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Rafael Rosell



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    Session 9: Poster Discussion # 1: Diagnosis, Early Stage and Locally Advanced (ID 23)

    • Event: LALCA 2019
    • Type: Poster Discussion Session
    • Track:
    • Presentations: 1
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      F9.07 - Poster Discussion (ID 951)

      16:15 - 17:15  |  Presenting Author(s): Rafael Rosell

      • Abstract
      • Slides

      Abstract not provided

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    EP1.04 - Immuno-oncology (ID 194)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 3
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.04-44 - Exploration of Factors Relating to Paradoxical Immune Response in Patients Treated with Immune Checkpoint Inhibitors for NSCLC (Now Available) (ID 2634)

      08:00 - 18:00  |  Author(s): Rafael Rosell

      • Abstract
      • Slides

      Background

      Although the introduction of immune checkpoint inhibitors (ICIs) has yielded substantial benefits in terms of survival in the treatment of Non-Small Cell Lung Cancer (NSCLC), the possibility of activation of dormant autoimmune diseases or onset of immune mediated toxicities is a reality. The objective of this study was to explore intrinsic immunological factors associated with poor outcomes.

      Method

      In a retrospective cohort study of 48 patients, without any prior medical history of autoimmunity, treated for advanced/metastatic NSCLC with ICI´s were assessed. Determination of HLA-A*02011 as well as acute phase reactants and antiphospholipid antibodies was performed. Additionally, evaluation of survival in a time to event manner was conducted using the Kaplan Meier method and Cox regressions

      Result

      Median follow-up was 27.3 months, of the included patients 26 were male (54%) with a median age of 62 years old and there were no individuals with and ECOG performance score >1. Median overall survival (OS) was reached at 22.47 months. When analyzing the presence of the HLA-A*02011 serotype, 6 patients tested positive (12.5%). Additionally, all presented with borderline or abnormal B2glycoprotein IgM and IgG, 2Bmicroglubulin and elevated C reactive protein. Four patients (66%) experienced reactive lymphadenopathy during treatment and all suffered some form of venous thromboembolism. When analyzing OS, this group of patients had a significantly worse outcome (6.53 vs 22.47 months, HR= 4.47, [95%CI 1.47 – 13.61], p<0.001) compared with their counterparts. Overall response rate for the whole was superior for the HLA-A*02011 positive patients achieving 41.4% and 33%, p<0.001, respectively.

      Conclusion

      The presence of the HLA-A*02011 could potentially predispose to a paradoxical and pathological activation of the immune system without offering any benefit in terms of tumor control. Larger studies validating these findings are warranted.

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      EP1.04-45 - Relevance of Antibiotic Use on Clinical Activity of Immune Checkpoint Inhibitors in Hispanic Patients with Advanced NSCLC (CLICAP-ABs) (Now Available) (ID 2674)

      08:00 - 18:00  |  Author(s): Rafael Rosell

      • Abstract
      • Slides

      Background

      The composition of gut microbiota affects antitumor immune responses, as well as preclinical and clinical outcomes following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may influence the effectiveness of ICI.

      Method

      We examined patients with advanced non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy alone or in combination in three different countries of Latin America. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression free survival (PFS) and overall survival (OS) were assessed.

      Result

      18 of 140 (13%) NSCLC patients received ATB. The most commonly used ATB were b-lactam or quinolones for pneumonia or urinary tract infections. In NSCLC patients, ATB was associated with 4 cases of primary PD (28.6% versus 31.5%, P=0.818), non-significant decreased PFS (median 2.66 versus 1.94 months, HR 1.63, [95% CI 0.71-3.72], P=0.247) and significantly deleterious OS (median 12.42 versus 2.04 months, HR 2.3, [95% CI 1.08-4.95], P=0.03). In multivariate analyses, the impact of ATB remained significant for OS.

      Conclusion

      ATB were associated with reduced clinical benefit from ICI in Hispanic patients with NSCLC. Modulation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.

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      EP1.04-46 - Immunotherapy at Any Line Improves Survival in Hispanic Patients with Advanced Metastatic NSCLC Compared to Chemotherapy (Quijote-CLICaP) (Now Available) (ID 2776)

      08:00 - 18:00  |  Author(s): Rafael Rosell

      • Abstract
      • Slides

      Background

      Immunotherapy for NSCLMC offers a significant advantage to chemotherapy in selected cases. This benefit starts to disapear as the patients start two progress and requiere change in medication or even chemotherapy. The objective of this study was to compare survival outcomes of patients with advanced or metastatic NSCLC who received immunotherapy at first, second or beyond versus matched patients receiving standard chemotherapy.

      Method

      A retrospective multicenter international cohort study of 296 patients with unresectable/ metastatic NSCLC treated with immunotherapy either as first, second, third or fourth line was conducted. A matched comparison with a historical cohort of first line chemotherapy was conducted.

      Result

      Median age was 64 years (Range 34-90) and 40.2% were female patients. 91.2% of patients had an ECOG performance score ≤ 1. Immunotherapy as first line was given to 39 patients (13.7%), second line to 140 (48.8%), and as third line and beyond to 108 (37.6%). Median overall survival was 19.9 months (95% CI 14.5-22.7 months) and progression-free survival was 3.73 months (95% CI 2.8-4.2). Factors associated with increased survival included treatment as first-line (p < 0.001), type of response (p < 0.001) and PD-L1 status (p = 0.0039). Compared with the historical cohort, immunotherapy proved to be superior in terms of OS (p= 0.05) but not PFS (p= 0.2).

      Conclusion

      Patients who receive immune checkpoint inhibitors as part of their treatment for NSCLC have better OS compared with matched patients treated with standard chemotherapy, regardless of treatment line.

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    EP1.15 - Thymoma/Other Thoracic Malignancies (ID 205)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Thymoma/Other Thoracic Malignancies
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.15-28 - Survival of Thymoma Is Extensive in Latin-American Patients: Results from Over 10 Years of Experience (CLICaP-LATimus) (ID 2936)

      08:00 - 18:00  |  Author(s): Rafael Rosell

      • Abstract

      Background

      Thymomas are a group of rare neoplasm of the anterior mediastinum. Due to their low incidence, large cooperative studies are required to evaluate outcomes. The objective of this study is to present the results and experience in treatment of this pathology in Latin-America.

      Method

      A retrospective multicenter cohort study was conducted by The Latin-American Consortium for the Investigation of Lung Cancer (CLICaP). Patients with histologically proven thymomas between 1997 and 2018 were included in the analysis. Variables including clinical, pathological and therapeutic outcomes were registered in a centralized manner.

