Osimertinib after Chemoradiotherapy in Stage III EGFR-Mutated NSCLC.

BACKGROUND: Osimertinib is a recommended treatment for advanced non-small-cell lung cancer (NSCLC) with an epidermal growth factor receptor (EGFR) mutation and as adjuvant treatment for resected EGFR-mutated NSCLC. EGFR tyrosine kinase inhibitors have shown preliminary efficacy in unresectable stage III EGFR-mutated NSCLC. METHODS: In this phase 3, double-blind, placebo-controlled trial, we randomly assigned patients with unresectable EGFR-mutated stage III NSCLC without progression during or after chemoradiotherapy to receive osimertinib or placebo until disease progression occurred (as assessed by blinded independent central review) or the regimen was discontinued. The primary end point was progression-free survival as assessed by blinded independent central review. RESULTS: A total of 216 patients who had undergone chemoradiotherapy were randomly assigned to receive osimertinib (143 patients) or placebo (73 patients). Osimertinib resulted in a significant progression-free survival benefit as compared with placebo: the median progression-free survival was 39.1 months with osimertinib versus 5.6 months with placebo, with a hazard ratio for disease progression or death of 0.16 (95% confidence interval [CI], 0.10 to 0.24; P<0.001). The percentage of patients who were alive and progression free at 12 months was 74% (95% CI, 65 to 80) with osimertinib and 22% (95% CI, 13 to 32) with placebo. Interim overall survival data (maturity, 20%) showed 36-month overall survival among 84% of patients with osimertinib (95% CI, 75 to 89) and 74% with placebo (95% CI, 57 to 85), with a hazard ratio for death of 0.81 (95% CI, 0.42 to 1.56; P = 0.53). The incidence of adverse events of grade 3 or higher was 35% in the osimertinib group and 12% in the placebo group; radiation pneumonitis (majority grade, 1 to 2) was reported in 48% and 38%, respectively. No new safety concerns emerged. CONCLUSIONS: Treatment with osimertinib resulted in significantly longer progression-free survival than placebo in patients with unresectable stage III EGFR-mutated NSCLC. (Funded by AstraZeneca; LAURA ClinicalTrials.gov number, NCT03521154.).

Amivantamab plus Lazertinib in Previously Untreated EGFR-Mutated Advanced NSCLC.

BACKGROUND: Amivantamab plus lazertinib (amivantamab-lazertinib) has shown clinically meaningful and durable antitumor activity in patients with previously untreated or osimertinib-pretreated EGFR (epidermal growth factor receptor)-mutated advanced non-small-cell lung cancer (NSCLC). METHODS: In a phase 3, international, randomized trial, we assigned, in a 2:2:1 ratio, patients with previously untreated EGFR-mutated (exon 19 deletion or L858R), locally advanced or metastatic NSCLC to receive amivantamab-lazertinib (in an open-label fashion), osimertinib (in a blinded fashion), or lazertinib (in a blinded fashion, to assess the contribution of treatment components). The primary end point was progression-free survival in the amivantamab-lazertinib group as compared with the osimertinib group, as assessed by blinded independent central review. RESULTS: Overall, 1074 patients underwent randomization (429 to amivantamab-lazertinib, 429 to osimertinib, and 216 to lazertinib). The median progression-free survival was significantly longer in the amivantamab-lazertinib group than in the osimertinib group (23.7 vs. 16.6 months; hazard ratio for disease progression or death, 0.70; 95% confidence interval [CI], 0.58 to 0.85; P<0.001). An objective response was observed in 86% of the patients (95% CI, 83 to 89) in the amivantamab-lazertinib group and in 85% of those (95% CI, 81 to 88) in the osimertinib group; among patients with a confirmed response (336 in the amivantamab-lazertinib group and 314 in the osimertinib group), the median response duration was 25.8 months (95% CI, 20.1 to could not be estimated) and 16.8 months (95% CI, 14.8 to 18.5), respectively. In a planned interim overall survival analysis of amivantamab-lazertinib as compared with osimertinib, the hazard ratio for death was 0.80 (95% CI, 0.61 to 1.05). Predominant adverse events were EGFR-related toxic effects. The incidence of discontinuation of all agents due to treatment-related adverse events was 10% with amivantamab-lazertinib and 3% with osimertinib. CONCLUSIONS: Amivantamab-lazertinib showed superior efficacy to osimertinib as first-line treatment in EGFR-mutated advanced NSCLC. (Funded by Janssen Research and Development; MARIPOSA ClinicalTrials.gov number, NCT04487080.).

Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC.

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. METHODS: In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed. RESULTS: A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents. CONCLUSIONS: First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).

Identification and structural characterization of a mutant KRAS-G12V specific TCR restricted by HLA-A3.

Mutations in KRAS are some of the most common across multiple cancer types and are thus attractive targets for therapy. Recent studies demonstrated that mutant KRAS generates immunogenic neoantigens that are targetable by adoptive T-cell therapy in metastatic diseases. To expand mutant KRAS-specific immunotherapies, it is critical to identify additional HLA-I allotypes that can present KRAS neoantigens and their cognate T-cell receptors (TCR). Here, we identified a murine TCR specific to a KRAS-G12V neoantigen (7VVVGAVGVGK16) using a vaccination approach with transgenic mice expressing HLA-A*03:01 (HLA-A3). This TCR demonstrated exquisite specificity for mutant G12V and not WT KRAS peptides. To investigate the molecular basis for neoantigen recognition by this TCR, we determined its structure in complex with HLA-A3(G12V). G12V-TCR CDR3ß and CDR1ß formed a hydrophobic pocket to interact with p6 Val of the G12V but not the WT KRAS peptide. To improve the tumor sensitivity of this TCR, we designed rational substitutions to improve TCR:HLA-A3 contacts. Two substitutions exhibited modest improvements in TCR binding avidity to HLA-A3 (G12V) but did not sufficiently improve T-cell sensitivity for further clinical development. Our study provides mechanistic insight into how TCRs detect neoantigens and reveals the challenges in targeting KRAS-G12V mutations.

Rapid anti-myeloma activity by T cells expressing an anti-BCMA CAR with a human heavy-chain-only antigen-binding domain.

Multiple myeloma (MM) is a rarely curable malignancy of plasma cells. MM expresses B cell maturation antigen (BCMA). We developed a fully human anti-BCMA chimeric antigen receptor (CAR) with a heavy-chain-only antigen-recognition domain, a 4-1BB domain, and a CD3ζ domain. The CAR was designated FHVH33-CD8BBZ. We conducted the first-in-humans clinical trial of T cells expressing FHVH33-CD8BBZ (FHVH-T). Twenty-five patients with relapsed MM were treated. The stringent complete response rate (sCR) was 52%. Median progression-free survival (PFS) was 78 weeks. Of 24 evaluable patients, 6 (25%) had a maximum cytokine-release syndrome (CRS) grade of 3; no patients had CRS of greater than grade 3. Most anti-MM activity occurred within 2-4 weeks of FHVH-T infusion as shown by decreases in the rapidly changing MM markers serum free light chains, urine light chains, and bone marrow plasma cells. Blood CAR+ cell levels peaked during the time that MM elimination was occurring, between 7 and 15 days after FHVH-T infusion. C-C chemokine receptor type 7 (CCR7) expression on infusion CD4+ FHVH-T correlated with peak blood FHVH-T levels. Single-cell RNA sequencing revealed a shift toward more differentiated FHVH-T after infusion. Anti-CAR antibody responses were detected in 4 of 12 patients assessed. FHVH-T has powerful, rapid, and durable anti-MM activity.

Efficacy and safety of tepotinib in Asian patients with advanced NSCLC with MET exon 14 skipping enrolled in VISION.

