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Background Liquid biopsy circulating tumor DNA (ctDNA) mutational analysis holds great promises for precision medicine targeted therapy and more effective cancer management. However, its wide adoption is hampered by high cost and long turnaround time of sequencing assays, or by inadequate analytical sensitivity of existing portable nucleic acid tests to mutant allelic fraction in ctDNA. Methods We developed a ctDNA Epidermal Growth Factor Receptor (EGFR) mutational assay using giant magnetoresistive (GMR) nanosensors. This assay was validated in 36 plasma samples of non-small cell lung cancer patients with known EGFR mutations. We assessed therapy response through follow-up blood draws, determined concordance between the GMR assay and radiographic response, and ascertained progression-free survival of patients. Results The GMR assay achieved analytical sensitivities of 0.01% mutant allelic fraction. In clinical samples, the assay had 87.5% sensitivity (95% CI = 64.0—97.8%) for Exon19 deletion and 90% sensitivity (95% CI = 69.9—98.2%) for L858R mutation with 100% specificity; our assay detected T790M resistance with 96.3% specificity (95% CI = 81.7–99.8%) with 100% sensitivity. After 2 weeks of therapy, 10 patients showed disappearance of ctDNA by GMR (predicted responders), whereas 3 patients did not (predicted nonresponders). These predictions were 100% concordant with radiographic response. Kaplan-Meier analysis showed responders had significantly (P Conclusions The GMR assay has high diagnostic sensitivity and specificity and is well suited for detecting EGFR mutations at diagnosis and noninvasively monitoring treatment response at the point-of-care.

Radiologic screening of high-risk adults reduces lung-cancer-related mortality1,2; however, a small minority of eligible individuals undergo such screening in the United States3,4. The availability of blood-based tests could increase screening uptake. Here we introduce improvements to cancer personalized profiling by deep sequencing (CAPP-Seq)5, a method for the analysis of circulating tumour DNA (ctDNA), to better facilitate screening applications. We show that, although levels are very low in early-stage lung cancers, ctDNA is present prior to treatment in most patients and its presence is strongly prognostic. We also find that the majority of somatic mutations in the cell-free DNA (cfDNA) of patients with lung cancer and of risk-matched controls reflect clonal haematopoiesis and are non-recurrent. Compared with tumour-derived mutations, clonal haematopoiesis mutations occur on longer cfDNA fragments and lack mutational signatures that are associated with tobacco smoking. Integrating these findings with other molecular features, we develop and prospectively validate a machine-learning method termed 'lung cancer likelihood in plasma' (Lung-CLiP), which can robustly discriminate early-stage lung cancer patients from risk-matched controls. This approach achieves performance similar to that of tumour-informed ctDNA detection and enables tuning of assay specificity in order to facilitate distinct clinical applications. Our findings establish the potential of cfDNA for lung cancer screening and highlight the importance of risk-matching cases and controls in cfDNA-based screening studies.

Stereotactic ablative radiation therapy (SABR) results in high rates of primary tumor control for early-stage non-small cell lung cancer (NSCLC). For patients with isolated hilar or mediastinal nodal recurrence (INR) after SABR, the optimal salvage treatment strategy is unclear. The purpose of this study was to determine the rate of INR after SABR for early-stage NSCLC and to describe patterns of care and treatment outcomes after salvage therapy.This retrospective cohort study included 342 patients with stage T1-3N0M0 NSCLC treated with definitive SABR from 2003 to 2018. We evaluated the incidence of INR and baseline factors between patients who did and did not experience INR. Among patients who experienced INR, we described treatment patterns and outcomes including overall survival (OS) and progression free survival (PFS) from the time of nodal failure using the Kaplan-Meier method.With a median follow-up of 3.3 years, the 3-year INR rate was 10.6% (95% CI, 6.6%-13.4%). Among the 34 patients experiencing INR, the 3-year rates of OS and PFS were 39.3% (24.4%-63.3%) and 26.7% (14.1%-0.3%), respectively. The 34 patients with INR were treated with radiation therapy alone (26.7%), concurrent chemoradiation therapy (43.3%), chemotherapy alone (13.3%), or observation (16.7%). Patients treated with concurrent chemoradiation therapy had the best survival outcomes, with a 3-year OS and PFS of 81.5% (61.1%-100.0%) and 63.9% (40.7%-100.0%), respectively. Of the patients treated with salvage radiation therapy or concurrent chemoradiation therapy, 14.3% experienced grade 3 toxic effects, and no patients had grade ≥4 toxic effects.In this study, INR occurred in approximately 10% of patients treated with SABR for early-stage NSCLC. The highest rates of OS and PFS among patients with INR were observed in those treated with salvage chemoradiation therapy.