      Result

      A total of 105 patients were included. Median age at diagnosis was 54 years old (20-84), and with 60% (n = 38) of the included patients were female. Only 11% (n=7) of the patients had an ECOG performance score >1. Twenty-four patients (22.9%, 95%CI 14.8-30.9) presented with pulmonary or distant metastatic involvement with a median of 2 metastatic sites. Furthermore, 21.9 % of patients (n=23, 95%CI 13.9-29.8%) concurrently presented myasthenia gravis. Surgery was performed in 55 patients (52.3%, 95%CI 42.8 – 61.9%), comprising of 15 tumorectomies, 37 thymectomies and 5 biopsies achieving an R0 resection rate of 78% (95%CI 67.3-89.1%). Adjuvant treatment in the form of either chemotherapy, radiotherapy or both was offered to 3(5%), 7(12.7%) and 5(9%) patients, respectively. Disease progression was documented in 10 cases (9%, 95%CI3.9-15.1%) of which 6 (60%) were locoregional, 1 (10%) distant progression and 3 (30%) both locoregional and distant. Median overall survival (OS) was estimated at around 139.5 months (95%CI 86.1-NA). Cox regression indicated that OS was significantly improved by resection (139.5 vs 25.7 months, HR 4.17 [95%CI 12.6-17.8 months]).

      Conclusion

      Survival in patients with thymomas continues to be very favorable, especially in patients who receive adequate local control. The benefit of adjuvant treatment in this setting remains unclear.

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      EP1.15-29 - Real World Characterization and Treatment of Patients with Thymic Carcinoma: Lessons from a Latin-American Study (CLICaP-LATimus) (Now Available) (ID 2921)

      08:00 - 18:00  |  Author(s): Rafael Rosell

      • Abstract
      • Slides

      Background

      Thymic carcinoma is a rare tumor that represents a clinical challenge, especially in resource limited settings. The objective of the present study was to characterize patients who presented this disease in Latin-America.

      Method

      From 2014 until 2018, a multinational Latin-American cooperative retrospective cohort study was performed. Patients with histologically confirmed thymic carcinoma were included. Clinical, pathological and treatment variables were collected across 7 participating nations.

      Result

      A total of 31 patients were included. Median age at diagnosis was 58 years old (34-69), 48% (n=15) of individuals were women with all but 2 patients (6.5%) achieving an ECOG performance score <2. All patients debuted with Stage IV disease; 24 patients (66%, [95%CI 62-92%]) as stage IVa and 7 as stage IVb (33%, [95%CI 7-37%]) with a median LDH level of 396.5 U/L (153-1529 U/L) and a median of 2 metastatic sites. 13 (41.9%, [95%CI 25-59%]) patients received preoperatory treatment consisting of chemotherapy (n=8, 42%) and chemoradiotherapy (n=5, 16%). Among these patients only 4 (12.9%) were subjected to surgery, two of which underwent a tumorectomy and 2 a thymectomy. 28 (90%, [95%CI 79.9-100%]) received palliative chemotherapy either with sunitinib (n=7, 25%) or cytotoxic agents. Median overall survival (OS) was reached at 20.2 months (95%CI 19-NA months). Patients who received preoperative treatment had a significantly prolonged OS (17.6 vs 26 months, HR 2.93 [95%CI 1.04-8.27 months], p = 0.03).

      Conclusion

      Thymic carcinoma constitutes an aggressive disease that is often diagnosed in advanced stages. These results suggest that multimodal treatment can be beneficial even in locally advanced cases. Larger clinical trial validating these conclusions are warranted.

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    MA02 - Miscellaneous Topics in the Management of Early Stage Lung Cancer (ID 116)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Now Available
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      MA02.01 - Reccurrence Pattern After Adjuvant Customized Chemotherapy Based on BRCA Expression Level (SCAT Trial) (Now Available) (ID 2760)

      10:30 - 12:00  |  Author(s): Rafael Rosell

      • Abstract
      • Presentation
      • Slides

      Background

      •Postop platinum-based CT improves outcomes in completely resected NSCLC with nodal involvement, (St II-IIIA). Customization is feasible in adjuvant setting (tissue availability) . Analysis of expressionin genes involved in DNA repair could be use to select CT regiment. •BRCA1 plays an important role in DNA repair pathways and functions as a differential regulator of response to cisplatin and antimicrotubuleagents. SCAT trial results found that for low BRCA1 levels subgroup Cis-Gemcitabine was superior to Cis-Docetaxel and in high BRCA1 levels subgroup Docetaxel single agent without platinum achieved similar survival to Cis-Doc. Analysis of recurrence pattern in different subgroups of the trials has been performed

      Method

      From Jun/2007 to May/2013 591 patients were screened and 500 p were included (108 in Control arm treated with Cisplatin-Docetaxel and 392 in Experimental arm treated with Cisplatin-Gemcitabine, Cisplatin-Docetaxel or Docetaxel alone according terciles BRCA1 expression level). With a cut-off September 30th 2018 and a median follow-up of 60 months, recurrence pattern are analysed in each arm and subgroup treatment and comparison are made for incidence of risk of recurrence, single/multiple recurrence, thoracic/extrathoracic and site of metastases (liver, bone, brain)

      Result

      Cumulative recurrence 232/456 evaluable patients (p) (50.8%). Recurrence were seen in 182/354 patients treated in experimental arm and in 50/102 p treated in the control arm (RR 1.04; 0.83-1.30) (p=0.672). Majority of recurrences 159/232 (68.5%) were single site recurrence. Intrathoracic recurrences in 121/232 (52%) while extrathoracic metastatic disease 111/232 (47.8%). No significant differences were seen for single/multiple, intra/extrathoracic recurrences between experimental and control arm. More frequent distant metastatic sites were: bone (42 p), brain (38 p) and liver (11 p) In the experimental group between different treatments no significant differences were found for the overall metastatic rate or for the single/multiple, intrathoracic/extrathoracic recurrences. For specific metastatic sites related to experimental treatment a significant reduction of risk of brain metastases were found in the experimental group with high level BRCA1 treated with Docetaxel single agent (p=0.0016)

      Conclusion

      For NSCLC resected patients with lymph node involvement (Stages II-IIIA) risk of recurrence remains high with cumulative rate > 50%. There were no differences in the Relative Risk (1.04) of recurrence when control and experimental arm are compared. Majority of recurrences were single site (68.5%) and intrathoracic (52%) but distant metastases developed in 47.8% os p. More frequent metastatic site was bone, followed by brain and liver. Brain metastases risk were significant lower for patients with low BRCA1 expression treated with single agent Docetaxel

