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Junichi Soh
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MA09 - EGFR & MET (ID 128)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Targeted Therapy
- Presentations: 1
- Now Available
- Moderators:Jordi Remon, Juergen Wolf
- Coordinates: 9/08/2019, 15:15 - 16:45, Melbourne (1991)
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MA09.10 - Comprehensive Analysis of Secondary Mutation as Resistance Mechanism to Seven MET-TKIs for MET Exon 14 Skipping in Vitro (Now Available) (ID 117)
15:15 - 16:45 | Author(s): Junichi Soh
- Abstract
- Presentation
Background
MET exon 14 skipping mutation have been attracting attentions of thoracic oncologists as a new target of therapy for lung cancer. The efficacy of MET-TKI has been reported, while these tumors, almost always acquire resistance, as in the case of other oncogene-addicted lung cancers. However, its resistance mechanisms are not fully understood.
Method
MET exon14 skipping mutation was introduced to Ba/F3 cell retrovirally. Using N-ethyl-N-nitrosourea mutagenesis, we derived resistant clones to seven MET-TKIs and searched for secondary MET mutations. We evaluated their sensitivities to following different TKIs. Type Ia, crizotinib; Type Ib, capmatinib, tepotinib and savolitinib; Type II, cabozantinib, merestinib and glesatinib.
Result
We sequenced 201 resistant clones and could obtain 80 clones which had secondary mutations in the MET tyrosine kinase domain. A total of 26 different missense mutations occurring at 12 codons were identified. Of them, D1228 and Y1230 in the activation loop were common sites for type I TKIs that bind to active kinase form (DFG-in), while L1195 and F1200 were those for type II TKIs that bind to inactive form (DFG-out). In general, resistant mutations against type I were sensitive to type II, and vice versa.
Conclusion
We identified mutation sites specific for TKI types as resistance mechanisms and complementary activities between type I and type II inhibitors against those mutations. These finding should provide relevant clinical implication for treating patients with lung cancer harboring MET exon 14 skipping.
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MA20 - Thymic Tumors: From Molecular to Clinical Results and New Challenges in Other Rare Thoracic Tumors (ID 149)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Thymoma/Other Thoracic Malignancies
- Presentations: 1
- Now Available
- Moderators:Kazuya Kondo, Edith Michelle Marom
- Coordinates: 9/10/2019, 11:30 - 13:00, San Francisco (2009)
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MA20.11 - Surgical Treatment for Metastatic Lung Tumors from Sarcomas of Soft Tissue and Bone (Now Available) (ID 2391)
11:30 - 13:00 | Author(s): Junichi Soh
- Abstract
- Presentation
Background
Sarcoma is one of the refractory malignant tumors and often develops pulmonary metastasis. The purpose of this study was to evaluate the impact of surgical resection for metastatic lung tumors from sarcomas of soft tissue and bone retrospectively.
Method
Between 2006 and 2015, we had a total of 158 patients with metastatic lung tumors from soft-tissue and bone sarcomas who underwent pulmonary metastasectomy for the first time. In total, 265 surgical procedures were performed in Okayama University Hospital in this period. We analyzed the age, sex, site of primary lesion, histology, extent of primary tumors at the initial diagnosis, extent of pulmonary metastases at the first pulmonary metastasectomy, presence or absence of local recurrence and/or extrapulmonary metastases with or before pulmonary metastases, operative procedures, size of the largest lesions resected, maximum number of the resected tumors, postoperative complications, and the prognosis at the end of 2018.
Result
Average number of resected tumors per intervention was 4.0 (range 1-19). These sarcoma patients consisted of 36 males and 122 females, and their average age was 53.7 years (range 14-88 years). Leiomyosarcoma was the most common histological subtype (n = 92, 58.2%) and uterus was the most common location of the primary disease (n = 71, 44.9%). Operative procedures were composed of 202 partial resections, 35 segmentectomies with or without partial resections, 26 lobectomies with or without partial resections, 1 pneumonectomy, and 1 basal segmental auto-transplantation after pneumonectomy. The postoperative complications were limited, showing that pulmonary metastasectomies for sarcomas are acceptable. Overall 3-year survival after the first pulmonary metastasectomy was 50.6%. In univariate analysis, the survival was significantly better for the group with disease-free interval of more than 2 years from the date of the initial treatment for primary disease until the date of diagnosis for the first pulmonary metastasis, the one who underwent pulmonary resections three times or more, and the one in which size of the largest resected lesion was 20 mm or less. Those factors significant in univariate analysis were all significant in multivariate analysis.
