Osimertinib in the treatment of resected EGFR-mutated non-small cell lung cancer: a cost-effectiveness analysis in the United States.

Background: In the double-blind phase III ADAURA randomized clinical trial, adjuvant osimertinib showed a substantial overall survival benefit in patients with stage IB to IIIA, EGFR-mutated, completely resected non-small cell lung cancer (NSCLC). We conduct a cost-effectiveness analysis comparing the use of adjuvant osimertinib to placebo in patients with stage IB to IIIA, EGFR-mutated, resected NSCLC. Methods: Based on the results obtained from the ADAURA trial, a Markov model with three-state was employed to simulate patients who were administered either osimertinib or placebo until disease recurrence or completion of the study period (3 years). Quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER) were calculated with a willingness-to-pay (WTP) threshold of $150,000 per QALY. Both univariate and probabilistic sensitivity analyses were carried out to explore the robustness of the model. Results: Osimertinib produced additional 1.59 QALYs with additional costs of $492,710 compared to placebo, giving rise to ICERs of $309,962.66/QALY. The results of the univariate sensitivity analysis indicated that the utility of disease-free survival (DFS), cost of osimertinib, and discount rate had the greatest impact on the outcomes. Probabilistic sensitivity analysis showed that osimertinib exhibited a 0% chance of being considered cost-effective for patients using a WTP threshold $150,000/QALY. Conclusion: In our model, osimertinib was unlikely to be cost-effective compared to placebo for stage IB to IIIA, EGFR-mutated, completely resected NSCLC patients from the perspective of a U.S. payer at a WTP threshold of $150,000 per QALY.

Cost-effectiveness of atezolizumab plus chemotherapy for advanced/recurrent endometrial cancer.

OBJECTIVE: This study assessed the cost-effectiveness of atezolizumab in combination with chemotherapy for patients with advanced or recurrent endometrial cancer (EC) from the U.S. payer's perspective. METHODS: A cost-effectiveness study was conducted using a Markov model based on ENGOT-en7/MaNGO/AtTEnd clinical trials. The population consisted of patients with EC, stratified by mismatch repair-deficient (dMMR) and mismatch repair-proficient (pMMR) subgroups. The model simulated patients receiving either atezolizumab plus chemotherapy or chemotherapy alone. Cost, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated using a Willingness-to-Pay (WTP) threshold of $150,000/QALY. Sensitivity analyses were performed. RESULTS: Adding atezolizumab to chemotherapy in dMMR EC resulted in an incremental gain of 3.31 QALYs but at an additional cost of $855,042, leading to an ICER of $258,391.07/QALY compared to chemotherapy alone. In pMMR EC, there was a gain of 0.50 QALYs with an additional cost of $140,502, resulting in an ICER of $279,239.72/QALY. The overall ICER for EC was $216,459.34/QALY. Scenario analysis indicated that administering atezolizumab for a maximum of 2 years improved cost-effectiveness in dMMR EC, with an ICER of $70,695.96/QALY falling within the predetermined WTP threshold. CONCLUSION: For patients with advanced or recurrent EC, the combination of atezolizumab and chemotherapy may not prove cost-effective. However, administering atezolizumab for a limited period of maximum 2 years could improve cost-effectiveness in dMMR EC.

Cost-effectiveness of pembrolizumab plus chemotherapy for advanced endometrial cancer.

OBJECTIVE: To assess the cost-effectiveness of pembrolizumab in combination with chemotherapy compared to chemotherapy alone, based on the results of the NRG-GY018 trial, in patients with advanced or recurrent endometrial cancer (EC), stratified by mismatch repair-deficient (dMMR) and mismatch repair-proficient (pMMR) subgroups. METHODS: A Markov model was used to simulate patients receiving either pembrolizumab plus chemotherapy or chemotherapy alone. Lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were calculated using a willingness-to-pay (WTP) threshold of $150,000/QALY. Univariate and probabilistic sensitivity analyses were conducted to assess the robustness of our findings. RESULTS: The addition of pembrolizumab to chemotherapy led to an incremental gain of 4.05 QALYs at an additional cost of $167,224, resulting in an ICER of $41,305.09/QALY compared to chemotherapy alone in dMMR EC. Additionally, there were 0.93 additional QALYs at an additional cost of $83,661, which resulted in an ICER of $90,284.80/QALY in pMMR EC. Sensitivity analyses indicated that the cost of pembrolizumab, utility of progressed disease, and utility of progression-free survival had the greatest impact on the results. Probabilistic sensitivity analysis showed that pembrolizumab was considered cost-effective at a 100% probability at a WTP threshold of $150,000 per QALY. CONCLUSION: Pembrolizumab, when combined with chemotherapy, was found to be cost-effective compared to chemotherapy alone both for patients with advanced or recurrent dMMR and pMMR EC from the perspective of a payer in the United States.