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    MA10 - Emerging Technologies for Lung Cancer Detection (ID 129)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Screening and Early Detection
    • Presentations: 1
    • Now Available
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      MA10.11 - Sensitivity and Optimal Clinicopathological Features of Genetic Targeted Liquid Biopsy in pN0M0 Lung Adenocarcinoma (Now Available) (ID 788)

      15:15 - 16:45  |  Author(s): Rafael Rosell

      • Abstract
      • Presentation
      • Slides

      Background

      Liquid biopsy for diagnosis of early-stage lung cancer is still challenging. The optimal marker and methodology has not been established. In Asia, almost 40-50% of lung adenocarcinomas harbor the EGFR mutation and L858R is a representative of a somatic EGFR mutation. We evaluated the usefulness of the EGFR somatic mutation in liquid biopsy using droplet digital PCR (ddPCR), which is a sensitivity device to detect several types of genetic mutations.

      Method

      We examined weather L858R could be detected from preoperative ctDNA by ddPCR. Cases without EGFR mutation (wild type) were utilized as negative control. All involved cases underwent surgical resection after preoperative HRCT and PET-CT. Serum for ctDNA extraction was collected before the operation. L858R in the primary site was confirmed by resected surgical specimen. Clinicopathological features (e.g.: whole and invasive tumor size on HRCT, SUV max on PET-CT, histological subtype) were also explored for an optimal liquid biopsy candidate.

      Result

      Forty-five pN0M0 lung adenocarcinoma patients harboring L858R were enrolled. Twenty-one and 24 cases showed part-solid and pure solid appearance on HRCT, respectively. Median whole and invasive tumor size on HRCT was 21 and 19 mm, respectively. 91.1% (41/45) cases were clinical stage IA1-IB and 97.8% (44/45) cases were pathological stage IA1-IB. In wild type cases, positive droplet for L858R was almost completely undetectable. Whereas, L858R was significantly detected in 7 EGFR mutant cases (sensitivity is 15.56%, 7/45). Among 7 positive cases, 6 cases showed pure solid appearance in preoperative HRCT. Except for pure solid appearance, there was no significant features related to the positive result. If cases are limited to pure solid appearance, 25.0% (6/24) of cases could be diagnosed by liquid biopsy. Even small-sized tumors (1.1 cm in diameter) or tumors with slight accumulation on PET-CT (SUV max 0.5) could be detected if it showed pure solid appearance on HRCT.

      Conclusion

      L858R can be a definitive marker for liquid biopsy using ddPCR in pN0M0 lung adenocarcinoma. 15.56% (7/45) of cases were diagnosed in pN0M0 cases. Limited to pure solid tumor, 25.0% (6/24) could be detected. Liquid biopsy can be a useful diagnostic option, especially for tumors with pure solid appearance.

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    P1.01 - Advanced NSCLC (ID 158)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.01-56 - Increased ROS1 and RET Transcripts in Fusion-Negative NSCLC Patients (ID 2477)

      09:45 - 18:00  |  Author(s): Rafael Rosell

      • Abstract

      Background

      Fusion involving anaplastic lymphoma kinase (ALK), RET proto-oncogene (RET) or v-ros UR2 sarcoma virus oncogene homolog 1 (ROS1) occur in non-small cell lung cancers (NSCLC) and are important biomarkers for targeted therapies. However, little is known about the RNA expression levels of these genes regardless of fusions.

      Method

      We used a custom nCounter panel (NanoString Technologies) designed to detect several genetic alterations, including fusions and mRNA expression levels of ALK, ROS1 and RET in formalin-fixed paraffin embedded (FFPE) samples. RNA was purified from NSCLC tumor samples and analyzed with the custom panel. The counts corresponding to the 3’ probes were normalized using the geometrical mean of the housekeeping genes and then added to evaluate total mRNA expression levels. Cut-off values for overexpression were established as the average counts for each gene plus two times the standard deviation.

      Result

      A total of 400 stage III-IV NSCLC patients (p) from two different institutions were retrospectively analyzed. Overexpression of ALK was found in 55 p (13.8%). Of them, 48 (87%) were also positive for EML4-ALK fusions. One ALK-translocated patient with low levels of ALK mRNA expression did not respond to therapy. Fifteen p (3.8%) showed ROS1 overexpression. In contrast with ALK, only three of them (15%) had a concomitant ROS1 fusion. Among the remaining 12 patients overexpressing ROS1, four were ALK positive, five harbored mutations in EGFR and three were non-smoker females with no known drivers. Regarding RET, high expression levels were found in 14 p (3.5%) and only one of them showed a RET fusion (7%). Among the remaining 13 p, three presented neuroendocrine features and seven were smoker or ex-smoker without other known drivers.

      Conclusion

      Overexpression of ALK mRNA in NSCLC is associated with EML4-ALK translocations. In contrast, a significant number of fusion negative patients show high ROS1 or RET mRNA levels. Further research is warranted to determine the clinical relevance of this finding.

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    P1.03 - Biology (ID 161)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 2
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.03-14 - HLA-E and FAT1 in Head and Neck and Lung Cancer. The Effect of Osimertinib or Olmutinib with Artesunate (Dihydroartemisinin) (ID 912)

      09:45 - 18:00  |  Author(s): Rafael Rosell

      • Abstract
      • Slides

      Background

      Cisplatin and cetuximab have little effect in head and neck squamous cell carcinoma (HNSCC) and lung squamous cell carcinoma (LSCC). HLA-E expression suppressed the cetuximab effect and HLA-E is overexpressed in both HNSCC and LSCC. In addition, FAT1 inactivating mutations are present in 30% of HNSCCs and 19% of LSCCs. Dihydroartemisinin (DHA) inhibits STAT3 and increases cisplatin effect in HNSCC. Osimertinib and olmutinib increase intracellular accumulation of doxorubicin by blocking the efflux function of ABC transporters. We posit that osimertinib or olmutinib, plus DHA, could have activity in the HNSCC cell lines, FaDu and CAL27, with loss of FAT1 expression.

      Method

      Osimertinib and olmutinib plus DHA were tested in the FaDu and CAL27 cell lines. Tumor cell proliferation assays (MTTs) and mouse xenografts were performed, and western blotting analysis was carried out. FaDu CTXR clone #3 (cetuximab-resistant, a gift from Bhola) and SCCNC4 (EGFR exon 20 S768_D770 dup, a gift from Hermsen) were also examined.