Conclusion
Surgical resections for metastatic lung tumors from sarcomas of soft tissue and bone were performed without major complications, indicating the acceptable feasibility. If disease-free interval is more than 2 years and the size of the largest resected lesion is less than 20 mm, patients may maximally benefit from pulmonary resection. In order to increase the opportunities of pulmonary resections, we should preserve the lung parenchyma as much as possible when performing pulmonary metatstasectomy, resulting in the better survival.
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-55 - Comparison of PD-L1 Expression Status Between Pure-Solid Versus Part-Solid Tumors in Lung Adenocarcinomas (ID 169)
09:45 - 18:00 | Author(s): Junichi Soh
- Abstract
Background
Recent studies have reported clinicopathological and prognostic differences between lung adenocarcinomas with ground-glass opacity (GGO) versus those without GGO (pure-solid tumors). However, it is unknow if the expression status of PD-L1 protein differs between these two groups.
Method
One-hundred twenty-four stage IA – IB lung adenocarcinoma patients who received pulmonary resection between 2007 – 2009 were included in this study. PD-L1 staining was performed in our previous study using E1L3N antibody. PD-L1 status was classified as positive if 1% or more tumor cells showed membrane staining; and was classified as strong positive if 50% or more tumor cells did so.
Result
Among 124 lung adenocarcinoma patients, 45 had lung adenocarcinomas with GGO and 79 had pure-solid lung adenocarcinomas. We observed no significant differences between these two groups in terms of clinical factors (gender, age, and smoking status). However, the rates of PD-L1 positive tumors (4% vs 25%, p < 0.01) and PD-L1 strong positive tumors (2% vs 16%, p = 0.02) were significantly lower in lung adenocarcinomas with GGO. In multivariate analyses, these correlations between the presence / absence of GGO and PD-L1 expression status were still evident as shown in Table 1.
Conclusion
Lung adenocarcinomas with GGO were less frequent to express PD-L1 compared to pure-solid lung adenocarcinomas.
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P1.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 186)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.16-35 - The Prognostic Impact of Sarcopenia on the Clinical Outcome of Thoracic Surgery for Non-Small Cell Lung Cancer in Elderly Patients (ID 1544)
09:45 - 18:00 | Author(s): Junichi Soh
- Abstract
Background
The elderly patients who undergo surgery for non-small cell lung cancer (NSCLC) is increasing in Japan whereas they are at high risk for surgery because of weakness of physical strength and increased comorbidity. Skeltal muscle depletion, referred to as sarcopenia, has recently been identified as a risk factor of poor clinical outcomes after surgery in the patients with various malignancies including NSCLC. We investigated the impact of sarcopenia on the clinical outcome of thoracic surgery for NSCLC in elderly patients.
Method
We enrolled 259 patients over 65 years old with NSCLC who underwent pulmonary resection (lobectomy or segmentectomy) without any induction treatment before surgery in our hospital during 2012 to 2015. Sarcopenia was assessed by the psoas muscle mass index (PMI, cm2/m2) using the computed tomography imaging at the third lumbar vertebra level before surgery. Postoperative complications, which were observed within 30days after surgery, were classified according to Clavien-Dindo classification. Overall survival (OS) was evaluated by the Kaplan-Meier method with log-rank test (univariate analyses) and by the cox proportional hazard model (multivariate analyses).