Cost-effectiveness of first-line versus second-line use of brigatinib followed by lorlatinib in patients with ALK-positive non-small cell lung cancer.

Background: The ALTA-1 L trial and EXP-3B arm of NCT01970865 trial found that both brigatinib and lorlatinib showed durable and robust responses in treating ALK-positive non-small cell lung cancer (NSCLC) patients. However, brigatinib and lorlatinib treatments are costly and need indefinite administration until the disease progression. Thus, it remains uncertain whether using brigatinib followed by lorlatinib before chemotherapy is cost-effective compared to reserving these two drugs until progression after chemotherapy. Methods: We used a Markov model to assess clinical outcomes and healthcare costs of treating ALK-positive NSCLC individuals with brigatinib followed by lorlatinib before chemotherapy versus a strategy of reserving these drugs until progression after chemotherapy. Transition probabilities were estimated using parametric survival modeling based on multiple clinical trials. The drug acquisition costs, adverse events costs, administration costs were extracted from published studies before and publicly available data. We calculated lifetime direct healthcare costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios from the perspective of a United States payer. Results: Our base-case analysis indicated that the incremental cost-effectiveness ratios of using first-line brigatinib followed by lorlatinib compared with second-line brigatinib followed by lorlatinib is $-400,722.09/QALY which meant that second-line brigatinib followed by lorlatinib had less costs and better outcomes. Univariate sensitivity analysis indicated the results were most sensitive to the cost of brigatinib. Probability sensitivity analysis revealed that using brigatinib followed by lorlatinib before chemotherapy had a 0% probability of cost-effectiveness versus delaying these two drugs until progression after chemotherapy at a willingness-to-pay threshold of $150,000 per QALY. Sensitivity analyses conducted revealed the robustness of this result, as incremental cost-effectiveness ratios never exceeded the willingness-to-pay threshold. Conclusion: Using brigatinib as first-line treatment followed by lorlatinib for ALK-positive NSCLC may not be cost-effective given current pricing from the perspective of a United States payer. Delaying brigatinib followed by lorlatinib until subsequent lines of treatment may be a reasonable strategy that could limit healthcare costs without affecting clinical outcomes. More mature data are needed to better estimate cost-effectiveness in this setting.

Cost-effectiveness of tisotumab vedotin as a second- or third-line therapy for cervical cancer.

OBJECTIVE: To evaluate the cost-effectiveness of tisotumab vedotin to treat recurrent or metastatic cervical cancer in second- or third-line from the U.S. payer perspective. METHODS: A Markov model with three-state was employed to simulate recurrent or metastatic cervical cancer patients who were administered either tisotumab vedotin or investigator's choice of chemotherapy based on the phase II, open-labeled innovaTV 301 randomized clinical trial. The data on cost and health preferences were collected from the literature. RESULTS: Tisotumab vedotin generated an additional 0.25 quality-adjusted life-years (QALYs) compared to chemotherapy, but at an additional cost of $206,779. This results in incremental cost-effectiveness ratios of 839,107.88 per QALY. The results of the univariate sensitivity analysis indicated that cost of tisotumab vedotin, utility of progressive disease and progression-free survival had the greatest impacts on the outcomes. Probability sensitivity analysis showed that tisotumab vedotin had a 0% chance of being considered cost-effective. CONCLUSION: Tisotumab vedotin was unlikely cost-effective compared to chemotherapy for recurrent or metastatic cervical cancer patients at a willingness-to-pay threshold of $150,000/QALY from the perspective of a U.S. payer. Lowering the prices of tisotumab vedotin could potentially enhance its cost-effectiveness.

First-line versus second-line use of pralsetinib in treatment of rearranged during transfection (RET) fusion-positive advanced non-small cell lung cancer: a cost-effectiveness analysis.