BACKGROUND: Tepotinib, a MET inhibitor approved for the treatment of MET exon 14 (METex14) skipping NSCLC, demonstrated durable clinical activity in VISION (Cohort A + C; N = 313): objective response rate (ORR) 51.4% (95% CI: 45.8, 57.1); median duration of response (mDOR) 18.0 months (95% CI: 12.4, 46.4). We report outcomes in Asian patients from VISION (Cohort A + C) (cut-off: November 20, 2022). METHODS: Patients with advanced METex14 skipping NSCLC, detected by liquid or tissue biopsy, received tepotinib 500 mg (450 mg active moiety) once daily. PRIMARY ENDPOINT: objective response (RECIST 1.1) by independent review. Secondary endpoints included: DOR, progression-free survival (PFS), overall survival (OS), safety, and health-related quality of life (HRQoL). RESULTS: Across treatment lines in 106 Asian patients (39.6% female, 43.4% smoking history, 79.2% adenocarcinoma, 47.2% treatment-naive), ORR was 56.6% (95% CI: 46.6, 66.2), mDOR 18.5 months (10.4, ne), mPFS 13.8 months (10.8, 22.0), and mOS 25.5 months (19.3, 36.4). Consistent efficacy observed, regardless of baseline characteristics. HRQoL remained stable during treatment. Treatment-related adverse events (TRAEs) occurred in 95.3% of patients (39.6% Grade ≥3). Most common TRAEs: peripheral edema (62.3%), creatinine increase (38.7%). CONCLUSIONS: Tepotinib demonstrated robust and durable efficacy, with a manageable safety profile, in Asian patients with METex14 skipping NSCLC. CLINICAL TRIAL REGISTRATION: NCT02864992.

Effects of Early Short-Course Corticosteroids on Immune-Related Adverse Events in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Inhibitors.

INTRODUCTION: In real-world practice, most non-small cell lung cancer (NSCLC) patients receiving combined immunochemotherapy are exposed to short-course corticosteroids following immune checkpoint inhibitor (ICI) infusion to prevent chemotherapy-related adverse events. However, whether this early short-course corticosteroid use prevents immune-related adverse events (irAEs) remains unknown. METHODS: Between January 1st, 2015, and December 31st, 2020, NSCLC patients who received at least one cycle of ICI with or without chemotherapy were enrolled. Early short-course corticosteroids were defined as corticosteroids administered following ICI injection and before chemotherapy on the same day and no longer than 3 days afterward. The patients were categorized as either "corticosteroid group" or "non-corticosteroid group" depending on their exposure to early short-course corticosteroid. The frequencies of irAEs requiring systemic corticosteroid use and irAEs leading to ICI discontinuation were compared between the two groups, and exploratory survival analyses were performed. RESULTS: Among 252 eligible patients, 137 patients were categorized as "corticosteroid group" and 115 patients as "non-corticosteroid group." The corticosteroid group enriched patients in the first-line setting (n = 75, 54.7%), compared to the non-corticosteroid group (n = 28, 24.3%). Thirty patients (21.9%) in the corticosteroid group and 35 patients (30.4%) in the non-corticosteroid group developed irAEs requiring systemic corticosteroid use (odds ratio [OR], 0.64; 95% confidence interval [CI], 0.35-1.18; p = 0.15). Eight patients (5.8%) in the corticosteroid group, as compared with 18 patients (15.7%) in the non-corticosteroid group, permanently discontinued ICI due to irAEs (OR, 0.34; 95% CI, 0.12-0.85; p = 0.013). CONCLUSION: Early short-course corticosteroids following each ICI injection may reduce the rate of irAEs that lead to ICIs discontinuation, warranting further investigation of its prophylactic use to mitigate clinically significant irAEs.

MiR-574-5p activates human TLR8 to promote autoimmune signaling and lupus.

