Dual MET and ERBB inhibition overcomes intratumor plasticity in osimertinib-resistant-advanced non-small-cell lung cancer (NSCLC).

BACKGROUND: Third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib are the last line of targeted treatment of metastatic non-small-cell lung cancer (NSCLC) EGFR-mutant harboring T790M. Different mechanisms of acquired resistance to third-generation EGFR-TKIs have been proposed. It is therefore crucial to identify new and effective strategies to overcome successive acquired mechanisms of resistance. METHODS: For Amplicon-seq analysis, samples from the index patient (primary and metastasis lesions at different timepoints) as well as the patient-derived orthotopic xenograft tumors corresponding to the different treatment arms were used. All samples were formalin-fixed paraffin-embedded, selected and evaluated by a pathologist. For droplet digital PCR, 20 patients diagnosed with NSCLC at baseline or progression to different lines of TKI therapies were selected. Formalin-fixed paraffin-embedded blocks corresponding to either primary tumor or metastasis specimens were used for analysis. For single-cell analysis, orthotopically grown metastases were dissected from the brain of an athymic nu/nu mouse and cryopreserved at -80°C. RESULTS: In a brain metastasis lesion from a NSCLC patient presenting an EGFR T790M mutation, we detected MET gene amplification after prolonged treatment with osimertinib. Importantly, the combination of capmatinib (c-MET inhibitor) and afatinib (ErbB-1/2/4 inhibitor) completely suppressed tumor growth in mice orthotopically injected with cells derived from this brain metastasis. In those mice treated with capmatinib or afatinib as monotherapy, we observed the emergence of KRAS G12C clones. Single-cell gene expression analyses also revealed intratumor heterogeneity, indicating the presence of a KRAS-driven subclone. We also detected low-frequent KRAS G12C alleles in patients treated with various EGFR-TKIs. CONCLUSION: Acquired resistance to subsequent EGFR-TKI treatment lines in EGFR-mutant lung cancer patients may induce genetic plasticity. We assess the biological insights of tumor heterogeneity in an osimertinib-resistant tumor with acquired MET-amplification and propose new treatment strategies in this situation.

Efficacy and safety of nivolumab for patients with pre-treated type B3 thymoma and thymic carcinoma: results from the EORTC-ETOP NIVOTHYM phase II trial.

BACKGROUND: Thymic malignancies are rare intrathoracic tumors, which may be aggressive and difficult to treat. They represent a therapeutic challenge in the advanced/metastatic setting, with limited treatment options after the failure of first-line platinum-based chemotherapy. They are frequently associated with autoimmune disorders that also impact oncological management. MATERIALS AND METHODS: NIVOTHYM is an international, multicenter, phase II, two-cohort, single-arm trial evaluating the activity and safety of nivolumab [240 mg intravenously (i.v.) q2 weeks] alone or with ipilimumab (1 mg /kg i.v. q6 weeks) in patients with advanced/relapsed type B3 thymoma or thymic carcinoma, after exposure to platinum-based chemotherapy. The primary endpoint is progression-free survival rate at 6 months (PFSR-6) based on RECIST 1.1 as per independent radiological review. RESULTS: From April 2018 to February 2020, 55 patients were enrolled in 15 centers from 5 countries. Ten patients (18%) had type B3 thymoma and 43 (78%) had thymic carcinoma. The majority were male (64%), and the median age was 58 years. Among the 49 eligible patients who started treatment, PFSR-6 by central review was 35% [95% confidence interval (CI) 22% to 50%]. The overall response rate and disease control rate were 12% (95% CI 5% to 25%) and 63% (95% CI 48% to 77%), respectively. Using the Kaplan-Meier method, median progression-free survival and overall survival by local assessment were 6.0 (95% CI 3.1-10.4) months and 21.3 (95% CI 11.6-not estimable) months, respectively. In the safety population of 54 patients, adverse events (AEs) of grade 1/2 were observed in 22 (41%) patients and grade 3/4 in 31 (57%) patients. Treatment-related AEs of grade 4 included one case of neutropenia, one case of immune-mediated transaminitis, and two cases of myocarditis. CONCLUSIONS: Nivolumab monotherapy demonstrated an acceptable safety profile and objective activity, although it has been insufficient to meet its primary objective. The second cohort of NIVOTHYM is currently ongoing to assess the combination of nivolumab plus ipilimumab.