Background: The ARROW study demonstrated favorable clinical efficacy and safety of pralsetinib (PRL) in treating rearranged during transfection (RET) fusion positive non-small cell lung cancer (NSCLC) in clinical trials. However, due to the high cost of PRL, evaluating its cost-effective characteristics is crucial. Currently, there has been no cost-effectiveness analysis specifically for PRL. Therefore, the aim of this study was to assess the cost-effectiveness characteristics of using PRL as a first-line therapy versus reserving it until the second-line versus solely relying on chemotherapy from the perspective of payers in the United States. Methods: A Markov model was developed to evaluate the 3 above mentioned PRL-based treatment strategies. Clinical data from the ARROW trial were incorporated into the model, and costs and utilities values were obtained through previously published literature and public databases, with both being discounted at 3% per year. To ensure the robustness of the model, both probabilistic and univariate sensitivity analyses were performed. The primary endpoints included quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratio (ICER). Results: Compared to chemotherapy, the use of PRL in the first-line therapy resulted in an additional 0.07 QALYs at a cost of $133,561, with an ICER of $1,353,849.65 per QALY. Similarly, when used in the second-line setting, PRL led to an additional 0.09 QALYs at a cost of $92,797, with an ICER of $559,232.70 per QALY. The ICER value in the first-line or in the second-line therapy strategy was higher than the US willingness-to-pay (WTP) threshold of $150,000 per QALY. Univariable sensitivity analyses revealed that the cost of PRL and the utility of progressed disease had the most significant impact on the ICER. To be considered cost-effective at a WTP threshold of $150,000 per QALY, the cost of PRL would need to be reduced by 71.34% in first-line treatment or 84.49% in second-line treatment. Conclusions: Based on current pricing, neither PRL as first-line nor second-line therapy was found to be cost-effective for patients with RET fusion-positive advanced NSCLC compared to chemotherapy. Reserving PRL until second-line therapy may be a compromise approach to maintaining control over healthcare expenses yet still achieving favorable clinical outcomes.

Inetetamab, a novel anti-HER2 monoclonal antibody, exhibits potent synergistic anticancer effects with cisplatin by inducing pyroptosis in lung adenocarcinoma.

Cisplatin is a first-line chemotherapy drug for lung adenocarcinoma (LUAD). However, its therapeutic efficacy is limited because of serious side effects and acquired drug resistance. Targeting HER2 has been proven to be a viable therapeutic strategy against LUAD. Moreover, inetetamab, an innovative anti-HER2 monoclonal antibody, has a more potent antibody-dependent cell-mediated cytotoxicity (ADCC)-inducing effect than trastuzumab, which has been shown to be an effective and rational strategy in the clinic when combined with multiple chemotherapeutic agents. Thus, the present study aimed to explore the synergistic effects of cisplatin (DDP) and inetetamab in LUAD cells and investigate the detailed underlying mechanisms. Here, in vitro and in vivo, we found that the combination of inetetamab and cisplatin induced synergistic effects, including induction of pyroptosis, in LUAD. Mechanistic studies revealed that inetetamab combined with cisplatin inhibited HER2/AKT/Nrf2 signaling to increase ROS levels, which triggered NLRP3/caspase-1/GSDMB-mediated pyroptosis to synergistically enhance antitumor efficacy in LUAD cells. In addition, cisplatin enhanced the PBMC-killing ability of inetetamab by inducing GSDMB-mediated pyroptosis, which can be explained by increased secretion of IFN-γ. Our study reveals that the anti-HER2 monoclonal antibody inetetamab may be an attractive candidate for LUAD therapy, which opens new avenues for therapeutic interventions for LUAD.

First-line tremelimumab plus durvalumab and chemotherapy versus chemotherapy alone for metastatic non-small cell lung cancer: a cost-effectiveness analysis in the United States.

Importance: In the open-label phase III POSEIDON randomized clinical trial (RCT), a limited course of tremelimumab plus durvalumab and chemotherapy (T + D + CT) indicated in the first-line treatment of metastatic non-small cell lung cancer (mNSCLC), progression-free survival, and overall survival (OS) were substantially improved without significant additional tolerance burden compared to chemotherapy (CT). However, given the high cost of T + D + CT, its value needs to be evaluated in terms of both potency and cost. Objective: To evaluate the cost-effectiveness of T + D + CT versus CT in individuals with previously untreated mNSCLC from a U.S. payer perspective. Design, setting, and participants: A three-state Markov model was adopted to weigh the lifetime costs and effectiveness of T + D + CT versus CT for the treatment of first-line mNSCLC, according to the results of the POSEIDON phase III RCT involving 675 individuals with mNSCLC. Individuals were simulated to undergo either T + D + CT for up to four 21-day cycles, followed by durvalumab once every 4 weeks until disease progression or unacceptable toxic effects and one additional tremelimumab dose, or CT for up to six 21-day cycles (with or without pemetrexed maintenance; all groups) in the analysis. Main outcomes and measures: Lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER) were evaluated with a willingness-to-pay (WTP) threshold of $ 100,000 to $ 150,000 per QALY. The uncertainty of the model was investigated using univariate and probabilistic sensitivity analysis. Results: T + D + CT produced additional 0.36 QALYs with additional costs of $ 217,694, compared to CT, giving rise to ICERs of $ 608,667.86/QALY. The univariate sensitivity analysis demonstrated that the outcomes were most sensitive to the cost of durvalumab. Other variables with a large or moderate influence were the utility of progression-free survival state, utility of progressive disease state, and cost of tremelimumab. Probability sensitivity analysis revealed that T + D + CT had a 0% probability of cost-effectiveness in individuals with mNSCLC at a willingness-to-pay threshold of $ 100,000 to $ 150,000 per QALY. Conclusion and relevance: In this model, T + D + CT was estimated to be less cost-effective than CT for patients with mNSCLC at a WTP threshold of $ 100,000 to $ 150,000 per QALY in the United States. When new combination therapies with remarkable effect become pivotal in the first-line treatment, the price reduction of durvalumab and tremelimumab may be necessary to achieve cost-effectiveness in future possible context.

