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Most EGFR exon 20 insertion (EGFRex20ins) driver mutations in non–small cell lung cancer (NSCLC) are insensitive to approved EGFR tyrosine kinase inhibitors (TKI). To address the limitations of existing therapies targeting EGFR-mutated NSCLC, mobocertinib (TAK-788), a novel irreversible EGFR TKI, was specifically designed to potently inhibit oncogenic variants containing activating EGFRex20ins mutations with selectivity over wild-type EGFR. The in vitro and in vivo activity of mobocertinib was evaluated in engineered and patient-derived models harboring diverse EGFRex20ins mutations. Mobocertinib inhibited viability of various EGFRex20ins-driven cell lines more potently than approved EGFR TKIs and demonstrated in vivo antitumor efficacy in patient-derived xenografts and murine orthotopic models. These findings support the ongoing clinical development of mobocertinib for the treatment of EGFRex20ins-mutated NSCLC.Significance:No oral EGFR-targeted therapies are approved for EGFR exon 20 insertion (EGFRex20ins) mutation-driven NSCLC. Mobocertinib is a novel small-molecule EGFR inhibitor specifically designed to target EGFRex20ins mutants. Preclinical data reported here support the clinical development of mobocertinib in patients with NSCLC with EGFR exon 20 insertion mutations.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601

Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non–small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%–63%) with median duration of response of 14 months (5.0–not reached) and median progression-free survival of 7.3 months (4.4–15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors.Significance:No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population.See related commentary by Pacheco, p. 1617.This article is highlighted in the In This Issue feature, p. 1601

Supplementary Tables (S1-6) and Figures (S1-6)

GSEA analysis of mobocertinib and T-DM1 treated tumors versus mobocertinib-only treated tumors Genes involved in "INTERFERON ALPHA RESPONSE", "INFLAMMATORY RESPONSE", "INTERFERON GAMMA RESPONSE", "IL2 STAT5 SIGNALING", "TNFA SIGNALING VIA NFKB" and "IL6 JAK STAT3 SIGNALING" pathways of HALLMARK gene sets.

No targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients.Significance:This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.

Figure S1

Purpose: ERBB3 is overexpressed in a broad spectrum of human cancers, and its aberrant activation is associated with tumor pathogenesis and therapeutic resistance to various anticancer agents. Neuregulin 1 (NRG1) is the predominant ligand for ERBB3 and can promote the heterodimerization of ERBB3 with other ERBB family members, resulting in activation of multiple intracellular signaling pathways. AV-203 is a humanized IgG1/κ ERBB3 inhibitory antibody that completed a first-in-human phase I clinical trial in patients with advanced solid tumors. The purpose of this preclinical study was to identify potential biomarker(s) that may predict response to AV-203 treatment in the clinic.Experimental Design: We conducted in vivo efficacy studies using a broad panel of xenograft models representing a wide variety of human cancers. To identify biomarkers that can predict response to AV-203, the relationship between tumor growth inhibition (TGI) by AV-203 and the expression levels of ERBB3 and NRG1 were evaluated in these tumor models.Results: A significant correlation was observed between the levels of NRG1 expression and TGI by AV-203. In contrast, TGI was not correlated with ERBB3 expression. The correlation between the levels of NRG1 expression in tumors and their response to ERBB3 inhibition by AV-203 was further validated using patient-derived tumor explant models.Conclusions: NRG1 is a promising biomarker that can predict response to ERBB3 inhibition by AV-203 in preclinical human cancer models. NRG1 warrants further clinical evaluation and validation as a potential predictive biomarker of response to AV-203. Clin Cancer Res; 21(5); 1106–14. ©2014 AACR.

Purpose:This phase II study investigated daily or weekly sapanisertib (a selective dual inhibitor of mTOR complexes 1 and 2) in combination with fulvestrant.Patients and Methods:Postmenopausal women with estrogen receptor–positive (ER+)/HER2-negative (HER2−) advanced or metastatic breast cancer following progression during/after aromatase inhibitor treatment were randomized to receive fulvestrant 500 mg (28-day treatment cycles), fulvestrant plus sapanisertib 4 mg daily, or fulvestrant plus sapanisertib 30 mg weekly, until progressive disease, unacceptable toxicity, consent withdrawal, or study completion.Results:Among 141 enrolled patients, baseline characteristics were balanced among treatment arms, including prior cyclin-dependent kinase-4/6 (CDK4/6) inhibitor treatment in 33% to 35% of patients. Median progression-free survival (PFS; primary endpoint) was 3.5 months in the single-agent fulvestrant arm, compared with 7.2 months for fulvestrant plus sapanisertib daily [HR, 0.77; 95% confidence interval (CI), 0.47–1.26] and 5.6 months for fulvestrant plus sapanisertib weekly (HR, 0.88; 95% CI, 0.53–1.45). The greatest PFS benefits were seen in patients who had previously received CDK4/6 inhibitors. The most common adverse events were nausea, vomiting, and hyperglycemia, all occurring more frequently in the combination therapy arms. Treatment discontinuation due to adverse events occurred more frequently in the two combination therapy arms than with single-agent fulvestrant (32% and 36% vs. 4%, respectively).Conclusions:Fulvestrant plus sapanisertib daily/weekly resulted in numerically longer PFS in patients with ER+/HER2− advanced or metastatic breast cancer, compared with single-agent fulvestrant. The combination was associated with increased toxicity. Further development of sapanisertib using these dosing schedules in this setting is not supported by these data.

