SD 9.83) to 2.17 (SD 5.75) following MVD (p < 0.001). There was significant improvement across all subscales of the questionnaire between pre- and postoperative responses (p < 0.001). Regarding the systematic review, it is reported that approximately 90% of patients undergoing MVD for HFS experience a complete recovery from symptoms, whereas the mean peak improvement of symptoms following treatment with BT is 77%. Furthermore, patients undergoing MVD reported a greater improvement in the mean supplemental index of QOL as compared with patients receiving BT therapy. CONCLUSIONS Microvascular decompression offers a significant improvement in QOL in well-selected patients suffering from HFS, and may offer an increased benefit for QOL over BT injections.

MRI of the Trigeminal Nerve in Patients With Trigeminal Neuralgia Secondary to Vascular Compression.

OBJECTIVE: Trigeminal neuralgia is a debilitating facial pain disorder, frequently caused by vascular compression of the trigeminal nerve. Vascular compression that results in trigeminal neuralgia occurs along the cisternal segment of the nerve. CONCLUSION: Imaging combined with clinical information is critical to correctly identify patients who are candidates for microvascular decompression. The purpose of this article is to review trigeminal nerve anatomy and to provide strategies for radiologists to recognize important MRI findings in patients with trigeminal neuralgia.

A Blinded, Case-Control Trial Assessing the Value of Steady State Free Precession Magnetic Resonance Imaging in the Diagnosis of Trigeminal Neuralgia.

OBJECTIVE: High-resolution magnetic resonance imaging (MRI) may be a useful and readily available adjunct in identifying trigeminal neuralgia secondary to vascular contact (TNVC). This study evaluated the reliability and predictive ability of 1.5-tesla steady state free precession (SSFP) MRI sequences for the diagnosis of symptomatic vascular contact and response to operative intervention in patients with TNVC. METHODS: We performed a blinded, case-matched control trial evaluating SSFP MRI sequences in consecutive patients with unilateral TNVC with operatively proven vascular contact of the trigeminal nerve compared with healthy control subjects matched on age, sex, and laterality of the pathologic neurovascular complex. Interrater reliability was compared between 2 blinded, expert reviewers. Predictive ability of MRI was assessed in regard to accuracy, discrimination, and clinical utility. RESULTS: Inclusion criteria were met by 44 patients (22 consecutive patients with TNVC and 22 matched control subjects). Interrater reliability ranged from fair to excellent for vessel contact (κ = 0.40), location (κ = 0.81), type (κ = 0.72), and multiplicity (κ = 0.31). Vascular contact on MRI sequences did not differ significantly between cases and controls (75% vs. 82%, P = 0.30). MRI demonstrates accurate (Brier 0.15) and good discriminatory ability for clinical response after microvascular decompression (area under the receiver operating characteristic curve 0.81, 95% confidence interval = 0.6-1.0). Decision-curve analysis demonstrated that MRI could result in a net reduction of 5 cases likely to be unsuccessful per 100 patients treated. CONCLUSIONS: These results suggest the utility of SSFP MRI lies not in the diagnosis of TNVC, but rather in stratifying the likelihood of response to microvascular decompression in patients with characteristic symptoms.