TWF1 induces autophagy and accelerates malignant phenotype in lung adenocarcinoma via inhibiting the cAMP signaling pathway.

Many studies have shown that the actin cytoskeleton plays an essential role in the initiation and progression of cancer. As an actin-binding protein, Twinfilin1 (TWF1) plays an important role in regulating cytoskeleton-related functions. However, little is known about the expression and function of TWF1 in human tumors. The present study aimed to investigate the functional roles and the underlying molecular mechanisms of TWF1 in human lung adenocarcinoma (LUAD). By using bioinformatics databases and tumor tissues, TWF1 expression was found to be higher in LUAD tissues than in adjacent tissues and poor survival was predicted in patients with LUAD. In vitro and in vivo assays indicated that downregulation of TWF1 expression suppressed LUAD cells invasion and migration. Further studies revealed that TWF1 interacted with p62 and was involved in the regulation of autophagy. The molecular mechanisms underlying TWF1 were investigated by RNA-seq analysis and a series of functional experiments. The results showed that downregulation of TWF1 suppressed LUAD progression through the cAMP signaling pathway. Therefore, overexpression of TWF1 in LUAD promoted migration, invasion, and autophagy through the cAMP signaling pathway.

Clinical benefit of pembrolizumab in treatment of first line non-small cell lung cancer: a systematic review and meta-analysis of clinical characteristics.

OBJECTIVE: Pembrolizumab has become an integral first line therapeutic agent for non-small cell lung cancer (NSCLC), but its potential predictive role in clinical and molecular characteristics remains to be clarified. Accordingly, we performed a systematic review and meta-analysis to evaluate the clinical benefit of pembrolizumab in treatment of first line NSCLC and to select individuals with the greatest potential benefit from pembrolizumab therapy, in order to obtain a more accurate treatment of NSCLC in immunotherapy. METHODS: Mainstream oncology datasets and conferences were searched for randomized clinical trials (RCTs) published before August 2022. RCTs involved individuals with first line NSCLC treated with pembrolizumab monotherapy or in combination with chemotherapy. Two authors independently selected the studies, extracted data, and assessed the risk of bias. The basic characteristics of the included studies were recorded, along with 95 percent confidence intervals (CI) and hazard ratios (HR) for all patients and subgroups. The primary endpoint was overall survival (OS), and secondary endpoints was progression-free survival (PFS). Pooled treatment data were estimated using the inverse variance-weighted method. RESULTS: Five RCTs involving 2,877 individuals were included in the study. Pembrolizumab-based therapy significantly improved OS (HR 0.66; CI 95%, 0.55-0.79; p < 0.00001) and PFS (HR 0.60; CI 95%, 0.40-0.91; p = 0.02) compared with chemotherapy. OS was substantially enhanced in individuals aged < 65 years (HR 0.59; CI 95%, 0.42-0.82; p = 0.002), males (HR 0.74; CI 95%, 0.65-0.83; p < 0.00001), with a smoking history (HR 0.65; CI 95%, 0.52-0.82; p = 0.0003), with PD-L1 tumor proportion score (TPS) < 1% (HR 0.55; CI 95%, 0.41-0.73; p < 0.0001) and TPS ≥ 50% (HR 0.66; CI 95%, 0.56-0.76; p < 0.00001), but not in individuals aged ≥ 75 years (HR 0.82; CI 95%, 0.56-1.21; p = 0.32), females (HR 0.57; CI 95%, 0.31-1.06; p = 0.08), never smokers (HR 0.57; CI 95%, 0.18-1.80; p = 0.34), or with TPS 1-49% (HR 0.72; CI 95%, 0.52-1.01; p = 0.06). Pembrolizumab significantly prolonged OS in NSCLC patients, regardless of histology type (squamous or non-squamous NSCLC), performance status (PS) (0 or 1), and brain metastatic status (all p < 0.05). Subgroup analysis revealed that pembrolizumab combined with chemotherapy had more favorable HR values than pembrolizumab monotherapy in improving the OS of individuals with different clinical and molecular features. CONCLUSION: Pembrolizumab-based therapy is a valuable option for first line treating advanced or metastatic NSCLC. Age, sex, smoking history and PD-L1 expression status can be used to predict the clinical benefit of pembrolizumab. Cautiousness was needed when using pembrolizumab in NSCLC patients aged ≥ 75 years, females, never smokers, or in patients with TPS 1-49%. Furthermore, pembrolizumab in combination with chemotherapy may be a more effective treatment regimen.