Supplementary Table 1. The contingency table for the Fisher’s exact test for xenograft models used in the study. Supplementary Table 2. NRG1 and ERBB3 expression in human cancers from TCGA database. Supplementary Figure 1. Effect of AV-203 on xenograft models in vivo. Supplementary Figure 2. Analysis of NRG1 expression by immunohistochemistry. Supplementary Figure 3. Evaluation of NRG1 and ERBB3 expression in human cancers using TCGA database. Supplementary Figure 4. Correlation analysis between efficacy of AV-203 and the expression levels of ERBB3 (A) or NRG1 (B) in 32 human cancer xenografts included in the study.

Supplementary Figure from Sapanisertib plus Fulvestrant in Postmenopausal Women with Estrogen Receptor–Positive/HER2-Negative Advanced Breast Cancer after Progression on Aromatase Inhibitor

Supplementary Materials and Methods

Purpose:This open-label, multicenter, phase IB/II study evaluated sapanisertib, a dual inhibitor of mTOR kinase complexes 1/2, plus exemestane or fulvestrant in postmenopausal women with hormone receptor–positive (HR+)/HER2-negative (HER2−) advanced/metastatic breast cancer.Patients and Methods:Eligible patients had previously progressed on everolimus with exemestane/fulvestrant and received ≤3 (phase IB) or ≤1 (phase II) prior chemotherapy regimens. Patients received sapanisertib 3 to 5 mg every day (phase IB), or 4 mg every day (phase II) with exemestane 25 mg every day or fulvestrant 500 mg monthly in 28-day cycles. Phase II enrolled parallel cohorts based on prior response to everolimus. The primary objective of phase II was to evaluate antitumor activity by clinical benefit rate at 16 weeks (CBR-16).Results:Overall, 118 patients enrolled in phase IB (n = 24) and II (n = 94). Five patients in phase IB experienced dose-limiting toxicities, at sapanisertib doses of 5 mg every day (n = 4) and 4 mg every day (n = 1); sapanisertib 4 mg every day was the MTD in combination with exemestane or fulvestrant. In phase II, in everolimus-sensitive versus everolimus-resistant cohorts, CBR-16 was 45% versus 23%, and overall response rate was 8% versus 2%, respectively. The most common adverse events were nausea (52%), fatigue (47%), diarrhea (37%), and hyperglycemia (33%); rash occurred in 17% of patients. Molecular analysis suggested positive association between AKT1 mutation status and best treatment response (complete + partial response; P = 0.0262).Conclusions:Sapanisertib plus exemestane or fulvestrant was well tolerated and exhibited clinical benefit in postmenopausal women with pretreated everolimus-sensitive or everolimus-resistant breast cancer.

Supplementary Material containing Supplementary Methods, 5 Supplementary Figures, and 8 Supplementary Tables

Drawing on conservation of resources theory, we developed and evaluated a supportive leadership training (SLT) intervention designed to teach leaders ways to be supportive of their employees. Given the important role of supportive leaders in helping employees deal with excessive workloads, we theorized that the beneficial intervention effects on employee well-being would be particularly evident for employees who perceive higher levels of quantitative and qualitative workloads prior to the intervention. Using a cluster randomized controlled field trial, we tested the effects of the SLT on employee social well-being in terms of leader-member exchange (LMX) quality and employee hedonic well-being, including positive affective well-being, emotional exhaustion, and job satisfaction. The participants in the training were directors of childcare centers in Germany. To rigorously evaluate the intervention effects at the employee level, we collected survey data at baseline, 1 month postintervention, and 6 months postintervention, and we used an intent-to-treat approach to analyze the data. A total of 496 employees from 77 childcare centers provided data at baseline, of whom 266 and 226 employees participated in the 1-month and 6-month surveys, respectively. Linear mixed-effects models showed that the effectiveness of the intervention in terms of LMX quality and emotional exhaustion varied depending on the employees' baseline perceptions of quantitative workloads, such that employees with higher quantitative workloads benefited more from the SLT. The findings of this study improve the understanding of the types of outcomes of SLT and contribute to clarifying for whom SLT is effective. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Evidence points to an indirect relationship between transformational leadership (TFL) and employee well-being, and numerous work characteristics have been identified as mediators. However, the relative mediating effect of different types of job resources and job demands on the TFL–well-being relationship remains unclear, rendering it impossible to determine which ones are the most influential. This study aims to provide a comprehensive analysis of the relative mediation potential of different work characteristics in the TFL–well-being relationship in multiple three-level meta-analytical structural equation models of 243 samples. Based on the JD–R Model, this study extends this theoretical framework by suggesting TFL as a predisposing variable that influences both job resources and job demands, leading to changes in indicators of both positive and negative employee well-being. The results show that, while all the examined job resources and demands mediated the TFL–well-being relationship, organizational resources were identified as the strongest mediators. Furthermore, job demands had a strong mediating effect on the relationship between TFL and negative well-being, while job resources more strongly mediated TFL and positive well-being. We present a differentiated picture of how transformational leaders can influence their employees’ well-being at the workplace, providing valuable knowledge for future research and practice.

