Mobocertinib in Patients with EGFR Exon 20 Insertion-Positive Non-Small Cell Lung Cancer (MOON): An International Real-World Safety and Efficacy Analysis.

EGFR exon 20 (EGFR Ex20) insertion mutations in non-small cell lung cancer (NSCLC) are insensitive to traditional EGFR tyrosine kinase inhibitors (TKIs). Mobocertinib is the only approved TKI specifically designed to target EGFR Ex20. We performed an international, real-world safety and efficacy analysis on patients with EGFR Ex20-positive NSCLC enrolled in a mobocertinib early access program. We explored the mechanisms of resistance by analyzing postprogression biopsies, as well as cross-resistance to amivantamab. Data from 86 patients with a median age of 67 years and a median of two prior lines of treatment were analyzed. Treatment-related adverse events (TRAEs) occurred in 95% of patients. Grade ≥3 TRAEs were reported in 38% of patients and included diarrhea (22%) and rash (8%). In 17% of patients, therapy was permanently discontinued, and two patients died due to TRAEs. Women were seven times more likely to discontinue treatment than men. In the overall cohort, the objective response rate to mobocertinib was 34% (95% CI, 24-45). The response rate in treatment-naïve patients was 27% (95% CI, 8-58). The median progression-free and overall survival was 5 months (95% CI, 3.5-6.5) and 12 months (95% CI, 6.8-17.2), respectively. The intracranial response rate was limited (13%), and one-third of disease progression cases involved the brain. Mobocertinib also showed antitumor activity following EGFR Ex20-specific therapy and vice versa. Potential mechanisms of resistance to mobocertinib included amplifications in MET, PIK3CA, and NRAS. Mobocertinib demonstrated meaningful efficacy in a real-world setting but was associated with considerable gastrointestinal and cutaneous toxicity.

Longitudinal analysis of PD-L1 expression in patients with relapsed NSCLC.

BACKGROUND: The use and approval of immune checkpoint inhibitors for the treatment of non-small cell lung cancer (NSCLC) depends on PD-L1 expression in the tumor tissue. Nevertheless, PD-L1 often fails to predict response to treatment. One possible explanation could be a change in PD-L1 expression during the course of the disease and the neglect of reassessment. The purpose of this study was a longitudinal analysis of PD-L1 expression in patients with relapsed NSCLC. METHODS: We retrospectively analyzed PD-L1 expression in patients with early-stage NSCLC and subsequent relapse in preoperative samples, matched surgical specimens and biopsy samples of disease recurrence. Ventana PD-L1 (SP263) immunohistochemistry assay was used for all samples. PD-L1 expression was scored based on clinically relevant groups (0%, 1%-49%, and ≥50%). The primary endpoint was the change in PD-L1 score group between preoperative samples, matched surgical specimens and relapsed tumor tissue. RESULTS: 395 consecutive patients with stages I-III NSCLC and 136 (34%) patients with a subsequent relapse were identified. For 87 patients at least two specimens for comparison of PD-L1 expression between early stage and relapsed disease were available. In 72 cases, a longitudinal analysis between preoperative biopsy, the surgically resected specimen and biopsy of disease recurrence was feasible. When comparing preoperative and matched surgical specimens, a treatment-relevant conversion of PD-L1 expression group was found in 25 patients (34.7%). Neoadjuvant treatment showed no significant effect on PD-L1 alteration (p=0.39). In 32 (36.8%) out of 87 cases, a change in PD-L1 group was observed when biopsies of disease relapse were compared with early-stage disease. Adjuvant treatment was not significantly associated with a change in PD-L1 expression (p=0.53). 39 patients (54.2%) showed at least 1 change into a different PD-L1 score group during the course of disease. 14 patients (19.4%) changed the PD-L1 score group twice, 5 (6.9%) of them being found in all different score groups. CONCLUSION: PD-L1 expression shows dynamic changes during the course of disease. There is an urgent need for consensus guidelines to define a PD-L1 testing strategy including time points of reassessment, the number of biopsies to be obtained and judgment of surgical specimens.

Expanding Broad Molecular Reflex Testing in Non-Small Cell Lung Cancer to Squamous Histology.