Efficacy of PD-1/PD-L1 inhibitors in advanced gastroesophageal cancer based on characteristics: a meta-analysis.

Objective: Evaluate the potency of anti-PD-1/PD-L1 antibodies in advanced gastroesophageal cancer patients with different clinical features. Methods: Randomized, controlled trials comparing anti-PD-1/PD-L1 antibodies with chemotherapy in individuals with gastroesophageal cancer were retrieved. Results: 15 trials involving 9194 individuals were included. PD-1/PD-L1 inhibitors significantly improved overall survival (OS) but not progression-free survival. Significantly improved OS was observed in PD-L1 combined positive score ≥1, primary esophageal cancer, primary gastric cancer and Asian patients. Subgroup analysis revealed significant OS benefit achieved for esophageal squamous cell carcinoma, but not for esophageal adenocarcinoma. Conclusion: PD-1/PD-L1 inhibitors improved OS in advanced gastroesophageal carcinoma, especially in patients with esophageal cancer. Race, primary tumor sites and PD-L1 combined positive score can be used to predict the potency of immune checkpoint inhibitors.

Scientists studied a treatment called PD-1/PD-L1 inhibitors for stomach and esophagus cancer that has spread. They found that these treatments work well, especially for people with esophageal cancer. They looked at information from different studies and found that the treatment worked better for some people based on their race, where their cancer started and a test called a PD-L1 combined positive score. This information is important for doctors to decide how to treat their patients.

Toripalimab plus chemotherapy vs. chemotherapy in patients with advanced non-small-cell lung cancer: A cost-effectiveness analysis.

Background: The potency and safety of toripalimab combination with chemotherapy (TC) as the first-line therapy for advanced non-small cell lung cancer (NSCLC) have been demonstrated in the CHOICE-01 study. Our research explored whether TC was cost-effective compared to chemotherapy alone from the Chinese payer perspective. Materials and methods: Clinical parameters were obtained from a randomized, multicenter, registrational, placebo-controlled, double-blind, phase III trial. Standard fee databases and previously published literature were used to determine costs and utilities. A Markov model with three mutually exclusive health statuses (progression-free survival (PFS), disease progression, and death) was used to predict the disease course. The costs and utilities were discounted at 5% per annum. The main endpoints of the model included cost, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER). Univariate and probabilistic sensitivity analyses were performed to investigate the uncertainty. Subgroup analyses were performed to verify the cost-effectiveness of TC in patients with squamous and non-squamous cancer. Results: TC combination therapy yielded an incremental 0.54 QALYs with an incremental cost of $11,777, compared to chemotherapy, giving rise to ICERs of $21,811.76/QALY. Probabilistic sensitivity analysis revealed that TC was not favorable at 1 time GDP per capita. With a prespecified willingness-to-pay threshold (WTP) of three times the GDP per capita, combined treatment had a 100% probability of being cost-effective and had substantial cost-effectiveness in advanced NSCLC. Probabilistic sensitivity analyses showed that TC was more likely to be accepted with a WTP threshold higher than $22,195 in NSCLC. Univariate sensitivity analysis showed that the utility of PFS state, crossover proportions of the chemotherapy arm, cost per cycle of pemetrexed treatment, and discount rate were the dominant influencing factors. Subgroup analyses found that in patients with squamous NSCLC, the ICER was $14,966.09/QALY. In the non-squamous NSCLC, ICER raised to $23,836.27/QALY. ICERs were sensitive to the variance of the PFS state utility. TC was more likely to be accepted when WTP increases exceeded $14,908 in the squamous NSCLC subgroup and $23,409 in the non-squamous NSCLC subgroup. Conclusion: From the perspective of the Chinese healthcare system, TC may be cost-effective in individuals with previously untreated advanced NSCLC at the prespecified WTP threshold compared to chemotherapy, and more significant in individuals with squamous NSCLC, which will provide evidence for clinicians to make the best decisions in general clinical practice.