Immunotherapy has transformed lung cancer care in recent years. In addition to providing durable responses and prolonged survival outcomes for a subset of patients with heavily pretreated non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs)— either as monotherapy or in combination with other ICIs or chemotherapy—have demonstrated benefits in first-line therapy for advanced disease, the neoadjuvant and adjuvant settings, as well as in additional thoracic malignancies such as small-cell lung cancer (SCLC) and mesothelioma. Challenging questions remain, however, on topics including therapy selection, appropriate biomarker-based identification of patients who may derive benefit, the use of immunotherapy in special populations such as people with autoimmune disorders, and toxicity management. Patient and caregiver education and support for quality of life (QOL) is also important to attain maximal benefit with immunotherapy. To provide guidance to the oncology community on these and other important concerns, the Society for Immunotherapy of Cancer (SITC) convened a multidisciplinary panel of experts to develop a clinical practice guideline (CPG). This CPG represents an update to SITC’s 2018 publication on immunotherapy for the treatment of NSCLC, and is expanded to include recommendations on SCLC and mesothelioma. The Expert Panel drew on the published literature as well as their clinical experience to develop recommendations for healthcare professionals on these important aspects of immunotherapeutic treatment for lung cancer and mesothelioma, including diagnostic testing, treatment planning, immune-related adverse events, and patient QOL considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers using immunotherapy to treat patients with lung cancer or mesothelioma.

About 3%-5% of mNSCLC have ERBB2 (HER2) alterations, but currently, there are no FDA-approved targeted therapies for this indication. We compared treatment response between trastuzumab-based and non-targeted regimens in ERBB2-mutant mNSCLC.This retrospective, single-institution study included patients with mNSCLC with ERBB2 alterations identified by next-generation sequencing. Best overall response was determined using Response Evaluation Criteria in Solid Tumors 1.1.We identified 3 groups of patients: ERBB2-mutant/EGFR-wildtype mNSCLC (n = 33), ERBB2-amplified/EGFR-wildtype mNSCLC without concurrent ERBB2 mutations (n = 6), and ERBB2-altered/EGFR-mutant mNSCLC (n = 8). Observed mutations included A775_G776insYVMA (n = 23), Gly778_Pro780dup (n = 4), Ser310Phe (n = 3), and others (n = 5). Among the 33 with ERBB2-mutant/EGFR-wildtype mNSCLC, those with and without A775_G776insYVMA had significantly different median overall survival (OS) of 17.7 and 52.9 months, respectively (Cox regression multivariable HR: 5.03, 95% CI: 1.37-18.51, P = .02). In those with mNSCLC with A775_G776insYVMA, trastuzumab-based therapies were associated with greater OS (20.3 vs. 9.8 months; multivariable HR: 0.19, 95% CI: 0.04-0.87, P = .032). Objective response and disease control rates (median tumor size change) in the 33 patients with ERBB2-mutant/EGFR-wildtype mNSCLC were 40.0% and 80.0% (-35.8%), respectively, for patients treated with trastuzumab deruxtecan; 0% and 30.0% (-5.2%) for trastuzumab emtansine; and 7.1% and 50.0% (-13.0%) for trastuzumab/chemotherapy combinations.In ERBB2-mutant/EGFR-wildtype mNSCLC, while most trastuzumab-based regimens had modest activity in this real-world analysis, trastuzumab deruxtecan had highest response rates and best tumor size reduction. Receipt of any trastuzumab-based regimen was associated with greater OS with A775_G776insYVMA. There remains an unmet need for approved targeted therapies for ERBB2-mutant/EGFR-wildtype NSCLC.

The evidence of combined therapies of multi-target agents in first-line treatment of advanced non-small cell lung cancer (NSCLC) was limited. This study aimed to evaluate the safety and efficacy of anlotinib combined with epidermal growth factor receptor (This open-label, three-arm, prospective study (NCT03628521) enrolled untreated locally advanced/metastatic NSCLC patients. Patients withA total of 30, 30, and 22 patients were enrolled in cohorts A, B, and C, respectively. There were 3 patients did not complete the treatment in cohort A. In cohorts A and B, ≥ grade 3 treatment-related adverse events (TRAEs) occurred in 77.3% and 60.0% of patients, respectively. The most common TRAEs were rash (10.0%) and decreased platelet count (30.0%) in cohorts A and B, respectively. The ORRs were 92.9% and 60.0% in cohorts A and B, respectively, and DCRs were 96.4% and 96.7%, respectively. The ORR and incidence of ≥ grade 3 TRAEs of cohort C were, which 72.7% and 54.5%, which had been published previously. Median PFSs [95% confidence interval (CI)] were 21.6 (15.6 to 24.9), 13.0 [10.5 to not estimated (NE)], and 15.6 (12.9 to NE) months in cohorts A, B, and C, respectively. Median OS was 28.1 (95% CI: 21.82 to NE) months in cohort B. The 24-month OS rates in cohorts A and C were 87.1% and 83.9%, respectively.Anlotinib-based combinations with

Although obesity in trauma patients is accepted as a risk factor for postoperative complications, recent literature offers conflicting evidence regarding the effect of body mass index (BMI) on mortality in trauma patients undergoing laparotomy. To address this question, we examined the patient population of a Level 1 Trauma Center during a 3-year period to compare mortality rates and other outcomes between BMI groups undergoing laparotomy. Through retrospective chart review of electronic medical records, with subsequent stratification of data based on BMI, we found that mortality, injury severity score, and hospital length of stay all increase significantly with each incremental increase in BMI class. From these data, we concluded that higher BMI class leads to greater morbidity and mortality in trauma patients undergoing laparotomy at this institution.