Due to the success story of biomarker-driven targeted therapy, most NSCLC guidelines agree that molecular reflex testing should be performed in all cases with non-squamous cell carcinoma (non-SCC). In contrast, testing recommendations for squamous cell carcinoma (SCC) vary considerably, specifically concerning the exclusion of patients of certain age or smoking status from molecular testing strategies. We performed a retrospective single-center study examining the value of molecular reflex testing in an unselected cohort of 316 consecutive lung SCC cases, tested by DNA- and RNA-based next-generation sequencing (NGS) at our academic institution between 2019 and 2023. Clinicopathological data from these cases were obtained from electronic medical records and correlated with sequencing results. In 21/316 (6.6%) cases, we detected an already established molecular target for an approved drug. Among these were seven cases with an EGFR mutation, seven with a KRAS G12C mutation, four with an ALK fusion, two with an EGFR fusion and one with a METex14 skipping event. All patients harboring a targetable alteration were >50 years of age and most of them had >15 pack-years, questioning restrictive molecular testing strategies. Based on our real-world data, we propose a reflex testing workflow using DNA- and RNA-based NGS that includes all newly diagnosed NSCLC cases, irrespective of histology, but also irrespective of age or smoking status.

Early kinetics of C reactive protein for cancer-agnostic prediction of therapy response and mortality in patients treated with immune checkpoint inhibitors: a multicenter cohort study.

BACKGROUND: C reactive protein (CRP) kinetics have recently been suggested as predictive biomarkers for the efficacy of immune checkpoint inhibitor (ICI) therapy in selected cancer types. The aim of this study was to characterize early CRP kinetics as a tumor-agnostic biomarker for ICI treatment outcomes. METHODS: In this multicenter retrospective cohort study, two independent cohorts of patients with various cancer types undergoing palliative ICI treatment at Austrian academic centers served as the discovery (n=562) and validation cohort (n=474). Four different patterns of CRP kinetics in the first 3 months of ICI therapy were defined (CRP-flare responders, CRP-responders, CRP non-responders, patients with all-normal CRP). Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were defined as coprimary endpoints. Univariable and multivariable logistic regression, landmark analysis and Cox regression including CRP kinetics as time-dependent variable were performed. RESULTS: The ORR in patients with all-normal CRP, CRP responders, CRP flare-responders and CRP non-responders was 41%, 38%, 31% and 12%, respectively. The median OS and PFS estimates were 24.5 months (95% CI 18.5 to not reached) and 8.2 months (95% CI 5.9 to 12.0) in patients with all-normal CRP, 16.1 months (95% CI 12.6 to 19-8) and 6.1 months (95% CI 4.9 to 7.2) in CRP-responders, 14.0 months (95% CI 8.5 to 19.4) and 5.7 months (95% CI 4.1 to 8.5) in CRP flare-responders and 8.1 months (95% CI 5.8 to 9.9) and 2.3 months (95% CI 2.2 to 2.8) in CRP non-responders (log-rank p for PFS and OS<0.001). These findings prevailed in multivariable analysis and could be fully confirmed in our validation cohort. Pooled subgroup analysis suggested a consistent predictive significance of early CRP kinetics for treatment efficacy and outcome independent of cancer type. CONCLUSION: Early CRP kinetics represent a tumor-agnostic predictor for treatment response, progression risk and mortality in patients with cancer undergoing ICI therapy.

Real-world experience with capmatinib in MET exon 14-mutated non-small cell lung cancer (RECAP): a retrospective analysis from an early access program.