Result
Median age was 73 years old (65 - 92). One hundred fifty-five (60%) patients were male. Two hundred nine (81%) patients were cStage0 or I. Fifty-seven (22%) patients were squamous cell carcinoma (SCC). Postoperative pneumonia, arrhythmia, and delirium were observed in 17 (7%), 35 (14%) and 17 (7%) patients, respectively. Median follow-up was 48.7 months (range 3.0 – 79.6). Using the cutoff values as previously reported, 179 (69%) and 80 (31%) patients were diagnosed as sarcopenic and non-sarcopenic, respectively. Male and ever smoker were significantly more frequent in the sarcopenic patients than the non-sarcopenic patients (P < 0.001 and P = 0.018, respectively). The sarcopenic patients showed the trend of high incidence of Postoperative complications, however, there was no significant difference in OS between the sarcopenic and non-sarcopenic patients. Next, we performed the subgroup analysis to elucidate the prognostic factors only in the elderly sarcopenic patients. Among 179 sarcopenic patients, multivariate analysis including statistically significant factors in the univariate analysis revealed that the patients with restrictive lung disease, advanced cStage, postoperative pneumonia and delirium were inferior in OS [Hazard Ratio, 11.1, 3.6, 5.3 and 4.6; 95% confidence interval, 1.6 to 68.1, 1.1 to 13.0, 1.4 to 20.0 and 1.1 to 16.5; P= 0.011, 0.037, 0.017 and 0.041], suggesting the importance of the intensive perioperative management to avoid complications.
Conclusion
Perioperative complications are significantly associated with the prognosis of the sarcopenic elderly patients with NSCLC. Intensive perioperative management is mandatory for NSCLC patients with sarcopenia to improve the clinical outcome after thoracic surgery.
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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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P2.01-37 - Lower Risk of Hypercoagulability in Non-Small Cell Lung Cancer Patients with EGFR Mutations (ID 1602)
10:15 - 18:15 | Author(s): Junichi Soh
- Abstract
Background
Hypercoagulability is sometimes observed in cancer patients, including non-small cell lung cancer (NSCLC) patients. Plasma levels of fibrinogen or D-dimer are used as markers for hypercoagulability, and several previous studies have reported that upregulation of these markers are poor prognostic factors in NSCLCs. On the other hand, recent studies have highlighted clinical differences between NSCLCs with EGFR mutation and those without. However, there is no data about the difference in hypercoagulability between NSCLCs with EGFR mutation and those without.
Method
Between January 2007 to December 2016, 270 surgically resected NSCLC patients received EGFR mutation testing and were included in this study. Plasma fibrinogen and D-dimer levels were examined as one of pre-surgical examinations in all patients. We analyzed the correlation between plasma fibrinogen / D-dimer levels and EGFR mutation status.
Result
Among 270 patients in our cohort, 123 patients had EGFR mutation and 147 patients were wild type (WT) for the EGFR. In our cohort, plasma fibrinogen level was upregulated in 39 patients, while plasma D-dimer level was upregulated in 75 patients. Plasma fibrinogen was upregulated in 9 patients (7%) and in 30 patients (20%) in EGFR mutation group and in WT EGFR group, respectively (p = 0.0017). Plasma D-dimer was upregulated in 27 patients (22%) and in 48 patients (33%) in EGFR mutation group and in WT EGFR group, respectively (p = 0.049). These correlations were still significant after the adjustment with clinical factors including smoking status, age, and histology. In multivariate analysis, odds ratio and 95% CI in EGFR mutation group for upregulated plasma fibrinogen were 0.40 and 0.17 – 0.94, respectively (p = 0.037). On the other hand, odds ratio and 95% CI in EGFR mutation group for upregulated plasma D-dimer were 0.48 and 0.26 – 0.90, respectively (p = 0.022).
Conclusion
Plasma levels of fibrinogen and D-dimer were significantly lower in NSCLCs with EGFR mutation.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-20 - Potent in Vitro Activity of Tarloxotinib for HER2 Exon 20 Mutations in Lung Cancer and Mechanism of Acquired Resistance (ID 2093)
10:15 - 18:15 | Author(s): Junichi Soh
- Abstract
Background
Oncogenic HER2 (ERBB2) mutations are present in 2-3% of lung adenocarcinoma. No targeted therapy is currently approved for HER2-mutated lung cancers, and clinical trials using novel irreversible pan-HER inhibitors are underway. However, all of these irreversible pan-HER inhibitors are also active against wild-type (WT) EGFR, resulting in dose limiting toxicities. Tarloxotinib is a novel clinical-stage prodrug that releases a potent, irreversible pan-HER inhibitor (tarloxotinib-E) selectively in pathologically hypoxic regions of tumors. In this study, we evaluated tarloxotinib-E activity against various HER2 exon20 insertion mutations and explored the resistance mechanisms to tarloxotinib-E.