      Result

      1. DHA decreased HLA-E protein levels in a dose dependent manner in the FaDu CTXR.

      2. DHA was able to induce the expression of FAT1 in FaDu and CAL27 cells.

      3. Osimertinib plus DHA had a synergistic effect (<1, Combination index (CI)=0.468 and 0.593 in FaDu and CAL27, respectively). Olmutinib with DHA was also synergistic (CI=0.773 and 0.762 in FaDu and CAL27).

      4. Osimertinib plus DHA was validated in vivo in FaDu and CAL27 mice xenografts with significant tumor regression.

      5. Osimertinib plus DHA suppress the expression of onco-effectors: STAT3, Src, YAP and AXL.

      6. Osimertinib plus DHA was also synergistic in SCCNC4 (CI=0.596).

      Conclusion

      The findings indicate that DHA can revert resistance to cetuximab by repressing the expression of HLA-E. The combination of DHA plus osimertinib was active in the parental FaDu, but not in FaDu CTXR. For tumors with lack of FAT1 expression, the use of DHA reactivates FAT1 and YAP1 inhibition was noted. DHA has been tested for the treatment of systemic lupus erythematosus (SLE), orally, daily for 2 years. The results encourage development of clinical trials with DHA to re-sensitize HNSCC and LSCC cells to cetuximab-based therapy.

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      P1.03-31 - BRAF Mutations: Classes I, II and III in NSCLC Patients Included in the SLLIP Trial, Targeted Treatment According to Class (Now Available) (ID 897)

      09:45 - 18:00  |  Author(s): Rafael Rosell

      • Abstract
      • Slides

      Background

      BRAF V600 mutations have been found in 2% of non-small cell lung cancer (NSCLC) patients, with FDA approved treatment of dabrafenib plus trametinib and progression free survival (PFS) of 10.9 months. However, 50-80% of BRAF mutations in lung cancer are non-V600, and can be class 2, with intermediate to high kinase activity and RAS independence, or class 3, with impaired kinase activity, upstream signaling dependence and consequently sensitivity to receptor tyrosine kinase (RTK) inhibitors. Non-V600 tumors require combinatory therapy with RAF/MEK inhibitors and blockers of RTK signaling, like SHP2 (PTPN11) inhibitors.

      Method

      Plasma DNA of 185 newly diagnosed advanced lung adenocarcinoma patients was examined for BRAF and other mutations with a clinically validated cell-free DNA (cfDNA) assay (Guardant360, Guardant Health Inc. CA, U.S), and results were correlated with patient outcome. In addition, two NSCLC cell lines and one Triple Negative Breast Cancer (TNBC), H1395 (class 2 BRAF mutation), H1666 (class 3 BRAF mutation) and MDA-MB-231 (class 2 BRAF mutation) were treated with single or combined BRAF, MEK and SHP2 inhibitors and cell viability was assessed.

      Result

      BRAF mutations were found in 17/185 (9%) and BRAF amplification in five patients (3%). Three patients had BRAF V600E mutations (2%) and 14 patients non-V600 BRAF mutations (8%), including four class 2 and four class 3 mutations. Patients were treated with chemotherapy and/or immunotherapy, or targeted therapy for other co-alterations. PFS was 1.8, 6.1, 5.0, 5.3 and 5.3 months for Class 1, 2, 3, other BRAF, and BRAF amplification, respectively. These low survival rates indicate that new treatment options are urgently needed. In vitro results confirm sensitivity of class 3, and resistance of class 2 BRAF mutations to single SHP2 inhibition with RMC-4550 and SHP099, with similar results in TNBC and lung cancer cells. Combined dabrafenib and trametinib treatment indicated antagonistic effects, especially in the class 3 BRAF mutant cell line. Concomitant MEK and SHP2 inhibition was synergistic in both class 2 and 3 BRAF mutations.

      Conclusion

      It is evident that different classes of BRAF mutations require distinct treatments, which could even outweigh tumor type. Therefore, we should examine BRAF class in daily clinical practice. Upfront targeting of the MAPK signaling pathway combined with SHP2 inhibitors reveals synergistic interactions, and additional inquisition may pave the way for new treatment options in the most frequently found mutations in BRAF patients.

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    P1.04 - Immuno-oncology (ID 164)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.04-80 - Immunotherapy-Related Thrombosis: Considerations and Associated Factors in Non-Small Cell Lung Cancer (NSCLC) Patients (ID 2724)

      09:45 - 18:00  |  Author(s): Rafael Rosell

      • Abstract

      Background

      Widespread use of immune checkpoint inhibitors (ICIs) for the treatment of lung cancer has exposed a large number of patients to these medications, increasing the incidence of rare adverse reactions such as thromboses. The present study elaborates on factors related to the occurrence of these events.

      Method

      In a retrospective cohort study, a total of 48 patients, 24 who experienced thrombosis and 24 matched controls who underwent evaluation after initiation of ICIs therapy for advanced/metastatic NSCLC, were included. Clinical and pathological as well as serum inflammatory and coagulation markers were evaluated.

      Result

      Among the 48 patients, 46% (n=26) were female, median age was 62 years old and all patients had an ECOG performance score of < 2. The median overall survival reached by the cohort was 22.47 months. Among patients who developed thrombosis there were 8 cases of deep venous thrombosis (DVT) (33%), 13 pulmonary embolisms in addition to DVT (62.5%) and 1 case of brain venous sinus thrombosis (4.2%). Apart from expected thrombosis markers such as D dimer, differences in inflammatory and immune related markers between patients who experienced thrombosis and those who did not, were observed. Abnormal values were found in the thrombosis group for B2glycoprotein 1 (33% vs 0%, OR= 4.08, [95%CI 1.65 - 12.1], p= 0.005), B2glycoprotein 1 IgG (29.2% vs 0%, OR= 4.64, [95%CI 1.73 – 16.9], p= 0.007), C Reactive protein (83.3% vs 12.5%, OR= 35, [95%CI 7.9 - 213], p< 0.001), B2microglobulin (62.5% vs 8.3%, OR= 14, [95%CI 3.11-103.7], p = 0.002), Prothrombin time (41.7% vs 4.2%, OR= 2.4, [95%CI 1.64 -3.69], p =0.01) and C Coagulation protein (50% vs 16.6%, OR =1.79, [95%CI 1.53 – 2.91], p <0.001).