Background: Patients with non-small cell lung cancer (NSCLC) presenting with mesenchymal-epithelial transition (MET) exon 14 skipping mutation have an unfavorable prognosis with standard treatments. Capmatinib is a selective MET inhibitor, which showed promising efficacy in this patient population in early trials. Methods: We performed a retrospective, international, multicenter efficacy and safety analysis in patients with NSCLC treated with capmatinib in an early access program between March 2019 and December 2021. Results: Data from 81 patients with advanced MET exon 14 mutated NSCLC treated with capmatinib in first- or later-line therapy were analyzed. Median age was 77 years (range, 48-91), 56% were women, 86% had stage IV disease, and 27% had brain metastases. For all patients, the objective response rate (ORR) to capmatinib was 58% (95% CI, 47-69), whereas it was 68% (95% CI, 50-82) in treatment-naïve and 50% (95% CI, 35-65) in pretreated patients. The median progression-free survival was 9.5 months (95% CI, 4.7-14.3), whereas it was 10.6 months (95% CI, 5.5-15.7) in first-line and 9.1 months (95% CI, 3.1-15.1) in pretreated patients. After a median follow-up of 11.0 months, the median overall survival was 18.2 months (95% CI, 13.2-23.1). In patients with measurable brain metastases (n = 11), the intracranial ORR was 46% (95% CI, 17-77). Capmatinib showed a manageable safety profile. Grade ⩾ 3 treatment-related adverse events included peripheral edema (13%), elevated creatinine (4%), and elevated liver enzymes (3%). Conclusion: In patients with MET exon 14 skipping mutation, capmatinib showed durable systemic and intracranial efficacy and a manageable safety profile. This analysis confirms previously reported phase II data in a real-world setting.

Nintedanib plus Docetaxel after Immune Checkpoint Inhibitor Failure in Patients with Advanced Non-Small-Cell Lung Cancer: A Case Series.

Advances in the treatment of non-small-cell lung cancers (NSCLCs) lacking an actionable driver mutation have included the approval of immunotherapies, such as monotherapy or in combination with chemotherapy. However, limited evidence exists to guide clinical decision-making after progression with immunotherapy. The vascular endothelial growth factor (VEGF) signaling pathway promotes tumor angiogenesis and the development of an immunosuppressive tumor microenvironment (TME). Anti-VEGF treatment is postulated to favor an immunosupportive TME through an "angio-immunogenic switch." Nintedanib, an anti-VEGF receptor treatment, is approved in the EU and other countries, in combination with docetaxel for the treatment of locally advanced, metastatic, or locally recurrent adenocarcinoma NSCLC after failure of first-line chemotherapy. We present a case series from 5 patients treated with nintedanib plus docetaxel, after chemotherapy and immunotherapy, during routine clinical practice in Austria and Hungary. Four patients were treated with nintedanib plus docetaxel as a second- or third-line treatment after chemotherapy and immunotherapy, and a fifth patient received immunotherapy before and after nintedanib plus docetaxel. Although these patients would typically have a poor prognosis, each achieved a partial response with nintedanib plus docetaxel, with response duration from 8 months to over 30 months. Adverse events were manageable. The fifth patient case shows that nintedanib does not preclude later-line immunotherapy or chemotherapy, supporting the angio-immunogenic switch hypothesis. Overall, the case studies indicate that nintedanib plus docetaxel is an effective and well tolerated treatment, after sequential or combined chemo-immunotherapy for advanced NSCLC, and is compatible with a rechallenge with immunotherapy.

Real-world experience with anti-PD-1/PD-L1 monotherapy in patients with non-small cell lung cancer : A retrospective Austrian multicenter study.

OBJECTIVE: As real-world data regarding immunotherapy for non-small cell lung cancer are lacking for Austria, we conducted a retrospective study in six hospitals to present data from real-world practice. METHODS: Patients with metastatic non-small cell lung cancer were stratified into two groups, either patients with first-line pembrolizumab monotherapy (cohort 1) or patients with second-line nivolumab, pembrolizumab or atezolizumab monotherapy (cohort 2). Primary outcome measures were objective response rate and overall survival. A matched-pair analysis was performed to compare overall survival to patients from the Tyrolean Lung Cancer Project as a historical control group. RESULTS: In total, 89 patients were identified, 42 patients in cohort 1 and 47 patients in cohort 2. The objective response rates were 43.3% and 31.4%, respectively. The median overall survival was 17.0 months (95% CI 11.7-21.5 months) in cohort 1 and 18.7 months (95% CI 9.5-23.4 months) in cohort 2. Treatment-related adverse events grades 3 and 4 were reported in 11.2% of patients. The matched-pair analysis showed a median overall survival of 15.2 months (95% CI 7.6-20.4 months) for first-line pembrolizumab monotherapy compared to 9.8 months (95% CI 7.8-11.6 months) for the historical control (p = 0.43). In cohort 2, a median overall survival of 20.3 months (95% CI 6.9-26.2 months) for second-line immunotherapy compared to 5.4 months (95% CI 3.2-11.7 months) for the historical control (p = 0.18) was shown. CONCLUSION: The results are comparable with other real-world studies and, when matched to historical controls, support the improvement in outcomes made possible by these agents.