Efficacy of PD-1/PD-L1 inhibitors in gastric or gastro-oesophageal junction cancer based on clinical characteristics: a meta-analysis.

PURPOSE: Programmed death-1 (PD-1) and its ligand (PD-L1) inhibitors have been reported in several clinical trials for gastric cancer and gastroesophageal junction cancer (GC/GEJC). We presently carried out a meta analysis to evaluate the potency of PD-1/PD-L1 inhibitors in advanced GC/GEJC individuals with different clinical features and to determine patients more probably benefiting from the treatment. METHODS: Randomized clinical trials (RCTs) in databases that compared PD-1/PD-L1 inhibitors to chemotherapy in patients with GC/GEJC published before May 2022 were retrieved. Basic characteristics were extracted from the included studies as well as hazard ratios (HR) and 95 percent confidence intervals (CI) for all individuals and subgroups. The inverse variance weighting method was used to evaluate pooled treatment data. FINDINGS: Four RCTs involving 2,253 individuals were included. The results suggested that PD-1/PD-L1 inhibitors substantially enhanced overall survival (OS) (HR, 0.91; CI 95%, 0.83-1.00; p = 0.04) but not progression free survival (PFS) (HR, 1.17; CI 95%, 0.83-1.64; p = 0.38) in GC/GEJC individuals compared with chemotherapy. Significantly improved OS was observed in individuals aged < 65 years (HR, 0.84; p = 0.003), and men (HR, 0.88; p = 0.02), but not in individuals aged ≥ 65 years (HR, 0.97; p = 0.62), and women (HR, 0.98; p = 0.82). IMPLICATIONS: PD-1/PD-L1 inhibitors improve OS but not PFS compared with chemotherapy in GC/GEJC. Age and sex could be used to predict the treatment potency of PD-1/PD-L1 inhibitors in GC/GEJC.

Efficacy of PD-1/PD-L1 plus CTLA-4 inhibitors in solid tumors based on clinical characteristics: a meta-analysis.

Aims: To clarify the relationship between the potency of dual blockade of PD-1 or its ligand (PD-L1) plus CTLA-4 and patients with different clinical characteristics with solid tumors, the authors performed this meta-analysis. Patients & methods: 12 randomized clinical trials containing 7056 patients were included after the literature was filtered. Results: Dual blockade substantially enhanced overall survival and progression-free survival compared with standard of care, especially in patients aged <65 years old, those 65-74 years old, those with a smoking history, members of the White population and those with a high tumor mutation burden. Conclusion: Dual blockade therapy significantly improved patient survival outcomes. Age, smoking history, race and tumor mutation burden might be used to predict the potency of dual blockade therapy in solid tumors.

PD-1/PD-L1 plus CTLA-4 inhibitors therapy has been shown to be effective in many cancers. This meta-analysis found a correlation between efficacy and the characteristics of patients. Several datasets were used to screen the articles. Review Manager 5.3 was used for statistical analysis. A total of 7056 patients from 12 randomized, controlled trials were included. It was found that significant benefits were obtained by dual inhibitors. Their efficacy was correlated with patient age, smoking history, race and tumor mutation burden. These findings are important for clinical medication decisions.

High incidence and reversible bradycardia events following alectinib initiation.

BACKGROUND: With the widespread use of alectinib in patients with anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC), its cardiotoxicity has gradually emerged, including new-onset sinus bradycardia (SB). However, the incidence, timing, severity, and risk factors of alectinib-induced bradycardia remain unknown. METHODS: From January 2020 to June 2022, 93 patients with ALK-positive NSCLC treated with alectinib were enrolled in this retrospective analysis. These patients had heart rate (HR) recorded before and after alectinib administration. By reviewing electronic medical records and follow-up, the HR changes of patients during medication were recorded. The potential risk factors associated with alectinib-induced SB were explored. RESULTS: According to an HR cut-off of 60 beats per minute (bpm), 47 patients (50.54%) experienced at least one recorded bradycardia. The mean HR of total participants before alectinib administration was 78.32 (standard deviation [SD], 9.48) and after was 64.88 (SD, 12.21). The median maximum change in HR (range) for all patients was 11 (-55, +4) bpm. For the bradycardia subgroup, the HR of most patients (76.60%) hovered around 50-60 bpm, and 61.70% of SB occurred within 3 months after alectinib administration. Multivariate analysis indicated that baseline HR (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.79-0.93, p < 0.001) and history of hypertension (OR 13.71, 95% CI 2.49-76.38, p = 0.003) were independent risk factors for alectinib-related bradycardia. CONCLUSIONS: Alectinib-induced bradycardia had a high incidence, appeared relatively early, and was reversible by dose reduction or withdrawal.