      Conclusion

      Abnormalities in antiphospholipid antibodies, C reactive protein, B2microglobulin and coagulation in patients who suffered thrombosis during ICI treatment suggest that this phenomenon could be the result of immune and auto-inflammatory induced intravascular dysfunction.

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      P1.04-81 - Characterization of Hispanic Patients Who Experienced Hyperprogression During Treatment for Advanced NSCLC with Immunotherapy (ID 2922)

      09:45 - 18:00  |  Author(s): Rafael Rosell

      • Abstract

      Background

      Immunotherapy related hyperprogression is poorly characterized in Latin American patients. In this study we sought to characterize and identify factors associated with the presentation of hyperporgression after initiation of immunotherapy in patients with advanced non-small cell lung cancer (NSCLC).

      Method

      A multicenter international retrospective study on 110 patients was conducted. Clinical variables as well as routine blood studies were recorded before initiation of treatment. Regression analysis was used to find associations. A random forest tree analysis (RFTA) based on continuous and discrete variables was used to subcategorize patients based on occurrence of hyperprogression.

      Result

      Median age was 64 years (Range 34-90) and 59.8 % were male patients. ECOG performance status was >1 on 8.8% of patients. Median overall survival was 12.7 months (95% CI 9.67-14 months) and progression-free survival of 4.27 months (95% CI 3.97-5.0). 44 hyperprogressors were documented (19.8%, [95%CI 14.5-25.1%]). Median time to progression was approximately 5 weeks after initiation of treatment. Factors associated included albumin and hemoglobin levels (p = 0.046 and 0.037 respectively), presence of CNS (p= 0.0009) and bone metastasis (p = 0.004) and weight loss (p= 0.004). RFTA revealed that a leucocyte count over 5.300 cells/dl was present in all hyperprogressors.

      Conclusion

      Hyperprogression is a phenomenon after initiation of immunotherapy which is associated with clinical and paraclinical variables. These associations could be used to withhold certain agents and prevent its occurrence in NSCLC treatment.

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    P1.14 - Targeted Therapy (ID 182)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.14-61 - EGFR Inhibitors Plus Bevacizumab Are Superior Compared to EGFR Inhibitor Monotherapy in Advanced EGFR+ NSCLC Patients with BIM Deletions (ID 2697)

      09:45 - 18:00  |  Author(s): Rafael Rosell

      • Abstract

      Background

      BIM activation is essential for EGFR-TKIs triggered apoptosis in EGFR-mutant Non-small-cell lung cancer (NSCLC). A 2903-bp germline deletion in intron 2 of the BIM gene results in generation of alternatively spliced isoforms that lack the crucial BH3 domain, impairing the apoptotic response to TKIs and conferring NSCLC cells intrinsic resistance to these medications. Patients with both alterations have poor clinical evolution. The current study aimed to investigate the clinical efficacy and tolerability of EGFR-TKIs plus bevacizumab (Bev) versus EGFR-TKIs alone as first-line treatment in advanced NSCLC patients with EGFR mutations and BIM deletions (BIMdel).

      Method

      A retrospective analysis was conducted. BIMdel was detected using polymerase chain reaction (PCR) analysis and direct sequencing of DNA from tumor and peripheral blood cells (PBCs). We also assessed BIM protein expression by immunohistochemistry and BIM mRNA levels by RT-PCR. Clinical characteristics, overall survival (OS), progression-free-survival (PFS), objective response rate (ORR) and treatment-related adverse events were compared in the EGFR-TKIs versus EGFR-TKIs plus Bev groups.

      Result

      32 patients were included; 16 of them received EGFR-TKIs and 18 received EGFR-TKIs plus Bev. The addition of Bev resulted in a significantly higher ORR compared with TKIs alone (94% vs. 44%, p=0.0014). Median PFS was longer with the use of the combination compared with TKIs alone (11.1 vs. 7.77 months; p < 0.001). Median OS tended to be longer in the EGFR-TKIs plus Bev group than in TKIs alone (30.9 vs. 25.4 months; p = 0.06). EGFR-TKIs plus Bev was associated with more grade >3 hematological and thrombotic adverse events. The expression of BIM by immunohistochemistry did not influence PFS and OS, however when stratifying BIM mRNA levels by the median (≥2.2 vs. <2.1) allowed to find a prognostic trend in favor of those with higher BIM mRNA levels (32.2 vs. 25.2 months respectively; p = 0.058).

      Conclusion

      EGFR-TKIs plus Bev conferred a significantly higher ORR and PFS in advanced NSCLC patients with EGFR mutation and BIMdel. Further prospective studies are needed to validate these findings.

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    P1.17 - Treatment of Early Stage/Localized Disease (ID 188)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Treatment of Early Stage/Localized Disease
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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      P1.17-08 - mRNA Expression Level of Receptor Tyrosine Kinases and Non-Receptor Tyrosine Kinases as a Recurrence Risk in Resected Adenocarcinoma of the Lung (ID 786)

      09:45 - 18:00  |  Author(s): Rafael Rosell

      • Abstract

      Background

      The profile of receptor tyrosine kinases (RTK) and non-receptor tyrosine kinases (non-RTK) is crucial for tumor genesis and therapeutic strategy in several types of cancer. We previously reported that elevated mRNA expression level of some RTKs/non-RTKs (AXL, CDCP1, STAT3, YAP1) were related to poorer prognosis in lung adenocarcinoma patients receiving EGFR-TKI. The prognostic impact of RTKs/non-RTKs is unclear in early-stage lung cancer. This study aims to explore the usefulness of RTK and non-RTK to detect the risk of recurrence in resected NSCLC, especially in EGFR mutant adenocarcinoma.

      Method

      We retrospectively collected pathologic N0-2 adenocarcinoma cases resected in Japanese and Spanish institutions. mRNA expression levels of RTK or non-RTK (STAT3, YAP1, AXL, CDCP1, MET, SHP2, and EGFR) in surgical specimens were evaluated and the impact of expression level on recurrence-free survival (RFS) was compared. The oncological significance on RTK or non-RTK was validated in vitro.

      Result

      Among enrolled 268 cases, 100 cases (37.3%) harbored EGFR mutation. Forty-five EGFR mutation positive cases recurred and cases with higher mRNA expression level of EGFR showed worse RFS. In addition, higher expression of CDCP1 or SHP2 indicated poorer RFS in EGFR mutation positive cases. In vitro, combination of SHP099 (SHP2 inhibitor) and osimertinib showed synergism in EGFR mutation positive cell line (Combination index was 0.62).