In this multicohort retrospective analysis, the genotype clustering frequency ranked method was used for molecular clustering of tumor genomic data from 776 patients withGenotype clustering identified eight molecular subgroups and the CBM characterized their shared cancer pathway characteristics:CBM identified distinct PD-(L)1 immunotherapy sensitivity among molecular subgroups of

The extent of grey matter demyelination and neurodegeneration in the progressive multiple sclerosis (PMS) brains at post-mortem associates with more severe disease. Regional tissue atrophy, especially affecting the cortical and deep grey matter, including the thalamus, is prognostic for poor outcomes. Microglial and complement activation are important in the pathogenesis and contribute to damaging processes that underlie tissue atrophy in PMS. We investigated the extent of pathology and innate immune activation in the thalamus in comparison to cortical grey and white matter in blocks from 21 cases of PMS and 10 matched controls. Using a digital pathology workflow, we show that the thalamus is invariably affected by demyelination and had a far higher proportion of active inflammatory lesions than forebrain cortical tissue blocks from the same cases. Lesions were larger and more frequent in the medial nuclei near the ventricular margin, whilst neuronal loss was greatest in the lateral thalamic nuclei. The extent of thalamic neuron loss was not associated with thalamic demyelination but correlated with the burden of white matter pathology in other forebrain areas (Spearman r = 0.79, p 0.0001). Only thalamic neuronal loss, and not that seen in other forebrain cortical areas, correlated with disease duration (Spearman r = -0.58, p = 0.009) and age of death (Spearman r = -0.47, p = 0.045). Immunoreactivity for the complement pattern recognition molecule C1q, and products of complement activation (C4d, Bb and C3b) were elevated in thalamic lesions with an active inflammatory pathology. Complement regulatory protein, C1 inhibitor, was unchanged in expression. We conclude that active inflammatory demyelination, neuronal loss and local complement synthesis and activation in the thalamus, are important to the pathological and clinical disease outcomes of PMS.

Introduction: Immune checkpoint inhibitors (ICIs) are monoclonal antibodies used to activate the immune system against tumor cells. Despite therapeutic benefits, ICIs have the potential to cause immune related adverse events (irAE) such as myocarditis, a rare but serious side effect with up to 50% mortality in affected patients. Histologically, patients with ICI myocarditis have lymphocytic infiltrates in the heart, implicating T-cell-mediated mechanisms. However, the precise pathologic immune subsets and molecular changes in ICI myocarditis are unknown. Hypothesis: We hypothesize that ICI myocarditis is associated with significant quantitative and molecular changes in pathogenic immune cell subsets. Methods: To identify immune subset(s) associated with ICI myocarditis, we performed time-of-flight mass cytometry (CyTOF) on peripheral blood mononuclear cells from 40 patients and controls with autoimmune adverse events (irAE) on ICI including four patients with ICI myocarditis. We also profiled 15 patients/controls using single cell T-cell receptor (TCR) sequencing and RNA sequencing (scRNA-seq) with feature barcoding for surface marker expression confirmation. Results: With both methods, we found expansion of cytotoxic CD8+ T effector cells re-expressing CD45RA (Temra CD8+ cells) in ICI myocarditis patients compared to controls. Using TCR sequencing, these CD8+ Temra cells were clonally expanded in myocarditis patients. Transcriptomic analysis of these Temra CD8+ clones confirmed a highly activated and cytotoxic phenotype with expression of granzyme/perforin. Longitudinal study demonstrated progression of these Temra CD8+ cells into an exhausted phenotype two months after treatment with glucocorticoids. Differential expression of proinflammatory chemokines (CCL4/CCL4L2/CCL5) was uncovered in clonally expanded Temra CD8+ cells, and ligand-receptor analysis implicated their regulation of other inflammatory cells such as monocytes and NK cells. Conclusions: Clonal cytotoxic Temra CD8+ cells are significantly increased in patients with ICI myocarditis, and have unique transcriptional changes, including upregulation of chemokines CCL4/CCL4L2/CCL5, which may serve as attractive diagnostic/therapeutic targets.