SEOM clinical guidelines for the treatment of malignant pleural mesothelioma (2020).

Mesothelioma is a rare and aggressive tumour with dismal prognosis arising in the pleura and associated with asbestos exposure. Its incidence is on the rise worldwide. In selected patients with early-stage MPM, a maximal surgical cytoreduction in combination with additional antitumour treatment may be considered in selected patients assessed by a multidisciplinary tumor board. In patients with unresectable or advanced MPM, chemotherapy with platinum plus pemetrexed is the standard of care. Currently, no standard salvage therapy has been approved yet, but second-line chemotherapy with vinorelbine or gemcitabine is commonly used. Novel therapeutic approaches based on dual immunotherapy or chemotherapy plus immunotherapy demonstrated promising survival benefit and will probably be incorporated in the future.

How to integrate current knowledge in selecting patients for first line in NSCLC?

Non-small-cell lung cancer (NSCLC) accounts for 80% of all lung cancer, which is the leading cause of cancer mortality. The majority of NSCLC patients present with advanced disease at diagnosis. Standard chemotherapy using platinum-containing doublets has reached a therapeutic plateau with a median survival of ~1 year. The development of more effective strategies in the first-line setting remains challenging. In selected chemotherapy-naïve, advanced, non-squamous patients, the combination of bevacizumab with chemotherapy was shown to produce better outcomes than chemotherapy alone. The potential benefit of maintenance/sequential treatment after initial platinum-based chemotherapy should be discussed in detail with each patient. Epidermal growth factor receptor (EGFR) mutation determination should be carried out in subgroups of patients characterized by a high prevalence of sensitizing mutations. When a mutation is present, first-line treatment with an EGFR tyrosine kinase inhibitor may be considered. Finally, a phase I study using an oral ALK inhibitor has produced promising results in NSCLC patients with ALK rearrangements, indicating that ALK represents a new therapeutic target in a molecularly defined subset of NSCLC. Ongoing studies in first-line therapy are focusing on targeted therapies and patient selection.

Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients.

BACKGROUND: Promising results have been reported with immune checkpoint inhibitors (ICI) in a small proportion of MPM patients. MMR deficiency (dMMR) has been well described in several malignancies and was approved as a biomarker for anti-PD-1 inhibitors. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM including a subset of patients treated with immunotherapy. METHODS: Tumors of 159 MPM p diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR (MMR protein expression negative) and MMR intact (all MMR proteins positively expressed). We retrospectively collected clinical outcomes under standard chemotherapy and experimental immunotherapy in the entire cohort. RESULTS: MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. Twenty two patients received ICI with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1-26.1 m). The median overall survival (mOS) in all population was 15 months (m) (13.5-18.8 m). In a multivariable model factors associated to improved mOS were PS 0, neutrophil-lymphocyte ratio (NLR) < 5 and epithelioid histology (p < 0.001). CONCLUSIONS: In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate potential predictive biomarkers of ICI benefit in MPM.

Immune-checkpoint inhibition in first-line treatment of advanced non-small cell lung cancer patients: Current status and future approaches.

Immune checkpoint inhibitors are considered standard second-line treatment in advanced non-small cell lung cancer patients. This strategy has also become standard in first-line setting for a subgroup of patients with strongly positive PD-L1 tumors; therefore, PD-L1 status might be considered a new biomarker that deserves upfront testing. New combinations of immune checkpoint inhibitors and with chemotherapy have been tested in first-line treatment. However, some questions remain unanswered such as the best treatment strategy or the real upfront efficacy of these therapeutic strategies in the whole lung cancer population. In this review we summarize the main results in the first-line setting of recent phase III trials with immune checkpoint inhibitors in advanced non-small cell lung cancer patients.