      Conclusion

      Higher expression of SHP2 and CDCP1 is potential risk of recurrence in EGFR mutant lung adenocarcinoma. The synergism of SHP2 inhibitor plus EGFR-TKI suggests that the expression level of SHP2 is involved in tumorigenesis and is a promising predictor for recurrence in EGFR mutant lung adenocarcinoma.

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    P2.01 - Advanced NSCLC (ID 159)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Advanced NSCLC
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.01-56 - Copy Number Gains (CNGs) of Clinically Relevant Genes in Advanced NSCLC Patients (ID 2519)

      10:15 - 18:15  |  Author(s): Rafael Rosell

      • Abstract

      Background

      Somatic copy number variations (CNV; i.e. amplifications and deletions) have been implicated in the origin and development of multiple cancers and some of these aberrations are designated targets for therapies, such as amplified ERBB2 in breast cancer. In the case of NSCLC patients, MET alterations are receiving increasing attention as targets in precision medicine, and several clinical trials of anti-MET agents are ongoing. Routine testing for these potential targets on formalin-fixed paraffin embedded (FFPE) samples is mainly carried out by in-situ hybridization (FISH) approaches covering only a single gene of interest. Although this methodology is still the gold standard of CNV detection, it presents several drawbacks. Here we aimed to determine the potential of next generation sequencing (NGS) to simultaneously determine CNGs across many in FFPE samples

      Method

      FFPE biopsies from 140 stage IIIb-IV NSCLC patients (p) of our institution were prospective tested. Of them, 110 corresponded to samples at diagnostic and 30 after progression to targeted therapies. DNA was purified submitted to NGS using the 16-gene QIAact Lung Panel (Genereader®, Qiagen). Coverages for the genes analyzed were normalized using the total coverage of the panel. Cut-off values for CNVs were established as the average normalized coverage for each gene plus two times the standard deviation. Representative samples were analyzed by FISH

      Result

      Validation analyses in 8 cell lines showed 100% concordance between FISH and NGS for detection of EGFR, MET and ERBB2 amplifications. Among the 140 NSCLC p, MET was the gene showing a higher frequency of CNGs, followed by PIK3CA, NRAS, EGFR and KRAS (Table 1). In contrast, only one p was found to harbor a ROS1 CNG. Among the 17 samples with MET CNG (12%), 6 corresponded to p progressing to targeted therapies. In addition, 8 of the 17 samples with MET CNGs were submitted to FISH, 6 of them were positive and the remaining 2 samples had copy numbers higher than 3.5 by this technique. In the case of EGFR, CNGs were associated with sensitizing mutations, with 5 samples showing both alterations concomitantly. In contrast, PIK3CA, NRAS, ALK, BRAF, HER2, PDGFRA, KIT and MET CNGs were not associated with mutations (Table 1).

      n CNG

      %

      n MUTANT

      MET

      17

      12.1

      0

      PIK3CA

      12

      8.6

      0

      NRAS

      10

      7.1

      0

      EGFR

      10

      7.1

      5

      KRAS

      10

      7.1

      2

      ALK

      8

      5.7

      0

      BRAF

      8

      5.7

      0

      ERBB2

      8

      5.7

      0

      PDGFRA

      6

      4.3

      0

      KIT

      6

      4.3

      0

      ROS1

      1

      0.7

      0

      Conclusion

      CNGs in clinically relevant genes are present in a significant percentage of advanced NSCLC patients and, except in the case of EGFR, are not associated with driver mutations. Further research is warranted to determine the clinical implications of this finding.

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    P2.03 - Biology (ID 162)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Biology
    • Presentations: 2
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.03-16 - Agreement Between Different Methodologies for Non-Invasive p.T790M and EGFR Sensitizing Mutation Testing (ID 1965)

      10:15 - 18:15  |  Author(s): Rafael Rosell

      • Abstract
      • Slides

      Background

      Tyrosine kinase inhibitors (TKIs) are the current standard of care for patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC). However, most patients progressed within 1 to 2 years. The EGFR p.T790M mutation is the most common resistance mechanism to first and second generation EGFR TKIs. The identification of p.T790M mutation is of considerable clinical relevance as osimertinib has demonstrated clinical efficacy in this setting. Guidelines recommend testing for the p.T790M mutation in blood at relapse to TKIs, and re-biopsy only in case of a negative result. Several blood based methodologies for detection of EGFR mutations have been developed in the recent years. However, the number of comparison studies between platforms is very limited.

      Method

      This is a multicenter, cross-sectional study (ClinicalTrials.gov Identifier: NCT03363139) performed by the Spanish Lung Cancer Group. Samples from 75 consecutive EGFR mutant NSCLC patients were collected at disease progression to first line TKI treatment. The presence of EGFR mutations in the cfDNA was evaluated in 39 samples by 7 methodologies, namely: Cobas® EGFR Mutation Test v2 (Roche Diagnostics), Therascreen EGFR Plasma RGQ PCR Kit (Qiagen), QuantStudio® 3D Digital PCR System (Thermofisher), a 5′-nuclease real-time PCR (TaqMan®) assay in presence of PNA, OncoBEAM EGFR (Sysmex Inostics), NGS with two different gene panels: Oncomine® (Thermofisher) and Lung Cancer Panel (Qiagen). The agreement between methodologies was assessed using the kappa coefficient (K) and its corresponding 95% confidence intervals (95% CI). For quantitative variables the concordance correlation coefficient (ccc) was used.

      Result

      Complete results are available for 39 patients. Overall, the agreement between all methodologies for the detection of p.T790M mutation as well as the original EGFR sensitizing mutation was good (K=0.669; 95CI: 0.504-0.835 and K=0.750 95CI: 0.599-0.899 respectively). Remarkably, the agreement between FDA-approved methodologies for p.T790M detection was almost perfect (K=0.926; 95CI: 0.712-1) and good for the EGFR sensitizing mutations (K=0.657; 95CI: 0.417-0.902). Similarly, the agreement between NGS-based methodologies for the detection of p.T790M and the EGFR activating mutations was very high (K=0.843; 95CI: 0.567-1 and K=0.872 95CI: 0.595-1 respectively). Moreover, concordance between both technologies for p.T790M and EGFR sensitizing mutation mutant allele frequency was excellent (ccc=0.956; 95CI: 0.906-1 and ccc=0.980 95CI: 0.950-1 respectively). The proportion of samples that were positive for p.T790M detection varied from 28% (PCR based technologies) to 37% depending on the methodology.

      Conclusion

      NGS and PCR-based methodologies show a good to excellent agreement for the detection of EGFR mutations, including the p.T790M. Our results support the use of liquid biopsies for non-invasive testing of clinically relevant mutations (Data from the whole cohort will be presented at the meeting).