Safety and efficacy of immune checkpoint inhibitors in advanced cancer patients with autoimmune disease: A meta-analysis.

Cancer patients with autoimmune disease (AID) are usually excluded from clinical trials involving immune checkpoint inhibitors (ICIs). The available electronic databases were systematically searched from inception until July 3, 2022. We recorded the incidence of immune-related adverse events (irAEs), progression-free survival (PFS), and overall survival (OS) data of included studies. This meta-analysis included 14 studies comprising 11511 participants; however, only 8716 participants were treated with ICI. Therefore, the analysis was conducted on 8716 patients (769 patients with AID compared to 7947 patients without AID). The pooled risk ratio (RR) for any grade and grade ≥3 irAEs was 1.74 (95% confidence interval [CI]: 1.27-2.37) and 1.43 (95% CI: 1.10-1.88), respectively. The irAEs in the same system as that of the AID were referred to as AID-homogeneous irAEs; in the other cases, there were referred to as AID-heterogeneous irAEs. Subgroup analysis found that the higher risk of AID-homogeneous irAEs contributed to the higher risk of overall irAEs among patients with AID. The pooled hazard ratio (HR) for PFS and OS was 1.09 (95% CI: 0.96-1.24) and 1.07 (95% CI: 0.94-1.22), respectively. The results of PFS and OS subgroup analyses matched the overall results. Patients with AID had a significantly higher risk of developing any grade and ≥3 grade irAEs under ICI therapy, specifically AID-homogeneous irAEs; however, the frequency of AID-heterogeneous irAEs in patients with AID was similar to irAEs in patients without AID. No statistically significant differences in PFS and OS were observed between the two groups.

Oncogenic role of TWF2 in human tumors: A pan-cancer analysis.

To develop effective medicines, researchers must first understand the common and distinct mechanisms that drive oncogenic processes in human cancers. TWF1 and TWF2 belong to the actin-depolymerizing factor homology family. TWF1 has been identified as an important gene in lung, breast, and pancreatic cancer in recent investigations. TWF2's role in cancer remains largely unknown, no comprehensive pan-cancer studies have been conducted. We utilized the The Cancer Genome Atlas and Gene Expression Omnibus datasets to investigate the role of TWF2 in different types of cancers. TWF2 transcription in cancers and the number of TWF2 mutations were examined as part of our study. We also examined the possible functional pathways involved in TWF2-mediated oncogenicity. Our pan-cancer analysis provided a complete overview of the oncogenic effects of TWF2 in a wide range of human malignancies.

Efficacy of Atezolizumab for Advanced Non-Small Cell Lung Cancer Based on Clinical and Molecular Features: A Meta-Analysis.

Objective: Atezolizumab is becoming a significant therapy for non-small cell lung cancer (NSCLC), but its efficacy needs to be further improved. The aims of this study are to clarify the potency of atezolizumab-based therapy in advanced NSCLC patients with different clinical and molecular features, and to choose a better therapeutic regimen of atezolizumab to achieve more precise treatment in immunotherapy. Methods: Randomized clinical trials (RCTs) in the Cochrane Library, PubMed, Embase Science Direct, and Google Scholar, together with major oncology conferences that compared atezolizumab with chemotherapy-based treatment for individuals with advanced NSCLC published prior to February 2022, were searched. Studies, bias risk assessment, and data extraction were selected by two independent authors. We extracted the basic features of the included studies, together with the 95% confidence interval (CI) and hazard ratios (HRs), from all patients and subgroups. The combined treatment data were assessed using the inverse variance weighting method. Results: Seven RCTs including 4,859 patients were included. Our meta-analysis findings indicated that atezolizumab substantially enhanced OS (HR 0.82; 95% CI, 0.77-0.88; p < 0.00001) and PFS (HR 0.72; 95% CI, 0.61-0.85; p < 0.0001) in patients with advanced NSCLC compared with chemotherapy-based treatment. Atezolizumab substantially enhanced OS in patients aged <65 years old and 65-74 years old, those with wild-type EGFR, those without liver metastases, active or previous smokers, white patients and those with TC3 or IC3, TC2/3 or IC2/3, TC1/2/3 or IC1/2/3, and TC0 and IC0, but not in patients aged ≥75 years, never smokers, those with liver metastases, those with EGFR mutant, Asians, Black or African Americans, or those with TC1/2 or IC1/2. Patients with advanced NSCLC who received atezolizumab showed OS improvement regardless of sex (male or female), histological type (non-squamous or squamous NSCLC), performance status (0 or 1), and line of treatment (1st-line therapy or ≥2nd-line therapy). Subgroup analysis revealed that male individuals, those with non-squamous NSCLC, those with PS 1, active or previous smokers, and those with wild-type EGFR, TC3 or IC3, and TC1/2/3 or IC1/2/3 achieved OS benefit from atezolizumab treatment not related to the treatment line and treatment regimen. Conclusions: Age group, smoking history, liver metastasis status, EGFR mutation status, race, and PD-L1 expression can be used to predict the potency of atezolizumab and provide a better treatment regimen for patients with advanced NSCLC to achieve accurate and personalized treatment.