No targeted treatments are currently approved for HER2 exon 20 insertion–mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion–mutant lung cancer is still unclear. Here we conducted systematic characterization of preclinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion–mutant cell lines, the IC50 of mobocertinib was higher than poziotinib and comparable with or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC50/wild-type (WT) EGFR IC50 ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20YVMA allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20G776>VC lung tumors exhibited a sustained complete response to mobocertinib, whereas HER2 exon 20YVMA tumors showed only partial and transient response. Combined treatment with a second antibody–drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1), synergized with mobocertinib in HER2 exon 20YVMA tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4+ T-cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20YVMA insertion–mutant lung adenocarcinoma patients. Significance: This study elucidates the potent inhibitory activity of mobocertinib against HER2 exon 20 insertion–mutant lung cancer and the synergic effect of combined mobocertinib and T-DM1, providing a strong rationale for clinical investigation.

Mobocertinib, an oral epidermal growth factor receptor (EGFR) inhibitor targeting EGFR gene mutations, including exon 20 insertions (EGFRex20ins), in non–small cell lung cancer, was evaluated in a phase I/II dose-escalation/expansion trial (ClinicalTrials.gov NCT02716116). Dose escalation identified 160 mg/d as the recommended phase 2 dose and maximum tolerated dose. Among 136 patients treated with 160 mg/d, the most common any-grade treatment-related adverse events (TRAE; >25%) were diarrhea (83%), nausea (43%), rash (33%), and vomiting (26%), with diarrhea (21%) the only grade ≥3 TRAE >5%. Among 28 EGFRex20ins patients treated at 160 mg/d, the investigator-assessed confirmed response rate was 43% (12/28; 95% confidence interval, 24%–63%) with median duration of response of 14 months (5.0–not reached) and median progression-free survival of 7.3 months (4.4–15.6). Mobocertinib demonstrated antitumor activity in patients with diverse EGFRex20ins variants with a safety profile consistent with other EGFR inhibitors. Significance: No oral EGFR-targeted therapies are currently approved for patients with EGFRex20ins NSCLC. Mobocertinib demonstrated antitumor activity with manageable toxicity in patients with advanced EGFRex20ins NSCLC in this study, supporting additional development of mobocertinib in this patient population. See related commentary by Pacheco, p. 1617. This article is highlighted in the In This Issue feature, p. 1601

NFE2L2 and/or KEAP1 mutations are associated with worse prognosis in all non-small cell lung cancer (NSCLC). We determined real-world survival outcomes and treatment patterns among patients with advanced squamous cell NSCLC by NFE2L2 and KEAP1 mutation status.A retrospective study (January 2011-December 2018) was conducted using a de-identified US-based clinico-genomic database. Adult patients with advanced squamous cell NSCLC with ≥ 2 in-network visits and comprehensive genomic profiling during the study period were included. Outcomes included real-world progression free survival (rwPFS) by line of therapy and overall survival (OS). The real-world effectiveness of anti-PD-1/PD-L1 first-line therapy was also evaluated in patients with a NFE2L2 and/or KEAP1 mutation.Of 703 patients included (median age: 70.0 years), 31.6% had a NFE2L2 and/or KEAP1 mutation. The most common first- and second-line treatments regardless of mutation status were platinum-based chemotherapies and anti-PD-1/PD-L1 therapies. The most common third-line treatment was anti-PD-1/PD-L1 therapy in patients with a NFE2L2 and/or KEAP1 mutation and single-agent chemotherapy in patients with wild-type disease. Patients with a NFE2L2 and/or KEAP1 mutation versus wild-type disease had significantly shorter rwPFS (4.54 vs. 6.25 months; P = .003) following first- but not second- or third-line therapy and shorter median OS (13.59 vs. 17.37 months; P = .4105). No survival differences were observed in patients with a NFE2L2 and/or KEAP1 mutation receiving first-line anti-PD-1/PD-L1 therapies versus other therapies.Patients with advanced squamous cell NSCLC with a NFE2L2 and/or KEAP1 mutation have poor real-world survival, highlighting the need for a genotype-directed therapeutic strategy in this population.

In this study, we draw on conservation of resources theory to suggest that transformational leaders’ encouragement of extra effort in followers might reduce or increase followers’ emotional exhaust...

PurposeThis study of leaders and followers working in day-care centers aims to use a multilevel perspective on supportive leadership to examine its role in linking workload at the leader level and emotional exhaustion at the follower level. Integrating theoretical work on social support with conservation of resources (COR) theory, leaders' workload is proposed to be positively related to followers' feelings of emotional exhaustion through constraining the enactment of supportive leadership.Design/methodology/approachMultisource survey data from 442 followers and their leaders from 68 teams were collected to test the hypotheses.FindingsMultilevel analyses showed that leader workload was negatively related to followers' perception of supportive leadership, which, in turn, was positively related to followers' levels of emotional exhaustion. Leader workload was indirectly and positively related to follower emotional exhaustion via supportive leadership.Research limitations/implicationsThis study provides initial support for the idea that work contextual factors at the leader level create boundaries for the extent to which leaders may provide support to their followers and draws attention to the accountability of leaders' work contextual factors for followers' well-being.Practical implicationsThe findings suggest that organizations must not focus narrowly on training leaders on how to benefit followers but should also aim to optimize leaders' levels of workload to enable them to act in a supportive manner.Originality/valueBy considering both the receivers (i.e. followers) and providers (i.e. leaders) of support simultaneously, we take a crossover approach to COR theory and acknowledge that work contextual factors at higher organizational levels may spread to employee well-being at lower levels of the organization.