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      P2.03-45 - PKCι-PAK1 Pathway Modulates Sensitivity to Therapy in EGFR, KRAS Mutant Adenocarcinoma and Squamous Cell Carcinoma (ID 789)

      10:15 - 18:15  |  Author(s): Rafael Rosell

      • Abstract

      Background

      p21-activated kinase 1 (PAK1) stimulates growth and metastasis in several types of tumors, including non-small cell lung cancer (NSCLC). Protein kinase C iota (PKCi) is an enzyme highly expressed in NSCLC that regulates PAK1 signaling. To understand intrinsic and acquired resistance to different MAPK signaling inhibitors, we explored PKCι-PAK1 signaling in EGFR/KRAS mutant adenocarcinoma or squamous cell carcinoma (SCC) cell lines by combination therapy using PAK1 inhibitor and PKCι inhibitor.

      Method

      Three lung cancer cell lines were used: HCC827 and H23 lung adenocarcinoma cells that carries EGFR and KRAS mutations, respectively, and H520 (PAK1 amplified squamous cell carcinoma). Cell viability assays and western blotting were applied to evaluate the effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCι inhibitor). Since IPA-3 is only for laboratory use, we explored alternative PAK-1 inhibitor and tested combination effect with auranofin.

      Result

      IPA-3 plus auranofin was highly synergistic (Combination index was less than 0.4) in EGFR mutant adenocarcinoma (HCC827), KRAS mutant adenocarcinoma (H23) and SCC with PAK1 amplification (H520) cell lines in MTT assay and colony forming assay. We revealed OTSSP167 (a MELK inhibitor in phase I/II trials) inhibits phosphorylated PAK1 and combination of OTSSP167 plus auranofin showed similar synergism in the 3 cell lines. The combination of auranofin with either IPA-3 or OTSSP167 ablated EGFR phosphorylation and downstream signaling pathways: ERK, AKT, STAT3, YAP1 and inhibited the expression of RTKs: AXL, MET, and CDCP1.

      Conclusion

      The combination of IPA-3 plus auranofin is promising treatment in different subclasses NSCLC with driver EGFR or KRAS mutations, as well as SCC with PAK1 amplification. OTSSP167 also works as PAK1 inhibitor. The therapeutic effect of PAK-1 inhibitor and PKCι inhibitor was validated using OTSSP167 plus auranofin.

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    P2.04 - Immuno-oncology (ID 167)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Immuno-oncology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.04-79 - High Rate of Immune Related Pneumonitis in Lung Cancer Patients Treated with Anti PD-1 Antibodies (ID 1061)

      10:15 - 18:15  |  Author(s): Rafael Rosell

      • Abstract
      • Slides

      Background

      Treatment with anti PD-1/PD-L1 antibodies has demonstrated survival improvement in several malignancies, including non small cell lung cancer (NSCLC), but these therapies are not exempt from risks. Meta-analysis and clinical trials have reported immune related (ir) pneumonitis of any grade in 3-5% of patients treated with anti PD-1/PD-L1 antibodies, including grade 3 or higher in 0.8% to 1.8% of patients.

      Method

      We have retrospectively reviewed clinical reports from 125 cancer patients treated at our center with anti PD-1/PD-L1 antibodies (55 were treated with nivolumab, 27 with pembrolizumab, 33 with atezolizumab, 6 with avelumab, and 4 with durvalumab) from January 2016 to January 2019.

      Result

      Nineteen patients (15.2%) developed ir pneumonitis. Four (21%) patients had recurrent pneumonitis during tapering corticoesteroid dose after an initial improvement and finally died. Patient characteristics are summarized in Table 1. Median time to pneumonitis was 4 months (m) (range 1m to 9m). Twelve patients (9.6% %) had grade 3-5 and 7 patients (5.6 %) grade 1-2 pneumonitis. Nine (7.2 %) patients died from ir pneumonitis, including 4 patients with no tumor progression (1 had received only one cycle, and 3 patients had ongoing tumor response at 10m+, 12m+ and 30m+). Ir pneumonitis was more frequent with nivolumab (any grade 21.8 %, grade 3 or higher 18.2 %, including 7 fatal cases-12.7%-), while no patient treated with atezolizumab developed pneumonitis (Table 2).

      Table 1
      Total 19

      Gender

      Women, n (%)

      7 (36,8%)

      Age

      Median (range)

      63,4 (51-82)

      Cancer type, n (rate)

      NSCLC Adenoca

      NSCLC Squamous

      SCLC

      Mesothelioma

      13 (68,4 %)

      4 (21%)

      1 (5,3%)

      1 (5,3%)

      Line of therapy, n (rate)

      Adjuvant

      First line

      Second or further line

      1 (5,2 %)

      8 (42,1%)

      10 (52,6%)

      Tumor Response, n (rate)

      CR

      PR

      SD

      PD

      NE

      2 (10,5%)

      8 (42,1%)

      5 (26,3%)

      3 (15,8%)

      1 (5,2%)

      table 2
      Drug,n patients treated Any Grade, n (%) Grade 3-5, n (%) Grade 5, n (%)
      Nivolumab, 55 12 (21,8%) 10 (18,2%) 7 (12,7%)
      Pembrolizumab, 27 3 (11,1%) 1 (3,7%) 1 (3,7%)
      Atezolizumab, 33 0 0 0
      Durvalumab, 4 2 (50%) 0 0
      Avelumab, 6 2 (33,3%) 1 (16,7%) 1 (16,7%)
      Total, 125 19 (15,2%) 12 (9,6%) 9 (7,2%)

      Conclusion

      In our experience, ir pneumonitis rate with anti PD-1/PD-L1 antibodies in lung cancer patients was 15.2%, including 7.2% of fatal complications. It suggests that previous clinical trials could have under diagnosed this serious complication. Further studies must be performed in order to specifically assess the rate of pneumonitis in patients treated with anti PD-1 and anti PD-L1 antibodies in lung cancer patients.

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    PC02 - Combining with Chemo: Old School Is New Again (ID 84)

    • Event: WCLC 2019
    • Type: Pro-Con Session
    • Track: Advanced NSCLC
    • Presentations: 1
    • Now Available
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      PC02.02 - TKIs Should Be Given with Chemo (Now Available) (ID 3562)

      14:00 - 15:30  |  Presenting Author(s): Rafael Rosell

      • Abstract
      • Presentation
      • Slides

      Abstract

      TKIs Should Be Given with Chemotherapy. This is an open question, with some pros and cons, mainly due to the complexities of chemotherapy activity regarding genetic alterations. However, there are several promising hints that the combination could be useful, but not all chemotherapeutic drugs prove beneficial. This information will be provided in the presentation.