Method
We introduced WT HER2 or HER2 activating mutations, including A775_G776insYVMA, G776delinsVC, and P780_Y781insGSP into Ba/F3 cells by retroviral transfection. Growth inhibitory assays were performed in these Ba/F3 cells and in H1781 cells (G776delinsVC). Tarloxotinib-E resistant clones were established by exposing these Ba/F3 cells to 200nM of tarloxotinib-E after treatment with N-ethyl-N-nitrosourea. Acquired resistant cells to tarloxotinib-E were also developed from H1781 cells via chronic exposure to increasing concentrations of tarloxotinib-E. HER2 secondary mutations were detected by direct sequencing.
Result
Tarloxotinib-E displayed potent activity against WT and mutant HER2 Ba/F3 cells and H1781 cells. Furthermore, the IC50 of tarloxotinib (prodrug) for wild-type HER2 was > 100 times higher than that of tarloxotinib-E (active drug). So far, we established 12 tarloxotinib-E resistant clones from Ba/F3 models (6 with A775_G776insYVMA and 6 with G776delinsVC), all of which harbored C805S secondary mutation (corresponding to C797S of the EGFR).
Conclusion
Tarloxotinib-E exhibited potent activity for all HER2 exon 20 mutations. We identified secondary HER2 C805S mutation as a common mechanism of acquired resistance, consistent with the covalent binding mode of tarloxotinib via this residue. Additional resistant clones are currently being evaluated.
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P2.14 - Targeted Therapy (ID 183)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.14-16 - T790M or C797S Confers Acquired Resistance to Tarloxotinib and Poziotinib in EGFR Exon 20 Insertion-Driven Lung Cancer Models in Vitro (ID 1694)
10:15 - 18:15 | Author(s): Junichi Soh
- Abstract
Background
Lung cancers with EGFR exon 20 insertion mutations are refractory to current available tyrosine kinase inhibitors. Recent evidence suggests the therapeutic potential of the novel hypoxia-activated prodrug, tarloxotinib, a potent pan-HER inhibitor, or the repurposed 3rd generation inhibitor, poziotinib in these tumors. However, it is assumed that acquired resistance to these agents will be inevitable. In this study, we explored secondary mutations that may confer resistance to these agents using Ba/F3 models.
Method
Ba/F3 cells with various EGFR exon 20 mutations (A763insFQEA, V769insASV, D770insSVD, and H773insNPH) were generated by retroviral transfection. TKI resistant clones were established by exposure of parental cells to either tarloxotinib-E (active form of tarloxotinib) or poziotinib after treatment with N-ethyl-N-nitrosourea (ENU) mutagenesis agent. EGFR secondary mutations were detected by direct sequencing.
Result
ENU mutagenesis resulted in 62 tarloxotinib-E-resistant clones and 56 poziotinib-resistant clones using 200 nM of either drug. Ba/F3 cells with A763insFQEA were highly sensitive to these agents and only 1 tarloxotinib-resistant clone (C797S) was obtained. In Ba/F3 cells with V769insASV, all 14 tarloxotinib-resistant clones and 15 poziotinib-resistant clones developed T790M mutation. In Ba/F3 cells with D770insSVD cells, all 24 tarloxotinib-resistant clones and 20 poziotinib-resistant clones developed C797S mutation. In Ba/F3 cells with H773insNPH cells, 22 of 23 tarloxotinib-resistant clones and 21 of 22 poziotinib-resistant clones developed T790M mutation, while the rest of the clones harbored C797S mutation.
Conclusion
These results suggested that either T790M or C797S could cause acquired resistance to tarloxotinib and poziotinib in lung cancer models with EGFR exon 20 insertion mutations. Interestingly, the type of resistance mutation is likely to be dependent on the context of the original EGFR exon 20 insertion mutation.
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P2.17 - Treatment of Early Stage/Localized Disease (ID 189)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.17-41 - Treatment Outcomes of Pulmonary Resection in NSCLC Patients with Autoimmune Diseases (ID 3102)
10:15 - 18:15 | Author(s): Junichi Soh
- Abstract
Background
Surgical resection for early stage non-small cell lung cancer (NSCLC) patient with autoimmune disease(s) is a relatively rare occasion. Most of such patients have received steroid therapy with/without immunosuppressant agent for a long period before the surgery. However, short-term or long-term treatment outcomes of NSCLC patients with autoimmune disease are unclear.