Purpose: This phase II study investigated daily or weekly sapanisertib (a selective dual inhibitor of mTOR complexes 1 and 2) in combination with fulvestrant. Patients and Methods: Postmenopausal women with estrogen receptor–positive (ER+)/HER2-negative (HER2−) advanced or metastatic breast cancer following progression during/after aromatase inhibitor treatment were randomized to receive fulvestrant 500 mg (28-day treatment cycles), fulvestrant plus sapanisertib 4 mg daily, or fulvestrant plus sapanisertib 30 mg weekly, until progressive disease, unacceptable toxicity, consent withdrawal, or study completion. Results: Among 141 enrolled patients, baseline characteristics were balanced among treatment arms, including prior cyclin-dependent kinase-4/6 (CDK4/6) inhibitor treatment in 33% to 35% of patients. Median progression-free survival (PFS; primary endpoint) was 3.5 months in the single-agent fulvestrant arm, compared with 7.2 months for fulvestrant plus sapanisertib daily [HR, 0.77; 95% confidence interval (CI), 0.47–1.26] and 5.6 months for fulvestrant plus sapanisertib weekly (HR, 0.88; 95% CI, 0.53–1.45). The greatest PFS benefits were seen in patients who had previously received CDK4/6 inhibitors. The most common adverse events were nausea, vomiting, and hyperglycemia, all occurring more frequently in the combination therapy arms. Treatment discontinuation due to adverse events occurred more frequently in the two combination therapy arms than with single-agent fulvestrant (32% and 36% vs. 4%, respectively). Conclusions: Fulvestrant plus sapanisertib daily/weekly resulted in numerically longer PFS in patients with ER+/HER2− advanced or metastatic breast cancer, compared with single-agent fulvestrant. The combination was associated with increased toxicity. Further development of sapanisertib using these dosing schedules in this setting is not supported by these data.

No targeted treatments are currently approved for HER2 exon 20 insertion-mutant lung adenocarcinoma patients. Mobocertinib (TAK-788) is a potent irreversible tyrosine kinase inhibitor (TKI) designed to target human epidermal growth factor receptor 2 (HER2/ERBB2) exon 20 insertion mutations. However, the function of mobocertinib on HER2 exon 20 insertion-mutant lung cancer is still unclear. Here we conducted systematic characterization of pre-clinical models to understand the activity profile of mobocertinib against HER2 exon 20 insertions. In HER2 exon 20 insertion mutant cell lines, the IC(50) of mobocertinib was higher than poziotinib and comparable or slightly lower than afatinib, neratinib, and pyrotinib. Mobocertinib had the lowest HER2 exon 20 insertion IC(50) / WT EGFR IC(50) ratio, indicating that mobocertinib displayed the best selectivity profile in these models. Also, mobocertinib showed strong inhibitory activity in HER2 exon 20(YVMA) allograft and patient-derived xenograft models. In genetically engineered mouse models, HER2 exon 20(G776>VC) lung tumors exhibited a sustained complete response to mobocertinib, while HER2 exon 20(YVMA) tumors showed only partial and transient response. Combined treatment with a second antibody-drug conjugate (ADC) against HER2, ado-trastuzumab emtansine (T-DM1) synergized with mobocertinib in HER2 exon 20(YVMA) tumors. In addition to the tumor cell autonomous effect, sustained tumor growth control derived from M1 macrophage infiltration and CD4(+) T cell activation. These findings support the ongoing clinical development of mobocertinib (NCT02716116) and provide a rationale for future clinical evaluation of T-DM1 combinational therapy in HER2 exon 20(YVMA) insertion-mutant lung adenocarcinoma patients.

Social and healthcare workers are at high risk of experiencing sexual harassment in the workplace. Although sexual harassment is detrimental to people’s well-being, only a few studies have systematically investigated social and healthcare workers’ experiences of different forms of sexually harassing behaviors by patients, clients, and residents in Germany. This study aimed to address this gap by determining the prevalence rates and frequency of nonverbal, verbal, and physical sexual harassment by patients, clients, and residents against social and healthcare workers. In addition, we examined the associations of sexual harassment with workers’ well-being and described employees’ awareness of offers of organizational support for sexual harassment prevention and aftercare. Data were collected from n = 901 employees working in a total of 61 facilities, including inpatient and outpatient care, psychiatric facilities, hospitals, and facilities for persons with disabilities. While the prevalence, frequency, and predominant forms of sexual harassment differed across sectors, the results indicated that nonverbal, verbal and physical sexual harassment were highly prevalent in social and healthcare work, with both men and women being affected. Furthermore, we found that sexual harassment was positively related to impaired well-being (e.g., depressiveness and psychosomatic complaints). In terms of support offers for sexual harassment prevention and aftercare, we found that approximately one-third of social and healthcare workers were not aware of any offers at their facilities. In addition to highlighting the problem of sexual harassment by patients, clients, and residents in social and healthcare settings, this study provides recommendations for the development of interventions and suggests several avenues for future research.