      Resistance to erlotinib and, in general, to any generation of EGFR TKIs, is heterogeneous and requires the comprehensive dynamic molecular profiling of the tumor with either tissue, liquid biopsies, or both. Before the development of the third-generation EGFR TKIs, at the time of progression to erlotinib or gefitinib, patients were successfully treated with chemotherapy [Sequist et al Sci Trans Med 2011]. The alternation of chemotherapy and EGFR TKIs merits revisiting. The intercalation of erlotinib with chemotherapy has shown a median PFS of 16.8 months in EGFR-mutant NSCLC patients [Wu et al Lanect Oncol 2013]. The most salient biological concept to re-address the contribution of chemotherapy in EGFR-mutant NSCLC is the fact that nuclear cyclic GMP-AMP (cGAMP) synthase (cGAS) expression suppresses DNA repair and, therefore, can enhance the activity of EGFR TKIs. Preclinical data strongly favors this model, showing that etoposide or other chemotherapeutic drugs can promote the translocation of cGAS to the nucleus by phosphorylation of cGAS on the tyrosine residue 215. In the nucleus, cGAS is recruited to double stranded breaks, interacting with PARP1. The cGAS-PARP1 interaction jeopardizes the generation of the PARP1-Timeless complex and suppresses homologous recombination [Liu et al Nature 2018]. The fact that cGAS transcripts are increased in NSCLC is of clinical interest, indicating that cGAS could be a new biomarker involved in the response to immune checkpoint inhibitors [Gui et al Nature 2019].

      Multilayer research sheds light on potential safe and active combinatory therapies in EGFR-mutant NSCLC and many therapeutic approaches converge in the complex signaling pathway crosstalk. Perhaps tumor heterogeneity is not the major difficulty and the mechanisms of resistance are more dependent on the capacity of tumor cells to re-wire and re-program the signaling pathways that they use to grow and migrate [Karachaliou et al EBioMedicine 2018]. Epi-transcriptomics are also involved in resistance to EGFR TKIs (Figure) [Zanconato et al Nat Med 2018]. Several chromatin regulators have emerged as druggable targets, including bromodomain-containing protein 4 (BRD4). BRD4 interacts with YAP1, and Bromodomain and Extra-Terminal motif (BET) inhibitors impair the expression of YAP1 direct target genes, including AXL, FST1 and aurora A [Zanconato et al Nat Med 2018]. We have recently reported that the combination of EGFR TKIs with barasertib, an aurora kinase B inhibitor, illustrates a strong antiproliferative activity in a broad panel of EGFR-mutant resistant cell lines [Bertran-Alamillo Nat Comm 2019].

      DNA repair modulators may be associated with resistance to EGFR TKIs. In our original study of erlotinib in EGFR-mutant NSCLC [Rosell et al NEJM 2009], we explored the role of DNA repair genes on the treatment outcome. Among several transcripts examined, breast cancer type 1 susceptibility (BRCA1) gene mRNA surfaced as relevant in the repair of erlotinib-induced DNA damage through an H2A histone family member X (H2AX)-independent pathway [Rosell et al Clin Cancer Res 2011]. Normally, DNA damage repair involves a homologous recommendation, through H2AX [Wang et al Science 2007]. Patients with low BRCA1 mRNA expression had significantly longer PFS than patients with high BRCA1 mRNA levels, and BRCA1 levels were an independent predictor of PFS in the Cox-multivariate regression analysis.

      Finally, turning off the DNA damage checkpoint after DNA repair involves the removal of phosphorylated H2AX from the chromatin, followed by its replacement with canonical H2A. This exchange of phosphorylated H2AX for H2A is mediated by facilitates of chromatin transcription (FACT) (Figure). The ability of FACT to remove phosphorylated H2AX from the chromatin is inhibited by PARP1 [Rosell et al Clin Cancer Res 2011]. A novel class of drugs, curaxins, act as a chromatin trapping of the FACT, suppressing simultaneously NF-ĸB signaling and promoting activation of p53 [Gasparian et al Sci Trans Med 2011]. The combination of erlotinib with curaxins, or FACT inhibitors, like CBL0137 [Lindner et al Cancer Res 2018], may be a significant advance in the field of EGFR-mutant NSCLC therapy.figure.jpg

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    YI03 - Scientific Mentoring (ID 109)

    • Event: WCLC 2019
    • Type: Young Investigator Session
    • Track: Young Investigators
    • Presentations: 1
    • Now Available
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      YI03.03 - Scientific Mentorship: What Should You Expect? (Now Available) (ID 3705)

      10:30 - 12:00  |  Presenting Author(s): Rafael Rosell

      • Abstract
      • Presentation
      • Slides

      Abstract

      Scientific Mentorship: What Should You Expect?

      I am honored to speak to young investigators on mentorship. Over several decades I have had the opportunity to serve as mentor of many clinical investigators, both local and worldwide. Throughout the years, most of my mentors have been involved in translational research and laboratory work, which, on many occasions, has resulted in fruitful research, culminating in theses and publications in relevant journals. One of the key points in assuming the responsibility of training is to work very closely, as friends, standing side by side, studying the relevant research project and its progress. There are several emotions among the mentor and young investigators. The mentor feels joy and delights in seeing the young investigators progress, converting in an overall happiness at the project accomplishment. The mentors joy comes once every young investigator achieves the main objective of his/her work in process.

      Transparency is the fuel of friendship between the mentor and young investigator. The mentor should be fully involved and open, in order to build a strong mentor/investigator relationship. The mentor must show emotional honesty, even if there is the possibility of someone taking advantage of his/her vulnerabilities. Unmasking oneself is the only means to building successful scientific relationships. The mentor should apply an open policy of collaboration, assuming the young investigators could have an even greater capacity for research, than the mentor himself. Most of the time, this behavior will be a benefit for the investigators. There have been many examples of investigators contributing to important findings in a plethora of different research areas. Cancer biology was recognized as an important cancer field in the late 90’s, and many investigators have made exciting contributions in tumors, such as, non-Hodgkin’s lymphomas (Calvo et al JNCI 1998), gastric cancer (Wei et al JNCI 2011) and many others, culminating in salient publications in the field of lung cancer (Karachaliou et al JAMA Oncol 2015). The principal contributions will be included in the presentation.

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