We conducted a systematic literature review to identify evidence for cabozantinib activity in patients with solid tumors after prior checkpoint inhibitor (CPI) therapy.The review was conducted according to PRISMA guidelines and registered with PROSPERO (CRD42021259873). MEDLINE®, Embase, and the Cochrane Library were searched on 19 May 2021 to identify publications reporting the efficacy/effectiveness and safety/tolerability of cabozantinib in patients with solid tumors who had received prior CPI-based therapy. Publications were screened by one reviewer with uncertainties resolved by a second and/or the full author group. Risk of bias was assessed using Gradingof Recommendations Assessment, Development and Evaluation (GRADE) for clinical trials and the Newcastle-Ottawa Scale (NOS) for observational studies.Of 669 publications screened, 21 were eligible: 18 reported data on renal cell carcinoma, and one each for hepatocellular carcinoma, metastatic urothelial carcinoma, and non-small cell lung cancer. Of six trial publications, three reported moderate-quality evidence and three low-quality evidence. Of 15 observational studies, NOS scores ranged from 3 to 6, suggesting a high potential for uncertainty. The studies consistently reported clinical activity for cabozantinib after CPI therapy, across treatment lines and tumor types, with no new safety signals. The findings were limited by the quality and quantity of available data.Cabozantinib appears to have anti-tumor activity after prior CPI therapy in patients with solid tumors. Our results are driven largely by studies in renal cell carcinoma. Evidence from ongoing phase 3 trials is required to establish further the role of cabozantinib after CPI therapy.

Introduction: After the development of acquired resistance to osimertinib, the standard-of-care treatment for advanced EGFR-mutated NSCLC is chemotherapy. Whether afatinib, a pan-ErbB family tyrosine kinase inhibitor, is active after progression on osimertinib is unknown. Methods: We conducted a single-institution retrospective analysis of patients with advanced EGFR-mutated NSCLC who received afatinib-containing therapy after progression on osimertinib. Kaplan-Meier analyses evaluated progression-free survival (PFS) and overall survival (OS) from initiation of afatinib. Results: After progression on first (N=3) or second-line plus (N=12) osimertinib, 15 patients received afatinib monotherapy (N=3), afatinib and cetuximab (N=10), or afatinib and bevacizumab (N=2). The objective response rate was 6.7% and disease control rate was 53.3%. Median PFS was 2.5 months and median OS was 7.7 months. Median PFS of ≥ 6 months versus < 6 months on osimertinib was associated with a significantly greater median PFS on afatinib (4.0 versus 1.4 months; P=0.003), although there was no significant difference in median OS (9.3 versus 6.6 months; P=0.123). Best response of stable disease/partial response versus progressive disease on osimertinib was associated with a significantly greater median PFS on afatinib (3.4 versus 1.6 months; P=0.036) and a significantly greater median OS (8.7 versus 4.6 months; P=0.017). Conclusion: Afatinib-containing therapy had limited activity in patients with EGFR-mutated NSCLC after progression on osimertinib in this cohort of mostly second-line plus osimertinib. Response and longer PFS to prior osimertinib may be predictive of response to afatinib. Strategies based on osimertinib resistance mechanisms may further define the role of subsequent afatinib.

Structured Abstract Objectives The purpose of this study is to determine whether various serum marker levels [C-reactive protein (CRP), white blood cell (WBC) count, glucose] or body temperature at admission are associated with severity of odontogenic infections. Study Design This retrospective chart review of patients admitted to the hospital for treatment of severe odontogenic infections (SOIs) over a five-year period (2016- 2020) assigned patients with a severity score (SS) of greater than or equal to five to Group A and those with a SS of less than five to Group B. Serum marker levels and temperature at admission were collected, and comparisons between Group A and Group B were conducted for serum marker levels and body temperature at admission using two sample t-tests. Results The mean serum CRP and temperature at admission between the two groups was not statistically significant (p > 0.05). The mean WBC count and serum glucose at admission between the two groups was statistically significant (p = 0.001 and p = 0.036, respectively). Conclusions This study demonstrates that serum glucose and WBC at admission are significantly higher in patients with more severe SOIs. In addition, serum CRP and body temperature at admission are not adequate prognostic indicators of odontogenic infection severity.