SEOM clinical guidelines for the treatment of malignant pleural mesothelioma (2020)

Mesothelioma is a rare and aggressive tumour with dismal prognosis arising in the pleura and associated with asbestos exposure. Its incidence is on the rise worldwide. In selected patients with early-stage MPM, a maximal surgical cytoreduction in combination with additional antitumour treatment may be considered in selected patients assessed by a multidisciplinary tumor board. In patients with unresectable or advanced MPM, chemotherapy with platinum plus pemetrexed is the standard of care. Currently, no standard salvage therapy has been approved yet, but second-line chemotherapy with vinorelbine or gemcitabine is commonly used. Novel therapeutic approaches based on dual immunotherapy or chemotherapy plus immunotherapy demonstrated promising survival benefit and will probably be incorporated in the future (AU)

Analysis of expression of PTEN/PI3K pathway and programmed cell death ligand 1 (PD-L1) in malignant pleural mesothelioma (MPM).

BACKGROUND: Malignant pleural mesothelioma (MPM) frequently express elevated AKT/mTOR activity. Previous reports in gliomas, colon, breast and prostate cancer suggest that PTEN/PI3K pathway may be important for the induction of PD-L1 expression. This study explored the expression of PTEN/PI3K pathway and PD-L1 in MPM and its relationship with the patient́s prognosis MATERIAL AND METHODS: Twenty seven consecutive MPM patients were reviewed. Formalin-fixed, paraffin-embedded tissue biopsies were used for immunohistochemical analysis of PTEN/PI3K pathway and PD-L1 RESULTS: Expression of PTEN, mTOR, pAKT, p4EBP1, peif4E, pS6 and FOXO3a was found in 88.5%, 92.3%, 78.3%, 38.5%, 100%, 52.2% and 100% of tumors and PD-L1 in 23%. We found a significant correlation between pAKT, FOXO3a and PD-L1 expression and longer overall survival (p <0.05). We did not identify significant association between the level of PD-L1 expression and alterations in PI3K pathway CONCLUSIONS: This study shows PTEN/PI3K pathway and PD-L1 in MPM are frequently activated. Our results suggests that there is not association between PD-L1 and the involvement of the PI3K pathway in MPM.

Expression of Wilms' tumor gene (WT1) is associated with survival in malignant pleural mesothelioma.

INTRODUCTION: Calretinin and Wilms' tumor gene (WT1) are mesothelial markers routinely used to confirm the diagnosis of malignant pleural mesothelioma (MPM). We investigated the prognostic value of calretinin and WT1 expression in predicting survival in a series of patients diagnosed with MPM in our institution. MATERIALS AND METHODS: Fifty-two patients diagnosed of MPM were retrospectively reviewed. Calretinin and WT1 were stained for IHC analysis in formalin-fixed, paraffin-embedded sections and positivity was considered for tumors with >1 % of tumor cells stained. Survival data were calculated by the Kaplan-Meier method and Cox regression was used to evaluate the prognostic value of the variables. RESULTS: Calretinin IHC expression was positive in 83.7 % of patients and WT1 in 78.1 %. A significant association of calretinin and WT1 expression with epithelial histology was detected (p = 0.030 and p = 0.010). We found a significant increase in OS in patients with epithelial subtype, PS1 and neutrophil-lymphocyte ratio (NLR) ≤5 (p < 0.05). In the IHC markers analysis, we found a significant increase in OS for patients with WT1 positive expression (16.4 vs. 2.3 m, p = 0.013), but not differences for calretinin expression (16.6 vs. 5.0 months, p = 0.37). In the multivariate analysis, epithelial histology and WT1 remained as significant prognostic factors for survival (p = 0.004 and p = 0.010, respectively). CONCLUSION: In our series of 52 MPM patients, epithelial histology, PS, NLR and WT1 expression are significant prognostic factors for survival. We concluded that WT1, but not calretinin, is a useful prognostic factor in MPM. The role of WT1 assessment is worth of prospective validation in future studies on MPM.

Rectal metastases from squamous cell carcinoma: a case report and review of the literature.

Non-small-cell lung cancer (NSCLC) represents 85% of lung cancer. The most frequent sites of distant metastasis are the liver, adrenal glands, bones and brain. Gastrointestinal metastases are uncommon and rectal metastases are extremely rare. Here we report a case of squamous cell carcinoma of the lung with rectal metastases.

Neutrophil to lymphocyte ratio (NLR) as an indicator of poor prognosis in stage IV non-small cell lung cancer.