Abstract. To advance knowledge of the mechanisms underlying the relationship between leadership and employees’ well-being, this study examines leaders’ effects on their employees’ compensatory coping efforts. Using an extension of the job demands–resources model, we propose that high-quality leader–member exchange (LMX) allows employees to cope with high job demands without increasing their effort expenditure through the extension of working hours. Data analyses ( N = 356) revealed that LMX buffers the effect of quantitative demands on the extension of working hours such that the indirect effect of quantitative demands on emotional exhaustion is only significant at low and average levels of LMX. This study indicates that integrating leadership with employees’ coping efforts into a unifying model contributes to understanding how leadership is related to employees’ well-being. The notion that leaders can affect their employees’ use of compensatory coping efforts that detract from well-being offers promising approaches to the promotion of workplace health.

Mobocertinib is an oral tyrosine kinase inhibitor recently approved by the FDA for the treatment of patients (pts) with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations who have progressed on or after platinum-based chemotherapy. To understand the impact of co-occurring genetic alterations on the therapeutic response to mobocertinib, tumors from a subset of 72 platinum-pretreated pts with EGFR exon 20 insertions from the phase 1/2 study (NCT02716116) were collected before treatment and analyzed by next-generation sequencing. More than 200 co-occurring hotspot genetic alterations were detected in 43 pts, with some alterations detected with greater than 20% frequency, such as PTCH1 (67%), HNF1A (58%), TP53 (58%), and GNAQ (35%). In addition to EGFR exon 20 insertion mutations, co-occurring EGFR substitutions were also observed in the exon 20 loop following the C-helix (amino acid positions 770, 771, 772) in 4 pts and L858Q in 1 pt. The pt with the L858Q mutation had a confirmed partial response as assessed by an independent review committee, while the 4 pts with exon 20 substitutions were non-responders (2 had stable disease and 2 had progressive disease as best response). An abnormally high level of mutational burden was seen in 4 pts with EGFR exon 20 insertions, along with alterations in the mismatch repair gene MSH6 and/or the elongation factor MLLT3. Association analysis of mutations reported increased odds of association between the presence of PIK3CA, TP53, and EGFR alterations and a lack of mobocertinib response. Gene amplifications were observed in 12 pts (16%) affecting EGFR (6 pts), MYC (4 pts), CDK4 (3 pts), and CCND1 (2 pts). When assessed for association with lack of response (P values from the Fisher exact test), odds ratios were 2.47 (P=0.66) and 6.34 (P=0.085) for EGFR amplification and any-gene amplification, respectively. When combined, the presence of either PIK3CA mutations or any-gene amplification was associated with a lack of response to mobocertinib treatment with an odds ratio of 12.93. Following adjustment for selected clinical covariates in a multivariate model, the presence of either PIK3CA mutation or gene amplification was an independent predictor of lack of response to mobocertinib (P value of 0.047). Given the retrospective nature of these analyses and the insufficient control of statistical multiplicity, this finding should be considered exploratory. These data suggest that intrinsic genetic alterations, present at baseline in patients with NSCLC harboring an EGFR exon 20 insertion mutation, might impact the response to mobocertinib treatment. The presence of PIK3CA mutations, EGFR gene amplification, or cell cycle regulator MYC-CDK4-CCND1 amplification is associated with lack of response to mobocertinib, which might guide rational combinations for future clinical investigation. Citation Format: Sylvie Vincent, Zhenqiang Su, Adarsh Joshi, Kalyani Penta, Pingkuan Zhang. De novo molecular mechanisms of resistance to mobocertinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2781.

9108 Background: ctDNA is an important tool to diagnose and monitor mutations in pts with non–small cell lung cancer (NSCLC). We evaluated epidermal growth factor receptor gene ( EGFR) ex20ins mutations in tumor vs plasma samples, assessed changes in EGFR ex20ins variant allele frequency (VAF) with mobocertinib treatment and correlation with response, and identified potential emerging variants of acquired resistance. Methods: Tumor tissue samples were collected at baseline (BL) from pts with EGFR ex20ins+ advanced NSCLC receiving mobocertinib 160 mg QD in a phase 1/2 study (NCT02716116); plasma samples were collected at BL, after 2 treatment cycles (Cycle 3, Day 1 [C3D1]) and at disease progression/end of treatment (DP/EOT). ctDNA samples were analyzed by next-generation sequencing for EGFR ex20ins to determine concordance rate detection between tissue and plasma ctDNA at BL. Changes in VAF for EGFR ex20ins from BL were analyzed at C3D1 and DP/EOT by confirmed response (RECIST v1.1) to mobocertinib per independent review committee. Emerging variants at DP/EOT were evaluated by elimination of germline variants seen in healthy populations (gnomAD databases and 1000 Genomes) and nonharmful variants predicted by PolyPhen and SIFT tools or annotated as benign in ClinVar database. Results: BL EGFR ex20ins mutations were detected by ctDNA sequencing in 29 of 38 pts (76%) with tissue-confirmed EGFR ex20ins+ NSCLC. VAFs for EGFR ex20ins significantly decreased at C3D1 in mobocertinib-treated pts with confirmed partial response (PR; P=0.0057) or stable disease (SD; P=0.0016), but not in pts with progressive disease (PD; P=0.14) (Table). ctDNA at EOT/DP analysis identified numerous genetic variants; EGFR, TP53, and DNMT3A were the most common genes with emerging variants. Twelve emerging missense mutations were identified in EGFR in 9 pts, including mutations located in the exon 20 loop following the C-helix (6), T790M (5), and D379E (1). Conclusions: Concordance between tissue and plasma ctDNA for EGFR ex20ins mutations at BL was 76%. EGFR ex20ins VAF decreased significantly after 2 treatment cycles in mobocertinib-treated patients with PR and SD. Plasma ctDNA longitudinal monitoring may be useful to assess mutation status and disease progression in pts with NSCLC treated with mobocertinib. Clinical trial information: NCT02716116. [Table: see text]