Background Patient reported outcomes (PROs) have been associated with improved symptom management and quality of life in patients with cancer. However, the implementation of PROs in an academic clinical practice has not been thoroughly described. Here we report on the execution, feasibility and healthcare utilization outcomes of an electronic PRO (ePRO) application for cancer patients at an academic medical center. Methods We conducted a randomized trial comparing an experimental ePRO arm to standard of care in patients with advanced cancer in the thoracic, gastrointestinal, and genitourinary oncology groups at Stanford Cancer Center from March 2018 to November 2019. We describe the pre-implementation, implementation, and post-implementation phases of the ePRO arm, technological barriers, electronic health record (EHR) integration, clinician burden, and patient data privacy and security. Feasibility was pre-specified to be at least 70% completion of all questionnaires. Acceptability was based on patient and clinician feedback. Ambulatory healthcare utilization was assessed by reviewing numbers of phone messages, electronic portal messages, and referrals for supportive care. Results Of 617 ePRO questionnaires sent to 72 patients, 445 (72%) were completed. Most clinicians (87.5%) and patients (93%) felt neutral or positive about the ePRO tool’s ease of use. Exposure to ePRO did not cause a measurable change in ambulatory healthcare utilization, with a median of less than two phone messages and supportive care referrals, and 5–6 portal messages. Conclusions Web-based ePRO tools for patients with advanced cancer are feasible and acceptable without increasing clinical burden. Key lessons include the importance of pilot testing, engagement of stakeholders at all levels, and the need for customization by disease group. Future directions for this work include completion of EHR integration, expansion to other centers, and development of integrated workflows for routine clinical practice.

This chapter explores the implications of Michel Foucault’s concept of “governmentality” for grand strategy. It argues that debates on governmentality and grand strategy share an interest in wider conditions and practices of government that extend beyond strategic decision-making. They also mirror each other in analyzing the rational frameworks that accompany and support practices of government and strategy. The chapter reflects on the work of Sir Basil Liddell Hart in this light, particularly his focus on conditions of strategic success beyond war fighting. The argument is that governmentality offers a way to critically engage with grand-strategic discourses and their historically situated assumptions about the nature and scope of government. The chapter concludes with a brief case study on the relationship between foreign development aid, grand strategy, and governmentality.

Introduction : Patients with EGFR-mutant lung cancer who have had disease progression on osimertinib commonly receive platinum doublet chemotherapy, but whether adding immunotherapy or bevacizumab provides additional benefit is unknown. Methods : This was a retrospective analysis at 2 university-affiliated institutions. Patients with EGFR-mutant lung cancer who had progression on osimertinib and received next-line therapy with platinum doublet chemotherapy (chemo), platinum doublet chemotherapy plus immunotherapy (chemo-IO), or platinum doublet chemotherapy plus bevacizumab (chemo-bev), were identified; patients who continued osimertinib with these regimens were included. Efficacy outcomes including duration on treatment (DOT) and overall survival (OS) from the start of chemotherapy were assessed. Associations of treatment regimen with outcomes were evaluated using adjusted Cox regression models, using pairwise comparisons between groups. Results : 104 patients were included: 57 received chemo, 12 received chemo-IO, and 35 received chemo-bev. In adjusted models, patients who received chemo-IO had worse OS than did those who received chemo (hazard ratio (HR) 2.66, 95% CI 1.25-5.65; p=0.011) or those who received chemo-bev (HR 2.37, 95% CI 1.09-5.65; p=0.030). A statistically significant difference in OS could not be detected in patients who received chemo-bev versus those who received chemo (HR 1.50, 95% CI 0.84-2.69; p=0.17). Conclusions : In this retrospective study, giving immunotherapy with platinum doublet chemotherapy after progression on osimertinib was associated with a worse OS compared with platinum doublet chemotherapy alone. Platinum doublet chemotherapy without immunotherapy (with consideration of continuation of osimertinib, in selected cases) is a reasonable choice in this setting, while we await results of clinical trials examining optimal next-line chemotherapy-based regimens in EGFR-mutant lung cancer. Micro Abstract : Optimal treatment of EGFR-mutated lung cancer after progression on osimertinib is unknown. We retrospectively evaluated outcomes in patients who received platinum doublet chemotherapy alone or in combination with immunotherapy or bevacizumab. We found that the addition of immunotherapy to chemotherapy was associated with worse survival; statistically significant differences in survival could not be detected with the addition of bevacizumab to chemotherapy.

Circulating tumor DNA (ctDNA) molecular residual disease (MRD) following curative-intent treatment strongly predicts recurrence in multiple tumor types, but whether further treatment can improve outcomes in patients with MRD remains unclear. We applied CAPP-Seq ctDNA analysis to 218 samples from 65 patients receiving chemoradiation therapy (CRT) for locally advanced NSCLC, including 28 patients receiving consolidation immune checkpoint inhibition (CICI). Patients with undetectable ctDNA after CRT had excellent outcomes whether or not they received CICI. Among such patients, one died from CICI-related pneumonitis, highlighting the potential utility of only treating patients with MRD. In contrast, patients with MRD after CRT who received CICI had significantly better outcomes than patients who did not receive CICI. Furthermore, the ctDNA response pattern early during CICI identified patients responding to consolidation therapy. Our results suggest that CICI improves outcomes for NSCLC patients with MRD and that ctDNA analysis may facilitate personalization of consolidation therapy.