BACKGROUND: Neutrophil to lymphocyte ratio (NLR), an index of systemic inflammation, has been associated with worse survival for many types of cancer. The aim of this study is to investigate the clinical significance of the blood NLR as a prognostic factor in non-small cell lung cancer (NSCLC) patients. METHODS AND PATIENTS: Stage IV NSCLC patients diagnosed in our institution between April 2004 and March 2009 were retrospectively reviewed. Potential prognostic factors such as histology, gender, performance status, response to chemotherapy and NLR were analyzed. NLR was assessed baseline and during chemotherapy treatment. Overall survival (OS) and progression free survival (PFS) were calculated by the Kaplan-Meier method. RESULTS: A total of 171 patients were included in the study and 60 patients (35.1 %) presented a NLR ≥ 5. Median survival for the entire cohort was 9.3 months. We found that patients with undifferentiated carcinoma and patients with NLR ≥ 5 had a worse survival. Median PFS of patients with NLR <5 was 5.62 months and in patients with NLR ≥ 5 was 3.25 months (p = 0.098), and OS was 11.1 versus 5.6 months for patients with NLR<5 and NLR ≥ 5, respectively (p = 0.017). During the chemotherapy treatment, patients who normalized NLR after one cycle presented better outcomes (OS 8.7 vs. 4.3 months, p = 0.001, for patients who normalized NLR and for patients who remained persistently elevated). After multivariate analysis, histology and NLR remained independent predictors of survival (p < 0.05). CONCLUSION: In our analysis, elevated NLR is a predictor of shorter survival in patients with advanced NSCLC and the variation of NLR during the first cycle of treatment predicts survival. NLR is an easily measured, reproducible test that could be considered to be incorporated in the routine practice in NSCLC patients.

Exploratory analysis of activation of PTEN-PI3K pathway and downstream proteins in malignant pleural mesothelioma (MPM).

BACKGROUND: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with elevated AKT/mTOR activity. We aimed to identify the expression and phosphorylation status of PTEN, PI3K and downstream signaling in MPM. PATIENTS AND METHODS: Thirty consecutive MPM patients were identified. Clinical data analyzed: sex, age, histology, performance status (PS), white blood count, and neutrophil-lymphocyte ratio (NLR). Paraffin-embedded biopsies were used for immunohistochemical analysis. RESULTS: Overexpression of PTEN, pMAPK, mTOR, pAKT, 4E-BP1, p4E-BP1, eIF-4E, peIF-4E, p-S6 and FOXO3a in MPM was found in 90%, 100%, 93.3%, 80%, 100%, 43.3%, 96.7%, 100%, 63.3% and 100% of tumors respectively. There was a significant correlation between low pS6 protein expression and longer progression free survival (PFS: 7.9 vs 5.6 months; p = 0.04) and overall survival (OS: 23.4 vs 5.6 months; p = 0.05). Patients with concomitant low expression of pS6 and p4E-BP1 and overexpression of FOXO3a had significantly better prognosis (34.6 vs 1.9 months; p = 0.004). In multivariate analysis, histology and NLR were independent prognostic factors (p = 0.02 and p = 0.04 respectively), but pS6 only showed a trend (p = 0.8). CONCLUSIONS: This study shows PI3K pathway and downstream proteins in MPM are frequently activated and provides prognostic information. The role of PI3K pathway is worth of prospective validation in future studies on MPM.

Expression of Wilms’ tumor gene (WT1) is associated with survival in malignant pleural mesothelioma

INTRODUCTION: Calretinin and Wilms' tumor gene (WT1) are mesothelial markers routinely used to confirm the diagnosis of malignant pleural mesothelioma (MPM). We investigated the prognostic value of calretinin and WT1 expression in predicting survival in a series of patients diagnosed with MPM in our institution. MATERIALS AND METHODS: Fifty-two patients diagnosed of MPM were retrospectively reviewed. Calretinin and WT1 were stained for IHC analysis in formalin-fixed, paraffin-embedded sections and positivity was considered for tumors with >1 % of tumor cells stained. Survival data were calculated by the Kaplan-Meier method and Cox regression was used to evaluate the prognostic value of the variables. RESULTS: Calretinin IHC expression was positive in 83.7 % of patients and WT1 in 78.1 %. A significant association of calretinin and WT1 expression with epithelial histology was detected (p = 0.030 and p = 0.010). We found a significant increase in OS in patients with epithelial subtype, PS1 and neutrophil-lymphocyte ratio (NLR) ≤5 (p < 0.05). In the IHC markers analysis, we found a significant increase in OS for patients with WT1 positive expression (16.4 vs. 2.3 m, p = 0.013), but not differences for calretinin expression (16.6 vs. 5.0 months, p = 0.37). In the multivariate analysis, epithelial histology and WT1 remained as significant prognostic factors for survival (p = 0.004 and p = 0.010, respectively). CONCLUSION: In our series of 52 MPM patients, epithelial histology, PS, NLR and WT1 expression are significant prognostic factors for survival. We concluded that WT1, but not calretinin, is a useful prognostic factor in MPM. The role of WT1 assessment is worth of prospective validation in future studies on MPM (AU)