Endosomal single-stranded RNA-sensing Toll-like receptor-7/8 (TLR7/8) plays a pivotal role in inflammation and immune responses and autoimmune diseases. However, the mechanisms underlying the initiation of the TLR7/8-mediated autoimmune signaling remain to be fully elucidated. Here, we demonstrate that miR-574-5p is aberrantly upregulated in tissues of lupus prone mice and in the plasma of lupus patients, with its expression levels correlating with the disease activity. miR-574-5p binds to and activates human hTLR8 or its murine ortholog mTlr7 to elicit a series of MyD88-dependent immune and inflammatory responses. These responses include the overproduction of cytokines and interferons, the activation of STAT1 signaling and B lymphocytes, and the production of autoantigens. In a transgenic mouse model, the induction of miR-574-5p overexpression is associated with increased secretion of antinuclear and anti-dsDNA antibodies, increased IgG and C3 deposit in the kidney, elevated expression of inflammatory genes in the spleen. In lupus-prone mice, lentivirus-mediated silencing of miR-574-5p significantly ameliorates major symptoms associated with lupus and lupus nephritis. Collectively, these results suggest that the miR-574-5p-hTLR8/mTlr7 signaling is an important axis of immune and inflammatory responses, contributing significantly to the development of lupus and lupus nephritis.

Efficient matrix profile computation with Euclidean distance using Eigen transformation: Performance evaluation based on beat-to-beat interval (BBI) data.

The matrix profile serves as a fundamental tool to provide insights into similar patterns within time series. Existing matrix profile algorithms have been primarily developed for the normalized Euclidean distance, which may not be a proper distance measure in many settings. The methodology work of this paper was motivated by statistical analysis of beat-to-beat interval (BBI) data collected from smartwatches to monitor e-cigarette users' heart rate change patterns for which the original Euclidean distance ( L 2 $$ {L}_2 $$ -norm) would be a more suitable choice. Yet, incorporating the Euclidean distance into existing matrix profile algorithms turned out to be computationally challenging, especially when the time series is long with extended query sequences. We propose a novel methodology to efficiently compute matrix profile for long time series data based on the Euclidean distance. This methodology involves four key steps including (1) projection of the time series onto eigenspace; (2) enhancing singular value decomposition (SVD) computation; (3) early abandon strategy; and (4) determining lower bounds based on the first left singular vector. Simulation studies based on BBI data from the motivating example have demonstrated remarkable reductions in computational time, ranging from one-fourth to one-twentieth of the time required by the conventional method. Unlike the conventional method of which the performance deteriorates sharply as the time series length or the query sequence length increases, the proposed method consistently performs well across a wide range of the time series length or the query sequence length.

Statistical methods for predicting e-cigarette use events based on beat-to-beat interval (BBI) data collected from wearable devices.

The prevalence of e-cigarette use among young adults in the USA is high (14%). Although the majority of users plan to quit vaping, the motivation to make a quit attempt is low and available support during a quit attempt is limited. Using wearable sensors to collect physiological data (eg, heart rate) holds promise for capturing the right timing to deliver intervention messages. This study aims to fill the current knowledge gap by proposing statistical methods to (1) de-noise beat-to-beat interval (BBI) data from smartwatches worn by 12 young adult regular e-cigarette users for 7 days; and (2) summarize the de-noised data by event and control segments. We also conducted a comprehensive review of conventional methods for summarizing heart rate variability (HRV) and compared their performance with the proposed method. The results show that the proposed singular spectrum analysis (SSA) can effectively de-noise the highly variable BBI data, as well as quantify the proportion of total variation extracted. Compared to existing HRV methods, the proposed second order polynomial model yields the highest area under the curve (AUC) value of 0.76 and offers better interpretability. The findings also indicate that the average heart rate before vaping is higher and there is an increasing trend in the heart rate before the vaping event. Importantly, the development of increasing heart rate observed in this study implies that there may be time to intervene as this physiological signal emerges. This finding, if replicated in a larger scale study, may inform optimal timings for delivering messages in future intervention.

ULK1/2 Constitute a Bifurcate Node Controlling Glucose Metabolic Fluxes in Addition to Autophagy.