Purpose: Activation of NFE2L2 has been linked to chemoresistance in cell line models. Recently, somatic mutations that activate NFE2L2, including mutations in NFE2L2, KEAP1, or CUL3, have been found to be associated with poor outcomes in patients with non–small cell lung cancer (NSCLC). However, the impact of these mutations on chemoresistance remains incompletely explored. Experimental Design: We investigated the effect of Keap1 deletion on chemoresistance in cell lines from Trp53-based mouse models of lung squamous cell carcinoma (LSCC) and lung adenocarcinoma (LUAD). Separately, we identified 51 patients with stage IV NSCLC with KEAP1, NFE2L2, or CUL3 mutations and a matched cohort of 52 wild-type patients. Time to treatment failure after first-line platinum doublet chemotherapy and overall survival was compared between the two groups. Results: Deletion of Keap1 in Trp53-null murine LUAD and LSCC resulted in increased clonogenic survival upon treatment with diverse cytotoxic chemotherapies. In patients with NSCLC, median time to treatment failure (TTF) after first-line chemotherapy for the KEAP1/NFE2L2/CUL3-mutant cohort was 2.8 months compared with 8.3 months in the control group (P < 0.0001). Median overall survival (OS) was 11.2 months in the KEAP1/NFE2L2/CUL3-mutant group and 36.8 months in the control group (P = 0.006). Conclusions: Keap1 deletion confers chemoresistance in murine lung cancer cells. Patients with metastatic NSCLC with mutations in KEAP1, NFE2L2, or CUL3 have shorter TTF and OS after first-line platinum doublet chemotherapy compared with matched controls. Novel approaches for improving outcomes in this subset of patients with NSCLC are therefore needed.

Contains fulltext : 215810.pdf (Publisher’s version ) (Closed access) BACKGROUND: Anti-PD1/PD-L1 directed immune checkpoint inhibitors (ICI) are widely used to treat patients with advanced non-small-cell lung cancer (NSCLC). The activity of ICI across NSCLC harboring oncogenic alterations is poorly characterized. The aim of our study was to address the efficacy of ICI in the context of oncogenic addiction. PATIENTS AND METHODS: We conducted a retrospective study for patients receiving ICI monotherapy for advanced NSCLC with at least one oncogenic driver alteration. Anonymized data were evaluated for clinicopathologic characteristics and outcomes for ICI therapy: best response (RECIST 1.1), progression-free survival (PFS), and overall survival (OS) from ICI initiation. The primary end point was PFS under ICI. Secondary end points were best response (RECIST 1.1) and OS from ICI initiation. RESULTS: We studied 551 patients treated in 24 centers from 10 countries. The molecular alterations involved KRAS (n = 271), EGFR (n = 125), BRAF (n = 43), MET (n = 36), HER2 (n = 29), ALK (n = 23), RET (n = 16), ROS1 (n = 7), and multiple drivers (n = 1). Median age was 60 years, gender ratio was 1 : 1, never/former/current smokers were 28%/51%/21%, respectively, and the majority of tumors were adenocarcinoma. The objective response rate by driver alteration was: KRAS = 26%, BRAF = 24%, ROS1 = 17%, MET = 16%, EGFR = 12%, HER2 = 7%, RET = 6%, and ALK = 0%. In the entire cohort, median PFS was 2.8 months, OS 13.3 months, and the best response rate 19%. In a subgroup analysis, median PFS (in months) was 2.1 for EGFR, 3.2 for KRAS, 2.5 for ALK, 3.1 for BRAF, 2.5 for HER2, 2.1 for RET, and 3.4 for MET. In certain subgroups, PFS was positively associated with PD-L1 expression (KRAS, EGFR) and with smoking status (BRAF, HER2). CONCLUSIONS: : ICI induced regression in some tumors with actionable driver alterations, but clinical activity was lower compared with the KRAS group and the lack of response in the ALK group was notable. Patients with actionable tumor alterations should receive targeted therapies and chemotherapy before considering immunotherapy as a single agent.

Objectives There are limited treatment options for patients with thymic malignancies. Here we present data supporting treatment with single agent amrubicin, a third generation anthracycline and topoisomerase II inhibitor. Materials and methods This was a phase 2 open-label, single arm trial of amrubicin in patients with thymoma (T) or thymic carcinoma (TC), conducted at two academic institutions. Patients were included if they had received at least one prior chemotherapy regimen. The first 18 patients received amrubicin at 40 mg/m2 IV days 1–3 repeated every 3-weeks. Due to the high incidence of febrile neutropenia, dosing was subsequently amended to 35 mg/m2 for the final 15 patients. Results A total of 33 patients (14 T/19 TC) were enrolled from 2011 to 2014. Median number of prior therapies was 2. Best response included 6 partial responses, 21 stable disease, and 6 progressive disease (all TC). Objective response rate was 18% (90% exact binomial CI 8.2%–32.8%; T = 4/14 (29%), TC = 2/19 (11%)). Median progression-free survival was 7.7 months (T: 8.3 months; TC: 7.3) and median overall survival was 29.7 months (T: 54.1 months; TC: 18 months). There was a high rate of febrile neutropenia (7 patients) that occurred despite a reduction in amrubicin dose and one related death. Five patients had reduction in LVEF below 50% during the course of treatment resulting in treatment discontinuation in one patient. Conclusion Amrubicin shows promise as a single agent in heavily pre-treated patients with thymic malignancies. Notable side effects include febrile neutropenia and the use of growth factor support is essential. Further investigation of this agent is warranted.