Reflex testing in non-small cell lung carcinoma using DNA- and RNA-based next-generation sequencing-a single-center experience.

BACKGROUND: Targeted treatment modalities for non-small cell lung carcinoma (NSCLC) patients are expanding rapidly and demand a constant adaptation of molecular testing strategies. In this regard, broad reflex testing via next-generation sequencing (NGS) might have several advantages. However, real-world data regarding practical feasibility and clinical relevance are scarce, especially for RNA-based NGS. METHODS: We performed a retrospective study comparing NGS use in two consecutive years (2019 and 2020). In 2019, reflex testing mainly consisted of DNA-based NGS for mutations and immunohistochemistry (IHC) for ALK, ROS1, and NTRK fusion products. At the beginning of 2020, our approach has changed, with DNA- and RNA-based NGS panels now being simultaneously performed. This change in protocol allowed us to retrospectively evaluate if broad molecular reflex testing brings additional value to lung cancer patients. RESULTS: Within the whole cohort (n=432), both DNA- and RNA-based NGS yielded almost always evaluable results. Only in 6 cases, the RNA content was too little for an appropriate analysis. After integrating RNA-based NGS in the reflex testing approach, the number of detected fusions increased significantly (2.6% vs. 8.2%; P=0.0021), but also more patients received targeted therapies. Furthermore, exceedingly rare alterations were more likely to be detected, including the so far undescribed EGFR-NUP160 fusion. CONCLUSIONS: Our study demonstrates that a comprehensive approach to reflex NGS testing is practically feasible and clinically relevant. Including RNA-based panels in the reflex testing approach results in more detected fusions and more patients receiving targeted therapies. Additionally, this broad molecular profiling strategy identifies patients with emerging biomarkers, underscoring its usefulness in the rapidly evolving landscape of targeted therapies.

Diagnostic accuracy of the Aspergillus-specific bronchoalveolar lavage lateral-flow assay in haematological malignancy patients.

We evaluated the performance of the Aspergillus-specific lateral-flow device (LFD) test for diagnosing invasive pulmonary aspergillosis (IPA) in patients with underlying haematological malignancies. Participating centres were the two Austrian University Hospitals of Graz and Innsbruck. LFD performance was evaluated with 95 bronchoalveolar lavage fluid (BALF) samples from 72 patients collected prospectively in Graz, and with 24 BALF bio bank samples from 23 patients (21 samples with probable IPA) in Innsbruck. Invasive fungal infections were classified according to the revised European Organization of Research and Treatment of Cancer/Mycoses Study Group criteria. Overall, 27 patients (30 samples) had probable IPA, 32 (43 samples) possible and 36 (46 samples) did not fulfil IPA criteria. The vast majority of patients - in particular those with probable IPA - received mould-active treatment before bronchoscopy. Sensitivity, specificity, positive predictive value and negative-predictive-value for probable IPA diagnosis using the BALF-LFD test were 71%, 76%, 35% and 94% for the Graz cohort. Sensitivity of the BALF-LFD test for probable IPA was 57% in Innsbruck bio bank samples. Our results indicate that the BALF-LFD-test provides fast results with moderate sensitivities in patients with underlying haematological malignancies. Similar to other diagnostic tests and biomarkers sensitivity of the test may be influenced by ongoing systemic mould-active treatment.

Pulmonary ascariasis: two cases in Austria and review of the literature.

Ascariasis is the most common helminthic infection, with an estimated worldwide prevalence of 25%. The estimated mortality ranges from 0.8 to 1%. Second stage larvae pass through the intestinal wall and migrate via the portal vein system to the liver and then proceed to the lungs, where they may produce pneumonia and eosinophilia. Symptoms include wheezing, dyspnea, nonproductive cough, hemoptysis, and fever. Two cases of pulmonary ascariasis in Austrian males are reported. Both patients presented with dyspnea, nonproductive cough, fever, and eosinophilia (19 and 26%). One patient additionally had pulmonary infiltrates. Recent travel history was unremarkable in both individuals. Serology for Ascaris was positive twice in both patients, while microscopic examination of stool was negative for helminthic ova. Extensive diagnostic procedures were performed to rule out possible differentials for the patients symptoms. Both patients responded well to antiparasitic treatment with albendazole 400 mg and mebendazole 100 mg q12h for 3 days, respectively. This report highlights the importance of considering parasitic infection in patients presenting with eosinophilia and pulmonary symptoms also in Austria.