Metabolic reprogramming is fundamental to biological homeostasis, enabling cells to adjust metabolic routes after sensing altered availability of fuels and growth factors. ULK1 and ULK2 represent key integrators that relay metabolic stress signals to the autophagy machinery. Here, we demonstrate that, during deprivation of amino acid and growth factors, ULK1/2 directly phosphorylate key glycolytic enzymes including hexokinase (HK), phosphofructokinase 1 (PFK1), enolase 1 (ENO1), and the gluconeogenic enzyme fructose-1,6-bisphosphatase (FBP1). Phosphorylation of these enzymes leads to enhanced HK activity to sustain glucose uptake but reduced activity of FBP1 to block the gluconeogenic route and reduced activity of PFK1 and ENO1 to moderate drop of glucose-6-phosphate and to repartition more carbon flux to pentose phosphate pathway (PPP), maintaining cellular energy and redox homeostasis at cellular and organismal levels. These results identify ULK1/2 as a bifurcate-signaling node that sustains glucose metabolic fluxes besides initiation of autophagy in response to nutritional deprivation.

Upper Extremity Muscle Activation Pattern Prediction Through Synergy Extrapolation and Electromyography-Driven Modeling.

Patients with neuromuscular disease fail to produce necessary muscle force and have trouble maintaining joint moment required to perform activities of daily living. Measuring muscle force values in patients with neuromuscular disease is important but challenging. Electromyography (EMG) can be used to obtain muscle activation values, which can be converted to muscle forces and joint torques. Surface electrodes can measure activations of superficial muscles, but fine-wire electrodes are needed for deep muscles, although it is invasive and require skilled personnel and preparation time. EMG-driven modeling with surface electrodes alone could underestimate the net torque. In this research, authors propose a methodology to predict muscle activations from deeper muscles of the upper extremity. This method finds missing muscle activation one at a time by combining an EMG-driven musculoskeletal model and muscle synergies. This method tracks inverse dynamics joint moments to determine synergy vector weights and predict muscle activation of selected shoulder and elbow muscles of a healthy subject. In addition, muscle-tendon parameter values (optimal fiber length, tendon slack length, and maximum isometric force) have been personalized to the experimental subject. The methodology is tested for a wide range of rehabilitation tasks of the upper extremity across multiple healthy subjects. Results show this methodology can determine single unmeasured muscle activation up to Pearson's correlation coefficient (R) of 0.99 (root mean squared error, RMSE = 0.001) and 0.92 (RMSE = 0.13) for the elbow and shoulder muscles, respectively, for one degree-of-freedom (DoF) tasks. For more complicated five DoF tasks, activation prediction accuracy can reach up to R = 0.71 (RMSE = 0.29).

Real-world analysis of survival outcomes in advanced EGFR-mutant NSCLC patients treated with platinum-pemetrexed after EGFR-TKI treatment failure.

INTRODUCTION: EGFR tyrosine kinase inhibitors (TKIs) are the standard therapy for non-small-cell lung cancer (NSCLC) patients with EGFR-activating mutations in the first-line setting. Despite initial efficacy, resistance to EGFR-TKIs often develops, and platinum-based chemotherapy is the predominant subsequent treatment. For this study, we aimed to identify prognostic factors for overall survival (OS) and progression-free survival (PFS) among advanced EGFR-mutant NSCLC patients receiving platinum-pemetrexed after progression on EGFR-TKIs. Our analysis specifically focuses on 1st-line treatments limited to 1st- or 2nd-generation EGFR-TKIs, while not restricting later-line treatments involving osimertinib prior to chemotherapy. MATERIALS AND METHODS: From 2012 to 2017, 363 patients who received first-line treatment with first- or second-generation EGFR-TKIs, including gefitinib, erlotinib, and afatinib were enrolled. Some patients received different EGFR-TKIs, including osimertinib, as later-line treatment before platinum-pemetrexed. RESULTS: Median OS from the initiation of platinum-pemetrexed was 22.0 months and median PFS with platinum-pemetrexed was 6.2 months. In the multivariate Cox model, we identified three independent prognostic factors for better OS: postoperative recurrence (HR: 0.34, p = 0.004), first-line EGFR-TKI PFS ≥12 months (HR: 0.54, p = 0.002), and osimertinib treatment after platinum-pemetrexed (HR: 0.56, p = 0.005) while BMI <18.5 indicated poor prognosis (HR:1.76, p = 0.049). No statistically significant independent prognostic factors for PFS were found. Receiving osimertinib before platinum-pemetrexed treatment did not impact PFS with platinum-pemetrexed treatment (HR: 1.11, p = 0.64). CONCLUSION: Postoperative recurrence, first-line EGFR-TKI PFS ≥12 months and osimertinib treatment after platinum-pemetrexed predicted better OS, while BMI <18.5 predicted worse OS. Osimertinib treatment before platinum-pemetrexed treatment did not affect the efficacy of platinum-pemetrexed.