Objectives For patients with Epidermal Growth Factor Receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), frontline EGFR-tyrosine kinase inhibitor (TKI) therapy compared to chemotherapy improves outcomes. However, resistance to these agents uniformly develops. Recently, mutations in the KEAP1-NFE2L2 pathway have been implicated as a potential mechanism of acquired EGFR TKI resistance. Materials and methods We examined all patients with metastatic NSCLC with mutations in both EGFR and KEAP1/NFE2L2/CUL3 identified on next generation sequencing from 2015 - 2018. These patients were compared to a NSCLC control cohort with mutations in EGFR and wild type in KEAP1/NFE2L2/CUL3 matched on the basis of sex, smoking status, age and race. Time to treatment failure on EGFR TKI therapy and overall survival were examined. Results Among 228 EGFR mutant NSCLCs, 17 (7%) also carried mutations in KEAP1, NFE2L2, or CUL3. The most common co-mutation in both the KEAP1/NFE2L2/CUL3 mutant and wild-type cohort was TP53. Patients with KEAP1/NFE2L2/CUL3 mutations had a shorter median time to treatment failure on EGFR TKI (4.7 months) compared with the wild-type matched cohort (13.0 months), p= 0.0014. There was no difference in overall survival. Conclusion For NSCLC patients with mutations in EGFR, co-mutations in KEAP1/NFE2L2/CUL3 are associated with significantly decreased time to treatment failure. Our results suggest that these mutations represent a mechanism of intrinsic resistance to TKI treatment.

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The mesenchymal-to-epithelial transition (MET) gene is altered and becomes a driver mutation in up to 5% of non-small-cell lung cancer (NSCLC). We report our institutional experience treating patients with MET exon 14 skipping (METex14) mutations, including responses to the MET inhibitors crizotinib and cabozantinib. We identified cases of NSCLC with METex14 mutations using an institutionally developed or commercial next-generation sequencing assay. We assessed patient and disease characteristics by retrospective chart review. Some patients were treated off-label by the physician with crizotinib or cabozantinib, and tumor responses to these agents were assessed. A total of 15 patients with METex14-mutated NSCLC were identified, predominantly male (n=10) with a smoking history (60%) and a median age of 74.0 years. No other actionable somatic mutations were detected. Stage distribution included 26.7% stage I, 6.7% stage II, 6.7% stage III, and 60.0% stage IV. Among patients treated with crizotinib or cabozantinib (n=6), three patients showed partial response and one patient showed stable disease on the basis of RECIST criteria. Four patients experienced side effects requiring drug holiday, reduction, or cessation. Our findings highlight the diversity in presentation and histology of NSCLC with METex14 mutations, which were found in the absence of other actionable driver mutations. We observed evidence of tumor response to crizotinib and cabozantinib, supporting the previous reports that METex14 mutations in NSCLC are actionable driver events.

‘Kettling’ has emerged in recent decades as an established, if controversial, tactic of public order policing. Departing from a historical emphasis on dispersal, kettling instead acts to contain protesters within a police cordon for sustained periods of time. This article elaborates upon the spatial and temporal logics of kettling by investigating the conditions of its historical emergence. We argue that kettling should be understood as a territorial strategy that co-evolved in relation to forms of disruptive protest. Whereas techniques of crowd dispersal serve to diffuse a unified collective, ‘kettling’ aims to capture the volatile intensities of public dissent and exhaust its political energies. Drawing on police manuals, media coverage, accounts from activists and expert interviews, we show how the ‘kettle’ re-territorializes protest by acting on its spatio-temporal and affective constitution. By fabricating an inner outside of the urban milieu, freezing the time of collective mobilization and inducing debilitating affects such as fear and boredom, kettling intervenes into the scene of political subjectification that each congregation of protesting bodies seeks to fashion.

