Trastuzumab-Emtansine and Osimertinib Combination Therapy to Target HER2 Bypass Track Resistance in EGFR Mutation-Positive NSCLC.

Introduction: EGFR tyrosine kinase inhibitor improved the survival of patients with metastatic EGFR mutation-positive (EGFRm+) NSCLC. Despite high response rates, resistance develops inevitably in every patient. In up to 13%, HER2 protein overexpression is found on progression. We hypothesized that dual blockade of EGFR and HER2 by osimertinib combined with trastuzumab-emtansine (T-DM1) could reinduce tumor responses. Methods: In this multicenter, single-arm, phase 1-2 study (NCT03784599), patients with EGFRm+ NSCLC, progressing on osimertinib and HER2 overexpression were included. Patients were treated with T-DM1 3.6 mg/kg (intravenously) every 3 weeks and osimertinib 80 mg once a day. Primary end points were objective response rate (ORR) at 12 weeks and safety. Responses were assessed every 6 weeks (Response Evaluation Criteria in Solid Tumors 1.1). Sample size was calculated using Simon's two-stage minimax design (H0 = 41%, H1 > 55%, 80% power, one-sided type I error 10%: a ORR 16 of 36 was needed to proceed to 58 patients). Results: From January 2019 to April 2021, 27 patients were enrolled. ORR after 12 weeks of treatment was 4% (1 of 27). Median progression-free survival was 2.8 months (95% confidence interval: 1.4-4.6 mo). Most frequent treatment-related adverse events of any grade were fatigue, diarrhea, and nausea, among these, grade 3 in four patients. There were no grade 4 or 5 therapy-related adverse events. Conclusions: TRAEMOS (Trastuzumab-Emtansine and Osimertinib) is the first trial combining T-DM1 and osimertinib in patients with EGFRm+ NSCLC to target HER2 overexpression at osimertinib resistance. Safety profile was favorable compared with cytotoxic chemotherapy; but treatment revealed limited efficacy. Further clinical evaluation of this regimen is not warranted.

The value of prognostic and predictive parameters in early-stage lung adenocarcinomas: A comparison between biopsies and resections.

INTRODUCTION: Since lung adenocarcinoma (LUAD) biopsies are usually small, it is questionable if their prognostic and predictive information is comparable to what is offered by large resection specimens. This study compares LUAD biopsies and resection specimens for their ability to provide prognostic and predictive parameters. METHODS: We selected 187 biopsy specimens with stage I and II LUAD. In 123 cases, subsequent resection specimens were also available. All specimens were evaluated for growth pattern, nuclear grade, fibrosis, inflammation, and genomic alterations. Findings were compared using non-parametric testing for categorical variables. Model performance was assessed using the area under the curve for both biopsies and resection specimens, and overall (OS) and disease-free survival (DFS) was calculated. RESULTS: The overall growth pattern concordance between biopsies and resections was 73.9%. The dominant growth pattern correlated with OS and DFS in resected adenocarcinomas and for high-grade growth pattern in biopsies. Multivariate analysis of biopsy specimens revealed that T2-tumors, N1-status, KRAS mutations and a lack of other driver mutations were associated with poorer survival. Model performance using clinical, histological and genetic data from biopsy specimens for predicting OS and DSF demonstrated an AUC of 0.72 and 0.69, respectively. CONCLUSIONS: Our data demonstrated the prognostic relevance of a high-grade growth pattern in biopsy specimens of LUAD. Combining clinical, histological and genetic information in one model demonstrated a suboptimal performance for DFS prediction and good performance for OS prediction. However, for daily practice, more robust (bio)markers are required to predict prognosis and stratify patients for therapy and follow-up.

Cost-effectiveness of proton radiotherapy versus photon radiotherapy for non-small cell lung cancer patients: Exploring the model-based approach.

INTRODUCTION: Proton radiotherapy (PT) is a promising but more expensive strategy than photon radiotherapy (XRT) for the treatment of non-small cell lung cancer (NSCLC). PT is probably not cost-effective for all patients. Therefore, patients can be selected using normal tissue complication probability (NTCP) models with predefined criteria. This study aimed to explore the cost-effectiveness of three treatment strategies for patients with stage III NSCLC: 1. photon radiotherapy for all patients (XRTAll); 2. PT for all patients (PTAll); 3. PT for selected patients (PTIndividualized). METHODS: A decision-analytical model was constructed to estimate and compare costs and QALYs of all strategies. Three radiation-related toxicities were included: dyspnea, dysphagia and cardiotoxicity. Costs and QALY's were incorporated for grade 2 and ≥ 3 toxicities separately. Incremental Cost-Effectiven Ratios (ICERs) were calculated and compared to a threshold value of €80,000. Additionally, scenario, sensitivity and value of information analyses were performed. RESULTS: PTAll yielded most QALYs, but was also most expensive. XRTAll was the least effective and least expensive strategy, and the most cost-effective strategy. For thresholds higher than €163,467 per QALY gained, PTIndividualized was cost-effective. When assuming equal minutes per fraction (15 minutes) for PT and XRT, PTIndividualized was considered the most cost-effective strategy (ICER: €76,299). CONCLUSION: Currently, PT is not cost-effective for all patients, nor for patient selected on the current NTCP models used in the Dutch indication protocol. However, with improved clinical experience, personnel and treatment costs of PT can decrease over time, which potentially leads to PTIndividualized, with optimal patient selection, will becoming a cost-effective strategy.

Results of screening in early and advanced thoracic malignancies in the EORTC pan-European SPECTAlung platform.