Accuracy and clinical utility of heart rate variability derived from a wearable heart rate monitor in patients undergoing major abdominal surgery.

Low heart rate variability (HRV) can potentially identify patients at risk of intraoperative hypotension. However, it is unclear whether cheaper, readily accessible consumer heart rate (HR) monitors can provide similar utility to clinical Holter electrocardiograph (ECG) monitors. The objectives of this study were (1) to assess the validity of using the Polar H10 HR monitor as an alternative to a clinical Holter ECG and (2) to test total power (TP) as a predictor of intraoperative hypotension. The primary outcome was the level of agreement between Polar H10 and Holter ECG. Twenty-three patients undergoing major abdominal surgery with general anesthesia had 5-minute HR recordings taken concurrently with both devices during a pre-anesthetic consultation. Agreement between Polar H10 and Holter ECG was compared via Bland-Altman analysis and Lin's Concordance Correlation Coefficient. Patients were divided into groups based on TP < 500 m s 2 and TP > 500 m s 2 . Intraoperative hypotension was defined as MAP < 60 mmHg, systolic blood pressure < 80 mmHg, or 35% decrease in MAP from baseline. There was substantial agreement between Polar H10 and Holter ECG for average R-R interval, TP and other HRV indices. Reduced TP (< 500 ms 2 ) had a high sensitivity (80%) and specificity (100%) in predicting intraoperative hypotension. Patients with reduced TP were significantly more likely to require vasoactive drugs to maintain blood pressure.The substantial agreement between Polar H10 and Holter ECG may justify its use clinically. The use of preoperative recordings of HRV has the potential to become part of routine preoperative assessment as a useful screening tool to predict hemodynamic instability in patients undergoing general anesthesia.

Tepotinib in Non-Small-Cell Lung Cancer with MET Exon 14 Skipping Mutations.

BACKGROUND: A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driver MET occurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population. METHODS: In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmed MET exon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of a MET exon 14 skipping mutation was detected on liquid biopsy or tissue biopsy. RESULTS: As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment. CONCLUSIONS: Among patients with advanced NSCLC with a confirmed MET exon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).

Using patient-derived tumor organoids from common epithelial cancers to analyze personalized T-cell responses to neoantigens.

Adoptive cell transfer of tumor-infiltrating lymphocytes (TIL) can mediate durable complete responses in some patients with common epithelial cancers but does so infrequently. A better understanding of T-cell responses to neoantigens and tumor-related immune evasion mechanisms requires having the autologous tumor as a reagent. We investigated the ability of patient-derived tumor organoids (PDTO) to fulfill this need and evaluated their utility as a tool for selecting T-cells for adoptive cell therapy. PDTO established from metastases from patients with colorectal, breast, pancreatic, bile duct, esophageal, lung, and kidney cancers underwent whole exomic sequencing (WES), to define mutations. Organoids were then evaluated for recognition by autologous TIL or T-cells transduced with cloned T-cell receptors recognizing defined neoantigens. PDTO were also used to identify and clone TCRs from TIL targeting private neoantigens and define those tumor-specific targets. PDTO were successfully established in 38/47 attempts. 75% were available within 2 months, a timeframe compatible with screening TIL for clinical administration. These lines exhibited good genetic fidelity with their parental tumors, especially for mutations with higher clonality. Immunologic recognition assays demonstrated instances of HLA allelic loss not found by pan-HLA immunohistochemistry and in some cases WES of fresh tumor. PDTO could also be used to show differences between TCRs recognizing the same antigen and to find and clone TCRs recognizing private neoantigens. PDTO can detect tumor-specific defects blocking T-cell recognition and may have a role as a selection tool for TCRs and TIL used in adoptive cell therapy.