Inhibitors of PD-1 in Non-Small Cell Lung Cancer: A Meta-Analysis of Clinical and Molecular Features.

Objective: PD-1 inhibitors have become an indispensable treatment in Non-Small Cell Lung Cancer (NSCLC), but the potential predictive value of clinical and molecular features need to be clarified. The objective of the study was to study the potency of PD-1 inhibitors in patients with NSCLC in contexts of both clinical and molecular features, and to aid identification of patients for choice of type of PD-1 inhibitor therapy in order to acquire more accurate NSCLC treatment in immunotherapy. Method: PubMed, Google Scholar, Embase Science Direct, the Cochrane library, and major oncology conferences were searched for randomized clinical trials (RCTs) that were published prior to December 2021. RCTs that had PD-1 inhibitor alone or in combination with chemotherapy with non-PD-1 inhibitor for the treatment of NSCLC patients were selected. Two authors independently selected studies, data extraction and bias risk assessment. Basic characteristics of included studies, and also the 95% confidence interval and hazard ratios of the overall patients and subgroups were recorded. The inverse variance weighted method was used to estimate pooled treatment data. Result: A total of eleven RCTs including 5,887 patients were involved. PD-1 inhibitors-based therapy substantially enhanced OS compared with non-PD-1 inhibitor therapy in patients with age group <65 years, 65-74 years, active or previous smokers, without brain metastases, liver metastases, EGFR wild-type patients, individuals in East Asia and U.S./Canada, but not in patients with age group ≥75 years, never smokers, brain metastases, EGFR mutant patients or individuals in Europe. OS was improved in patients with NSCLC who received PD-1 inhibitors regardless of their gender (male or female), histomorphological subtypes (squamous or non-squamous NSCLC), performance status (0 or 1), and PD-L1 tumor proportion score (TPS) (<1%, ≥1%, 1-49%, or ≥50%). An analysis of subgroups revealed that, patients with age group <65 years old, male, non squamous cell carcinoma, PS 1, TPS ≥1%, and TPS ≥50% benefited from pembrolizumab treatment not related with treatment line and treatment regimen. Conclusion: Age group, smoking history, metastasis status/site, EGFR mutation status, and region can be used to predict the potency of PD-1 inhibitors, and to be individualized to choose different types of PD-1 inhibitors, and treatment regimen for NSCLC patients.

A Pan-Cancer Analysis of the Oncogenic Role of Twinfilin Actin Binding Protein 1 in Human Tumors.

BACKGROUND: Understanding common and unique mechanisms driving oncogenic processes in human tumors is indispensable to develop efficient therapies. Recent studies have proposed Twinfilin Actin Binding Protein 1 (TWF1) as a putative driver gene in lung cancer, pancreatic cancer and breast cancer, however a systematic pan-cancer analysis has not been carried out. METHODS: Here, we set out to explore the role of TWF1 in 33 tumor types using TCGA (The Cancer Genome Atlas), GEO (Gene Expression Omnibus) dataset, Human Protein Atlas (HPA), and several bioinformatic tools. RESULTS: As part of our analysis, we have assessed TWF1 expression across tumors. We found that over-expression of TWF1 generally predicted poor OS for patients with tumors with high TWF1 expression, such as mesothelioma, lung adenocarcinoma, cervical cancer and pancreatic adenocarcinoma. We also assessed the mutation burden of TWF1 in cancer and the TWF1-associated survival of cancer patients, compared the phosphorylation of TWF1 between normal and primary tumor tissues and explored putative functional mechanisms in TWF1-mediated oncogenesis. CONCLUSIONS: Our pan-cancer analysis provides a comprehensive overview of the oncogenic roles of TWF1 in multiple human cancers.