Most

Purpose:This open-label, multicenter, phase IB/II study evaluated sapanisertib, a dual inhibitor of mTOR kinase complexes 1/2, plus exemestane or fulvestrant in postmenopausal women with hormone receptor–positive (HR+)/HER2-negative (HER2−) advanced/metastatic breast cancer.Patients and Methods:Eligible patients had previously progressed on everolimus with exemestane/fulvestrant and received ≤3 (phase IB) or ≤1 (phase II) prior chemotherapy regimens. Patients received sapanisertib 3 to 5 mg every day (phase IB), or 4 mg every day (phase II) with exemestane 25 mg every day or fulvestrant 500 mg monthly in 28-day cycles. Phase II enrolled parallel cohorts based on prior response to everolimus. The primary objective of phase II was to evaluate antitumor activity by clinical benefit rate at 16 weeks (CBR-16).Results:Overall, 118 patients enrolled in phase IB (n = 24) and II (n = 94). Five patients in phase IB experienced dose-limiting toxicities, at sapanisertib doses of 5 mg every day (n = 4) and 4 mg every day (n = 1); sapanisertib 4 mg every day was the MTD in combination with exemestane or fulvestrant. In phase II, in everolimus-sensitive versus everolimus-resistant cohorts, CBR-16 was 45% versus 23%, and overall response rate was 8% versus 2%, respectively. The most common adverse events were nausea (52%), fatigue (47%), diarrhea (37%), and hyperglycemia (33%); rash occurred in 17% of patients. Molecular analysis suggested positive association between AKT1 mutation status and best treatment response (complete + partial response; P = 0.0262).Conclusions:Sapanisertib plus exemestane or fulvestrant was well tolerated and exhibited clinical benefit in postmenopausal women with pretreated everolimus-sensitive or everolimus-resistant breast cancer.

The aim of this study is to obtain a better understanding of the association between the frequency of nurses&rsquo, exposure to workplace aggression from patients and their levels of burnout. In particular, we seek to shed light on the role of the availability of follow-up counseling in organizations after critical incidents in mitigating the adverse relationships between physical and verbal aggression and nurses&rsquo, burnout. A total of 582 nurses reported how frequently they had experienced physical and verbal aggression from patients in the last 12 months and whether they had the opportunity to receive follow-up counseling in their organization. In addition, nurses rated the extent to which they experienced each of the three dimensions of burnout (i.e., emotional exhaustion, depersonalization, and personal accomplishment). The results showed that both physical and verbal aggression were substantially related to the burnout dimensions. Furthermore, we found that the availability of follow-up counseling in organizations attenuated the relationships between physical aggression and all three burnout dimensions. While we found that the availability of follow-up counseling moderated the relationship between verbal aggression depersonalization, the moderating effects were not significant for emotional exhaustion and personal accomplishment. The findings indicate that the availability of follow-up counseling might help minimize the adverse impact of exposure to aggression from patients on nurses&rsquo, mental health.

According to the concept of abusive supervision, abusive supervisors display hostility towards their employees by humiliating and ridiculing them, giving them the silent treatment, and breaking promises. In this study, we argue that abusive supervision may not be limited to mistreatment at the relationship level and that the abuse is likely to extend to employees&rsquo, work tasks. Drawing upon the notion that supervisors play a key role in assigning work tasks to employees, we propose that abusive supervisors may display disrespect and devaluation towards their employees through assigning illegitimate (i.e., unnecessary and unreasonable) tasks. Survey data were obtained from 268 healthcare and social services workers. The results showed that abusive supervision was strongly and positively related to illegitimate tasks. Moreover, we found that the relationship between abusive supervision and unreasonable tasks was stronger for nonsupervisory employees at the lowest hierarchical level than for supervisory employees at higher hierarchical levels. The findings indicate that abusive supervision may go beyond relatively overt forms of hostility at the relationship level. Task-level stressors may be an important additional source of stress for employees with abusive supervisors that should be considered to fully understand the devastating effects of abusive supervision on employee functioning and well-being.