Evaluation of combination treatment with DS-1205c, an AXL kinase inhibitor, and osimertinib in metastatic or unresectable EGFR-mutant non-small cell lung cancer: results from a multicenter, open-label phase 1 study.

The objective of this study was to evaluate the safety and tolerability of DS-1205c, an oral AXL-receptor inhibitor, in combination with osimertinib in metastatic or unresectable EFGR-mutant non-small cell lung cancer (NSCLC) patients who developed disease progression during EGFR tyrosine kinase inhibitor (TKI) treatment. An open-label, non-randomized phase 1 study was conducted in Taiwan, in which 13 patients received DS-1205c monotherapy at a dosage of 200, 400, 800, or 1200 mg twice daily for 7 days, followed by combination treatment with DS-1205c (same doses) plus osimertinib 80 mg once daily in 21-day cycles. Treatment continued until disease progression or other discontinuation criteria were met. At least one treatment-emergent adverse event (TEAE) was reported in all 13 patients treated with DS-1205c plus osimertinib; with ≥ 1 grade 3 TEAE in 6 patients (one of whom also had a grade 4 increased lipase level), and 6 patients having ≥ 1 serious TEAE. Eight patients experienced ≥ 1 treatment-related AE (TRAE). The most common (2 cases each) were anemia, diarrhea, fatigue, increased AST, increased ALT, increased blood creatinine phosphokinase, and increased lipase. All TRAEs were non-serious, with the exception of an overdose of osimertinib in 1 patient. No deaths were reported. Two-thirds of patients achieved stable disease (one-third for > 100 days), but none achieved a complete or partial response. No association between AXL positivity in tumor tissue and clinical efficacy was observed. DS-1205c was well-tolerated with no new safety signals in patients with advanced EGFR-mutant NSCLC when administered in combination with the EFGR TKI osimertinib. ClinicalTrials.gov ; NCT03255083.

Subtypes of Dual Users of Combustible and Electronic Cigarettes: Longitudinal Changes in Product Use and Dependence Symptomatology.

INTRODUCTION: Cross-sectional surveys found behavioral heterogeneity among dual users of combustible and electronic cigarettes. Yet, prior classification did not reflect dynamic interactions between cigarette and e-cigarette consumption, which may reveal changes in product-specific dependence. The contexts of dual use that could inform intervention were also understudied. METHODS: This study conducted secondary analysis on 13 waves of data from 227 dual users who participated in a 2-year observational study. The k-means method for joint trajectories of cigarette and e-cigarette consumption was adopted to identify the subtypes of dual users. The time-varying effect model was used to characterize the subtype-specific trajectories of cigarette and e-cigarette dependence. The subtypes were also compared in terms of use contexts. RESULTS: The four clusters were identified: light dual users, predominant vapers, heavy dual users, and predominant smokers. Although heavy dual users and predominant smokers both smoked heavily at baseline, by maintaining vaping at the weekly to daily level the heavy dual users were able to considerably reduce cigarette use. Yet, the heavy dual users' drop in cigarette dependence was not as dramatic as their drop in cigarette consumption. Predominant vapers appeared to engage in substitution, as they decreased their smoking and increased their e-cigarette dependence. They were also more likely to live in environments with smoking restrictions and report that their use of e-cigarettes reduced cigarette craving and smoking frequency. CONCLUSIONS: Environmental constraints can drive substitution behavior and the substitution behavior is able to be sustained if people find the substitute to be effective. IMPLICATIONS: This study characterizes subtypes of dual users based on the dynamic interactions between cigarette use and e-cigarette use as well as product-specific trajectories of dependence. The subtypes differ in not only sociodemographic characteristics but also contexts of cigarette and e-cigarette use. Higher motivation to use e-cigarettes to quit smoking and less permissive environment for smoking may promote substitution of cigarettes by e-cigarettes.