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Neutrophil to lymphocyte ratio (NLR) as an indicator of poor prognosis in stage IV non-small cell lung cancer

BACKGROUND: Neutrophil to lymphocyte ratio (NLR), an index of systemic inflammation, has been associated with worse survival for many types of cancer. The aim of this study is to investigate the clinical significance of the blood NLR as a prognostic factor in non-small cell lung cancer (NSCLC) patients. METHODS AND PATIENTS: Stage IV NSCLC patients diagnosed in our institution between April 2004 and March 2009 were retrospectively reviewed. Potential prognostic factors such as histology, gender, performance status, response to chemotherapy and NLR were analyzed. NLR was assessed baseline and during chemotherapy treatment. Overall survival (OS) and progression free survival (PFS) were calculated by the Kaplan-Meier method. RESULTS: A total of 171 patients were included in the study and 60 patients (35.1 %) presented a NLR ≥ 5. Median survival for the entire cohort was 9.3 months. We found that patients with undifferentiated carcinoma and patients with NLR ≥ 5 had a worse survival. Median PFS of patients with NLR <5 was 5.62 months and in patients with NLR ≥ 5 was 3.25 months (p = 0.098), and OS was 11.1 versus 5.6 months for patients with NLR<5 and NLR ≥ 5, respectively (p = 0.017). During the chemotherapy treatment, patients who normalized NLR after one cycle presented better outcomes (OS 8.7 vs. 4.3 months, p = 0.001, for patients who normalized NLR and for patients who remained persistently elevated). After multivariate analysis, histology and NLR remained independent predictors of survival (p < 0.05). CONCLUSION: In our analysis, elevated NLR is a predictor of shorter survival in patients with advanced NSCLC and the variation of NLR during the first cycle of treatment predicts survival. NLR is an easily measured, reproducible test that could be considered to be incorporated in the routine practice in NSCLC patients (AU)

Computed tomography (CT) predicts accurately the pathologic tumour size in stage I non-small-cell lung cancer (NSCLC)

INTRODUCTION: In stage I non-small-cell lung cancer (NSCLC) tumour size has been the most consistent determinant of survival. The choice of therapy option is based on accurate definition of the stage. The aim of our study is to correlate tumour size by computed tomography scan (CT) with pathologic size and to determine possible prognostic factors in surgically resected pathologic stage IA and IB NSCLC patients. METHODS: Retrospective review of CT scans and medical history data from 89 pathologic stage I NSCLC patients. Clinical prognostic factors analysed were age, gender, smoking status, pulmonary function, performance status (PS), surgical procedure, histopathology, vessel invasion, pleural infi ltration, tumour size and number of lymph nodes resected. According to the new TNM classification for lung cancer, tumour size was divided into five groups (I: <2 cm, II: 2-3 cm, III: 3-5 cm, IV: 5-7 cm and V: >7 cm). RESULTS: After a median surveillance of 55.2 months, 42 patients relapsed and 55 had died. The 5-year progressionfree survival was 55.7% and 5-year overall survival (OS) 49.9% (median 58.97 months). None of the clinical parameters analysed were predictors of OS. Significant correlation was found between tumour size in CT scan and pathologic stage (Pearson 0.75). CONCLUSIONS: In our analysis with 89 surgically resected stage IA and IB NSCLC patients we found a good correlation between clinical and pathologic tumour size by CT scan. The prognoses factors analysed had no significant impact on survival (AU)