Method
Between January 2007 to December 2018, thirty-nine NSCLC patients with autoimmune disease(s) received pulmonary resection with curative intent in our department. Patients with interstitial lung disease were excluded from this study. Patient clinical and pathological characteristics and treatment outcomes were evaluated.
Result
There were 17 males and 22 females in out cohort. The median age was 68 years old (39 – 84), and thirty patients were smokers. Twenty-three patients had rheumatoid arthritis, and among them, three patients had additional autoimmune disease (autoimmune hepatitis, Sjogren syndrome, or polyneuropathy). Other autoimmune diseases included Hashimoto disease (n = 4), systemic lupus erythematosus (n = 3), Behcet’s disease (n = 2), primary biliary cirrhosis (n = 2), and others. Only three patients received limited resections (2 partial resections and one segmentectomy), and 36 patients received lobectomy or bi-lobectomy. At the post-operative pathological diagnosis, there were 13 patients with squamous cell carcinomas, 21 patients with adenocarcinomas, four patients with pleomorphic carcinomas, and one patient with adenosquamous cell carcinoma. Post-surgical complications included pneumonia (n = 1, 3%), prolonged air leakage (n = 1, 3%), and no patient experienced bronchopleural fistula or empyema. The median post-surgical hospital stay was eight days ( 4 – 28 days).
Conclusion
Pulmonary resection for NSCLC patients with autoimmune disease(s) were safely performed. We will also report the long-term outcome for this cohort at the conference.
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P2.18 - Treatment of Locoregional Disease - NSCLC (ID 191)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.18-12 - Prognostic Nutrition Index Affects Prognosis of Trimodality Therapy for Locally Advanced Lung Cancer with High T Factor (Now Available) (ID 1644)
10:15 - 18:15 | Presenting Author(s): Junichi Soh
- Abstract
Background
Pretreatment nutritional status critically affects the clinical outcomes. Induction chemoradiotherapy (iCRT) followed by surgery (trimodality therapy) is a high-invasive treatment option for patients with locally advanced non-small cell lung cancer (LA-NSCLC). LA-NSCLC is a heterogeneous disease. Direct invasion into the surrounding structures easily promotes the invasion-related symptoms which inpair quality of life, but lymph node metastasis rarely causes its related symptoms until the bulky metastatic lymph nodes invade the surrounding structures. These differences of disease extent are expected to affect not only clinical outcome of treatment but also nutritional condition before initiation of treatment. While the prognostic nutritional index (PNI) is known to be correlated with the clinical outcomes after surgery in patients with early NSCLC, the significance of the PNI in LA-NSCLC patients undergoing trimodality therapy has not yet been well examined. In this study, we investigated the clinical impact of PNI in the LA-NSCLC patients who underwent iCRT followed by surgery considering the heterogeneity of disease extent.
Method
We enrolled 127 patients who received trimodality therapy at our institution between 1999 and 2016. The PNI was examined at all three time-points in the patients: before iCRT, before surgery, and after surgery.
Result
Fifty-five and 72 patients were diagnosed as clinical T1/2 (cT1/2) and cT3/4 diseases, respectively, and, 42 and 85 patients were cN0/1 and cN2/3, respectively. The PNI significantly decreased as the treatment progressed among all 127 patients. Patients with cT3/4 disease showed significantly lower PNI values before and after surgery than those with cT1/2 disease. By contrast, the PNIs were equivalent at all time-points between patients with cN2/3 and cN0/1 disease. We performed receiver-operating characteristic curve analysis to determine the cutoff the pre-iCRT PNI for overall survival (OS) in all (n = 127), cT3/4 (n = 72) and cN2/3 patients. The ROC curve analyses indicated that a significant cutoff was identified only in cT3/4 patients. Univariate and multivariate analyses revealed that high pre-iCRT PNI values were significantly correlated with better survival in cT3/4 patients. By contrast, the prognostic impact of pre-iCRT PNI values could not be observed in cN2/3 patients
Conclusion
The nutritional status deteriorates as the treatment progresses during trimodality therapy. Intensive perioperative nutritional intervention is required especially for cT3/4 LA-NSCLC patients receiving trimodality therapy.