Access to a comprehensive molecular alteration screening is patchy in Europe and quality of the molecular analysis varies. SPECTAlung was created in 2015 as a pan-European screening platform for patients with thoracic malignancies. Here we report the results of almost 4 years of prospective molecular screening of patients with thoracic malignancies, in terms of quality of the program and molecular alterations identified. Patients with thoracic malignancies at any stage of disease were recruited in SPECTAlung, from June 2015 to May 2019, in 7 different countries. Molecular tumour boards were organised monthly to discuss patients' molecular and clinical profile and possible biomarker-driven treatments, including clinical trial options. FFPE material was collected and analysed for 576 patients with diagnosis of pleural, lung, or thymic malignancies. Ultimately, 539 patients were eligible (93.6%) and 528 patients were assessable (91.7%). The turn-around time for report generation and molecular tumour board was 214 days (median). Targetable molecular alterations were observed in almost 20% of cases, but treatment adaptation was low (3% of patients). SPECTAlung showed the feasibility of a pan-European screening platform. One fifth of the patients had a targetable molecular alteration. Some operational issues were discovered and adapted to improve efficiency.

Impact of the coronavirus disease 2019 pandemic on cancer treatment: the patients' perspective.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has inevitable consequences for medical care of patients without COVID-19. To assess the impact of this pandemic on oncological care, a nationwide survey was conducted among patients with cancer in the Netherlands. METHODS: The patients' perspective on oncological care was investigated using an online survey between March 29th 2020 and April 18th 2020. The survey consisted of 20 questions on four topics: patients' characteristics, contact with the hospital, consequences of the COVID-19 pandemic and concerns about COVID-19. RESULTS: Five thousand three hundred two patients with cancer completed this nationwide survey. Overall, 30% of patients reported consequences for their oncological treatment or follow-up. In the majority of cases, this resulted in conversion from hospital visit to consultation by phone or video. The most frequently adjusted treatments were chemotherapy (30%) and immunotherapy (32%). Among patients with delay and discontinuation of treatment, 55% and 63% of patients, respectively, were (very) concerned about these consequences of the COVID-19 pandemic. Consequences were independent of regional differences in COVID-19 incidence. However, patients in regions with high COVID-19 incidence were significantly more concerned. CONCLUSION: This is the first study investigating perspectives of patients with cancer during the COVID-19 pandemic. The study demonstrates the significant impact of the COVID-19 crisis on oncological care, indicating the need for psycho-oncological support during this pandemic.

Pre-cachexia in patients with stages I-III non-small cell lung cancer: systemic inflammation and functional impairment without activation of skeletal muscle ubiquitin proteasome system.

Cachexia is a prevalent phenomenon of non-small cell lung cancer (NSCLC) which is responsible for increased mortality and deterioration of physical performance. Preclinical research indicates that systemic inflammation induces cachexia-related muscle wasting through muscular Nuclear Factor-kappa B (NF-κB) signaling and subsequent ubiquitin proteasome system (UPS)-mediated proteolysis. As these pathways could be a target for early intervention strategies, it needs to be elucidated whether increased activation of these pathways is already present in early stage NSCLC cachexia. The aim of the present study was therefore to assess muscular NF-κB and UPS activation in patients with NSCLC pre-cachexia. Sixteen patients with newly diagnosed stages I-III NSCLC having <10% weight loss and ten healthy controls were studied. Body composition, systemic inflammation and exercise capacity were assessed in all subjects and NF-κB and UPS activity in vastus lateralis muscle biopsies in a subset. Patients showed increased plasma levels of C-reactive protein (CRP) (P<0.001), soluble Tumor Necrosis Factor receptor 1 (sTNF-R1) (P<0.05), fibrinogen (P<0.001) and decreased levels of albumin (P<0.001). No changes in fat free body mass or skeletal muscle NF-κB and UPS activity were observed, while peak oxygen consumption ( [Formula: see text] ) was significantly decreased in patients compared with healthy controls. In conclusion, this exploratory study demonstrates significantly reduced exercise capacity in NSCLC pre-cachexia despite maintenance of muscle mass and unaltered indices of UPS activation. The absence of muscular NF-κB-dependent inflammatory signaling supports the notion that transition of systemic to local inflammation is required to initiate UPS-dependent muscle wasting characteristic for (experimental) cachexia.

Topoisomerase IIalpha and other drug resistance markers in advanced non-small cell lung cancer.

Resistance to chemotherapy is common in non-small cell lung cancer. The aim of this study was to investigate the prognostic impact of in vitro established drug resistance markers on the response to chemotherapy in patients with advanced non-small cell lung cancer. Samples of 38 patients were analyzed by immunohistochemical staining, for topoisomerase IIalpha and IIbeta, Ki-67, MRP and LRP. In addition, mutation analysis of the topoisomerase IIalpha gene, the B/DNBS and the Tyr804 region, was performed. Lung tumor biopsies were taken prior for treatment with one of the following regimens; cisplatin/paclitaxel, cisplatin/VM26 or VP16, or carboplatin/VP16/ifosfamide. Seventeen patients obtained a partial response, 12 had stable disease and nine patients had progressive disease. None of the investigated markers was related with overall response rate. In one sample a point mutation in the B/DNBS region of the topo IIalpha gene was detected which substitutes IIe(510) with Val. This tumor had a partial response to four courses of cisplatin/VP16 treatment. The survival analysis showed that the patients with high topo IIalpha expressing tumors had a significantly worse survival compared with the patients with low or intermediate topo IIalpha expressing tumors. In conclusion, no relation was observed between expression of topoisomerase IIalpha, IIbeta, Ki-67, MRP or LRP and response rate. Furthermore, worse survival was seen in patients with high topoisomerase IIalpha expressing tumors. In one tumor sample, a newly described mutation in the B/DNBS region of the topo IIalpha gene was detected, which does not appear to be related to drug resistance.