Nuclear and cytoplasmic death receptor 5 as prognostic factors in patients with non-small cell lung cancer treated with chemotherapy.

BACKGROUND: Death receptor 4 (DR4) and death receptor 5 (DR5) are tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL) receptors that activate apoptosis via the extrinsic apoptosis pathway. DcR1 and DcR2 are decoy receptors for TRAIL that act antagonistically. Intracellular trafficking of TRAIL receptors has been described, but the role of the subcellular localization of TRAIL receptors in non-small cell lung cancer (NSCLC) progression is unclear. METHODS: Expression and intracellular localization of pro-apoptotic and decoy TRAIL receptors were analyzed by immunohistochemistry in 50 samples of advanced or recurrent NSCLC. Using confocal microscopy, localization of TRAIL receptors was studied in NSCLC cell lines. RESULTS: Cytoplasmic staining for all four TRAIL receptors was observed in the majority of samples. Nuclear staining was infrequent in the case of DR4 (12%) and DcR2 (8%), while DR5 and DcR1 were localized in the nucleus in 27% and 60% of samples. When overall survival was analyzed, cytoplasmic staining for DR5 in tumor cells (P=0.025) and nuclear staining for DR5 in tumor cells (P=0.007) were significant prognostic factors in univariate, as well as in multivariate analysis including clinicopathologic factors (P=0.026 and 0.021, respectively). In A549, NCI-H358, and A427 NSCLC cells all four TRAIL receptors were found to be mainly located perinuclearly, but also in the nucleus. CONCLUSION: The study for the first time shows that TRAIL receptors are found in different intracellular compartments including the nucleus in NSCLC cells and that both nuclear and cytoplasmic DR5 might predict improved survival in patients with advanced NSCLC.

An in vitro mechanistic study to elucidate the desipramine/bupropion clinical drug-drug interaction.

There are documented clinical drug-drug interactions between bupropion and the CYP2D6-metabolized drug desipramine resulting in marked (5-fold) increases in desipramine exposure. This finding was unexpected as CYP2D6 does not play a significant role in bupropion clearance, and bupropion and its major active metabolite, hydroxybupropion, are not strong CYP2D6 inhibitors in vitro. The aims of this study were to investigate whether bupropion's reductive metabolites, threohydrobupropion and erythrohydrobupropion, contribute to the drug interaction with desipramine. In human liver microsomes using the CYP2D6 probe substrate bufuralol, erythrohydrobupropion and threohydrobupropion were more potent inhibitors of CYP2D6 activity (K(i) = 1.7 and 5.4 microM, respectively) than hydroxybupropion (K(i) = 13 microM) or bupropion (K(i) = 21 microM). Furthermore, neither bupropion nor its metabolites were metabolism-dependent CYP2D6 inhibitors. Using the in vitro kinetic constants and estimated liver concentrations of bupropion and its metabolites, modeling was able to predict within 2-fold the increase in desipramine exposure observed when coadministered with bupropion. This work indicates that the reductive metabolites of bupropion are potent competitive CYP2D6 inhibitors in vivo and provides a mechanistic explanation for the clinical drug-drug interaction between bupropion and desipramine.

Telemedicine and teledermatology: Past, present and future.

Telemedicine is an emerging field within medicine with potential to revolutionize the delivery of health care. It is defined as the use of telecommunication technologies to transfer medical information. Teledermatology is a category of telemedicine. Early experiments were already made at the beginning of the 20(th) century, the breakthrough happened in the nineties because of the rapid progress of telecommunication technology. The latest advance is mobile telemedicine which is characterized by the use of mobile devices such as mobile phone and PDA (personal digital assistant). Advantages of telemedicine are the possibility of remote patient-care as well as the easy and fast access to expert opinions and education. This can either happen through exchange of previously stored data/images (store-and-forward method) or in real time. Since our society is increasingly becoming interconnected via technical advances, it is essential that medicine also has an objective understanding of the topic.