Retrospective and Real-time Measures of the Quantity of E-cigarette Use: An Ecological Momentary Assessment Study.

INTRODUCTION: Quantifying e-cigarette use is challenging because of the wide variety of products and the lack of a clear, objective demarcation of a use event. This study aimed to characterize the difference between retrospective and real-time measures of the quantity of e-cigarette use and identify the covariates that may account for discrepancies between the two types of measures. METHODS: This study analyzed data from 401 college student e-cigarette users in Indiana and Texas who responded to a web survey (retrospective) and 7-day ecological momentary assessments (EMA) (real-time) on their e-cigarette use behavior, dependence symptomatology, e-cigarette product characteristics, and use contexts from Fall 2019 to Fall 2021. Generalized linear mixed models were used to model the real-time measures of quantity offset by the retrospective average quantity. RESULTS: Although the number of times using e-cigarettes per day seems to be applicable to both retrospective and real-time measures, the number reported via EMA was 8.5 times the retrospective report. E-cigarette users with higher e-cigarette primary dependence motives tended to report more daily nicotine consumption via EMA than their retrospective reports (ie, perceived average consumption). Other covariates that were associated with discrepancies between real-time and retrospective reports included gender, nicotine concentration, using a menthol- or fruit-flavored product, co-use with alcohol, and being with others when vaping. CONCLUSIONS: The study found extreme under-reporting of e-cigarette consumption on retrospective surveys. Important covariates identified to be associated with higher than average consumption may be considered as potential targets for future vaping interventions. IMPLICATIONS: This is the first study that characterizes the direction and magnitude of the difference between retrospective and real-time measures of the quantity of e-cigarette use among young adults-the population most likely to use e-cigarettes. An average retrospective account of vaping events per day may significantly underestimate e-cigarette use frequency among young adults. The lack of insight into the degree of consumption among users with heavy primary dependence motives illustrates the importance of incorporating self-monitoring into cessation interventions.

Afatinib for the treatment of non-small-cell lung cancer with unusual EGFR mutations: a plain language summary.

WHAT IS EGFR & WHAT IS AFATINIB?: EGFR is a protein on cells that helps control their growth and division. Mutations in the gene for EGFR can cause cancer, including some cases of non-small-cell lung cancer (NSCLC). Afatinib is a medicine that blocks mutated EGFR and helps kill cancer cells. Many different types of EGFR mutation have been identified in people with NSCLC. Over three quarters of cases are caused by two types of EGFR mutation, known as common EGFR mutations, but some cases are caused by unusual/uncommon EGFR mutations. People with NSCLC who have these unusual/ uncommon EGFR mutations are often excluded from clinical trials. Consequently, researchers don't really know how well medicines like afatinib work in these people. WHAT IS THIS SUMMARY ABOUT?: This is a summary of a study reporting findings from a large database of people with non-small-cell lung cancer (also called NSCLC) who have unusual or uncommon changes in a gene called EGFR and who received afatinib. The researchers used the database to see how effective afatinib is in people who have different types of unusual EGFR mutation. Afatinib seems to work well in people with NSCLC who have not already been treated. Part of the study also looked at people who had received a similar treatment, called osimertinib, in the past compared to those who had not been treated with this medicine. WHAT DID THE RESEARCHERS FIND?: The researchers found that afatinib works well in most people with NSCLC who have unusual/uncommon EGFR mutations, although it seems to work better against certain types of these mutations than others. WHAT DO THE RESULTS OF THE STUDY MEAN?: The researchers concluded that afatinib is a treatment option for most people with NSCLC and unusual/uncommon EGFR mutations. It is important for doctors to identify the precise type of EGFR mutation in a tumor before starting treatment.