Although evidence reveals severe effects of sexual harassment on care workers&rsquo, mental health, there is a scarcity of studies that investigate care workers&rsquo, experiences of sexually inappropriate behavior from patients or clients. One reason for this lack of research is that validated measures that assess different types of sexual harassment experienced by employees working with patients or clients are lacking. In this study, we seek to establish a conceptual framework for investigating extraorganizational sexual harassment in healthcare work. Based on this theoretical framework, we developed and validated a measure for assessing sexually harassing behaviors from patients or clients. Data were gathered from heterogeneous samples of employees working in a variety of settings in healthcare. To evaluate the factorial structure of the measure, we conducted exploratory factor analysis (EFA) using a calibration sample (N = 179) and confirmatory factor analysis (CFA) using a cross-validation sample (N = 305). The construct validity of the measure was demonstrated by investigating relationships with indicators of care workers&rsquo, mental health. EFA revealed three factors, namely, nonverbal, verbal, and physical acts of sexual harassment. Examination of the measure comprising 14 items revealed acceptable internal consistencies and substantial correlations with indicators of care workers&rsquo, mental health. This study provides a useful and sound measure for assessing sexual harassment from patients or clients and paves the way for the development of a comprehensive theoretical framework for the assessment of sexual harassment. Furthermore, it facilitates future investigations of risk factors for sexual harassment and protective factors helping healthcare workers cope with sexual harassment from patients or clients.

Dialysis nurses face complex and demanding working conditions. Due to demographic changes, the number of dialysis patients has increased, while the number of skilled personnel is expected to decrease, leading to tremendous increases in quantitative demands in the near future. Against the background of increasing workload, focusing on the provision of job resources is considered a promising approach because resources can buffer the negative effects of job demands. The aim of this study is to investigate whether different job resources&mdash, in particular influence at work and feedback&mdash, play a buffering role in the relationship between job demands and employee well-being. The study used a cross-sectional paper&ndash, pencil survey design. Data were collected from 951 dialysis nurses working in dialysis facilities in Germany between October 2010 and March 2012 using validated measures of quantitative job demands, job-related resources (influence at work and feedback), and cognitive stress symptoms. To test the moderating role of resources, we applied hierarchical regression analyses. The findings indicate that feedback buffers the relationship between quantitative demands and well-being, that is, the positive relationship between quantitative demands and cognitive stress symptoms was weaker when feedback was high. However, we found no buffering role of influence at work. The results suggest that feedback is a promising resource that may buffer the negative impact of quantitative demands on well-being of dialysis nurses. The findings offer new approaches for training nurses and implementing a feedback culture.

Der Einfluss der personalen Fuhrung auf die Gesundheit der Beschaftigten wird in diesem Beitrag in den Fokus genommen. Im ersten Schritt geben wir einen Uberblick uber den aktuellen Forschungsstand. Bei einem Vergleich verschiedener gesundheitsforderlicher Fuhrungskonzepte wird die Relevanz der Beziehungsqualitat zwischen Fuhrungskraft und Beschaftigten (Leader-Member Exchange) hervorgehoben. Abschliesend wird die Gesundheit als Fuhrungsaufgabe konkretisiert und verschiedene Formen, wie die gesunde Selbstfuhrung, die menschengerechte Gestaltung der Arbeit und die Unternehmenskultur (Praventions- oder Gesundheitskultur) dargestellt.

The number of women in STEM fields, especially in computer science, is still very low. Therefore, in this chapter, the computer-related self-concept (CSC) is presented as a new approach to investigate gender differences in computing careers. The computer-related self-concept comprises computer-related attitudes, emotions, and behaviors, integrating different lines of research on computer-related self-cognitions. To establish connections with career development, an extensive online survey was conducted with more than 1100 male and female computing professionals. Results show that men have a significantly more positive computer-related self-concept than women. Furthermore, as hypothesized, the computer-related self-concept shows high correlations with career motivation. Therefore, it is concluded that the computer-related self-concept is a feasible approach to investigate and understand computer-related gender differences. Possible implications regarding measures to foster women's careers in computing are discussed along with prospects for future research.