278 Background: Regular distress screening of patients with cancer is mandated by cancer care guidelines, with 25-50% of patients with cancer experiencing some level of distress. The COVID-19 pandemic amplified symptoms of distress and shifted oncologic care delivery towards telemedicine. In light of challenges faced with implementation of such screening, especially during this pandemic, we sought to assess the feasibility of implementing patient-focused distress screening at a large academic cancer center and its associated network sites. Methods: We designed a modified distress screening tool with reflexive suicidality and mental health screening consisting of 1) Wellness Reflection, a questionnaire that incorporates questions from Patient-Reported Outcomes Measurement Information System-Global Health (PROMIS-GH) to monitor patients’ physical, mental, and social health and to assess patients’ needs for extra support, and 2) modified Patient Health Questionnaire 2+9 (PHQ 2+9) tool to screen for depression and suicide risk. This tool was used to triage patients in need of further assessment by the clinical team, including consideration for referrals to cancer supportive services. The two-tiered distress screening tool was delivered to patients at Stanford Cancer Center and 5 affiliate sites for in-person clinic visits starting September 2019. The Wellness Reflection was launched starting June 2020 for video visits. Results: From October 1, 2019 to May 14, 2021, 147,165 questionnaires representing 46,341 patients were collected. The overall Wellness Reflection questionnaire response rate was 55%; the video visit questionnaire response rate was ̃70%, higher than the in-person visit response rate of ̃50%. About 6% of questionnaires analyzed showed a request for more support, most commonly emotional and physical/symptom support, and this was consistent during the COVID-19 pandemic. 18.6% of questionnaire responses screened positive for further assessment, and those that triggered reflexive suicidality screening had a 17% positive PHQ 2+9 rate. Following assessment, 13,631 referrals to cancer supportive services were generated. Conclusions: The adoption of commonly available patient-reported outcome tools, including PROMIS-GH and PHQ 2+9, as a large-scale distress screening method for both in-person and tele-health clinic visits during the COVID-19 pandemic is feasible at a large academic cancer center and network sites. The volumes of positive screens and referrals were lower than expected despite broader implementation of distress screening and amplified symptoms of distress due to the pandemic.

Background In most studies, patients with EGFR L858R mutant non-small cell lung cancer (NSCLC) have a shorter duration of response to EGFR tyrosine kinase inhibitor (TKI) therapy than do patients with EGFR exon 19 deletion NSCLC. The role that co-mutations play in this observation is unknown. Methods We performed a single-institution retrospective analysis of patients with EGFR-mutant NSCLC (exon 19 deletion or L858R mutation) who received frontline EGFR TKI for metastatic disease between 2014 and 2019, and who had STAMP next-generation sequencing (NGS), a 130-gene platform. Time to treatment failure (TTF) and overall survival were calculated using Cox models adjusted for age, race, and brain metastases. Co-mutations in key tumor suppressor genes (TP53, RB1, KEAP1, CDKN2A, or CTNNB1) were identified and their effects on outcomes were evaluated. Analyses were stratified according to receipt of osimertinib versus nonosimertinib as frontline EGFR TKI. Results Of 137 patients, 72 (57%) had EGFR exon 19 deletions and 65 (43%) had EGFR L858R mutations. Median TTF and OS on frontline TKI was shorter for the L858R cohort versus the exon 19 deletion cohort in univariate analysis. In adjusted models, this difference persisted for TTF but was no longer significant for OS. The difference in TTF in L858R mutant tumors was driven by the presence of co-mutations in key tumor suppressor genes. Conclusion Patients with metastatic NSCLC with mutations in EGFR L858R had shorter TTF on frontline TKI compared to patients with EGFR exon 19 deletions. Co-mutations in tumor suppressor genes may play an important role in the differential response to TKI therapy.

Introduction Preclinical evidence suggests the feedforward cytokine loop of interleukin-6/Janus kinases (JAK)/STAT3 plays a role in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance in EGFR-mutated non-small cell lung cancer (NSCLC). Methods In this phase 1b study, the JAK1/2 and TANK-binding kinase 1 (TBK1) inhibitor momelotinib was evaluated in combination with erlotinib in patients with EGFR TKI-naive, EGFR-mutated NSCLC. After erlotinib lead-in (50, 75, 100, or 150 mg oral daily [QD]), momelotinib was combined and dose escalated in a 3 + 3 study design. The primary endpoint of maximum tolerated dose (MTD) of momelotinib was determined based on the incidence of dose-limiting toxicities (DLTs) during the first 28-day cycle. Secondary endpoints included efficacy and pharmacokinetics (PK). Results Eleven patients were enrolled across 3 dose levels of momelotinib (100 mg QD, 200 mg QD, and 100 mg twice daily [BID]). The MTD was momelotinib 200 mg QD in combination with erlotinib. Two DLTs of grade 4 neutropenia without fever and grade 3 diarrhea occurred at momelotinib 100 mg BID. Most common treatment-emergent adverse events included diarrhea, dry skin, fatigue, and decreased appetite; the vast majority being grades 1–2. The overall response rate was 54.5% (90% CI 27.1–80.0; all partial) and median progression-free survival was 9.2 months (90% CI 6.2–12.4). Momelotinib did not affect the PK of erlotinib. Conclusions The JAK1/2 and TBK1 inhibitor momelotinib in combination with erlotinib did not appear to enhance benefit over the historical data of erlotinib monotherapy in patients with EGFR-mutated NSCLC. ClinicalTrials.gov identifier NCT02206763.