Importance Metastatic non–small cell lung cancer (mNSCLC) withEGFRexon 20 insertion (EGFRex20ins) mutations is associated with a poor prognosis. Mobocertinib is an oral tyrosine kinase inhibitor designed to selectively targetEGFRex20ins mutations. Objective To evaluate treatment outcomes and safety of mobocertinib in patients with previously treatedEGFRex20ins-positive mNSCLC. Design, Setting, and Participants This 3-part, open-label, phase 1/2 nonrandomized clinical trial with dose-escalation/dose-expansion cohorts (28 sites in the US) and a single-arm extension cohort (EXCLAIM; 40 sites in Asia, Europe, and North America) was conducted between June 2016 and November 2020 (data cutoff date). The primary analysis populations were the platinum-pretreated patients (PPP) cohort and the EXCLAIM cohort. The PPP cohort included 114 patients with platinum-pretreatedEGFRex20ins-positive mNSCLC who received mobocertinib 160 mg once daily from the dose-escalation (n = 6), dose-expansion (n = 22), and EXCLAIM (n = 86) cohorts. The EXCLAIM cohort included 96 patients with previously treatedEGFRex20ins-positive mNSCLC (10 were not platinum pretreated and thus were excluded from the PPP cohort). Interventions Mobocertinib 160 mg once daily. Main Outcomes and Measures The primary end point of the PPP and EXCLAIM cohorts was confirmed objective response rate (ORR) assessed by independent review committee (IRC). Secondary end points included confirmed ORR by investigator, duration of response, progression-free survival, overall survival, and safety. Results Among the PPP (n = 114) and EXCLAIM (n = 96) cohorts, the median (range) age was 60 (27-84) and 59 (27-80) years, respectively; most patients were women (75 [66%] and 62 [65%], respectively) and of Asian race (68 [60%] and 66 [69%], respectively). At data cutoff, median follow-up was 14.2 months in the PPP cohort (median 2 prior anticancer regimens; 40 [35%] had baseline brain metastases), with confirmed ORR of 28% (95% CI, 20%-37%) by IRC assessment and 35% (95% CI, 26%-45%) by investigator assessment; median duration of response by IRC assessment was 17.5 months (95% CI, 7.4-20.3). Median progression-free survival by IRC assessment was 7.3 months (95% CI, 5.5-9.2). Median overall survival was 24.0 months (95% CI, 14.6-28.8). In the EXCLAIM cohort, median follow-up was 13.0 months, with confirmed ORR by IRC assessment of 25% (95% CI, 17%-35%) and by investigator assessment of 32% (95% CI, 23%-43%). The most common treatment-related adverse events were diarrhea and rash. Conclusions and Relevance In this open-label, phase 1/2 nonrandomized clinical trial, mobocertinib was associated with clinically meaningful benefit in patients with previously treatedEGFRex20ins-positive mNSCLC, with a manageable safety profile. Trial Registration ClinicalTrials.gov Identifier:NCT02716116

Abstract: In recent years, transformational leadership as a health-related factor has become a focal point of interest in research and practice. However, the pathways and mechanisms underlying this association are not yet well understood. In order to gain knowledge on how or why transformational leadership and employee well-being are associated, we investigated the mediating effect of the work characteristics role clarity and predictability. The study was carried out on 618 employees working in the health-care sector in Germany. We tested the mediator effect using structural equation modeling. The results indicate that role clarity and predictability fully mediate the relation between transformational leadership and negative indicators of well-being. These results give credit to the notion that work characteristics play an important role in identifying health-relevant aspects of leadership behavior. Our findings advance the understanding of how to enhance employee well-being and have implications for the design of leadership-related interventions of workplace health promotion.

Purpose Preclinical in vivo nuclear imaging of mice offers an enabling perspective to evaluate drug efficacy at optimal dose and schedule. In this study, we interrogated sufficient estrogen receptor occupancy and degradation for the selective estrogen receptor degrader (SERD) compound SAR439859 using molecular imaging and histological techniques. Material and methods [18F]FluoroEstradiol positron emission tomography (FES-PET), [18F]FluoroDeoxyGlucose (FDG) PET, and [18F]FluoroThymidine (FLT) PET were investigated as early pharmacodynamic, tumor metabolism, and tumor proliferation imaging biomarkers, respectively, in mice bearing subcutaneous MCF7-Y537S mutant ERα+ breast cancer model treated with the SERD agent SAR439859. ER expression and proliferation index Ki-67 were assessed by immunohistochemistry (IHC). The combination of palbociclib CDK 4/6 inhibitor with SAR439859 was tested for its potential synergistic effect on anti-tumor activity. Results After repeated SAR439859 oral administration over 4 days, FES tumoral uptake (SUVmean) decreases compared to baseline by 35, 57, and 55% for the 25 mg/kg qd, 12.5 mg/kg bid and 5 mg/kg bid treatment groups, respectively. FES tumor uptake following SAR439859 treatment at different doses correlates with immunohistochemical scoring for ERα expression. No significant difference in FDG uptake is observed after SAR439859 treatments over 3 days. FLT accumulation in tumor is significantly decreased when palbociclib is combined to SAR439859 (− 64%) but not different from the group dosed with palbociclib alone (− 46%). The impact on proliferation is corroborated by Ki-67 IHC data for both groups of treatment. Conclusions In our preclinical studies, dose-dependent inhibition of FES tumoral uptake confirmed target engagement of SAR439859 to ERα. FES-PET thus appears as a relevant imaging biomarker for measuring non-invasively the impact of SAR439859 on tumor estrogen receptor occupancy. This study further validates the use of FLT-PET to directly visualize the anti-proliferative tumor effect of the palbociclib CDK 4/6 inhibitor alone and in combination with SAR439859.

In this article, we draw upon the notion that employees’ work characteristics are an important pathway through which leaders influence employee well-being and propose a theoretical framework that integrates perspectives on leadership, occupational stress, and job design. Based on this integrative approach, we developed the health- and development-promoting leadership behavior questionnaire (HDLBQ) for assessing job demands emanating from and job resources provided through the leader. Validation of the measure in German, French, and English using an overall sample of 2,934 employees demonstrated adequate psychometric properties. An examination of the factorial structure revealed three higher-order factors: demanding, development-oriented, and support-oriented leadership. Multigroup confirmatory factor analysis indicated structural equivalence across the three language versions of the HDLBQ. Correlations with employee well-being were moderate, and the HDLBQ explained unique variance in employee well-being beyond that explained by transformational leadership. Suggestions for applications of the HDLBQ and approaches to enhance employee well-being at the workplace are discussed.