Totality outcome of afatinib sequential treatment in patients with EGFR mutation-positive non-small cell lung cancer in South Korea (TOAST): Korean Cancer Study Group (KCSG) LU-19-22

Background: Irrespective of the first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor chosen, acquired resistance to therapy is inevitable. Therefore, a key consideration when assessing therapeutic choices is the availability of subsequent treatment options following disease progression. We assessed clinical outcomes in patients who received first-line afatinib treatment with various second-line treatments including osimertinib for patients acquiring the T790M mutation. Methods: A total of 737 EGFR mutation-positive (EGFR M+) non-small cell lung cancer (NSCLC) patients receiving first-line afatinib treatment were categorized by second-line treatment: T790M+ sequentially treated with osimertinib (cohort A, n=116); T790M- given chemotherapy or others (cohort B, n=143); patients with unknown T790M status (cohort C, n=111); and patients who were undergoing afatinib treatment at the time of data collection, were dead, had discontinued afatinib treatment due to serious adverse events or were lost to follow-up (cohort D, n=367). The primary outcomes were total time on treatment (TOT) and TOT for first-line (TOT-1) and second-line treatments (TOT-2). Secondary outcomes were objective response rates (ORR), overall survival (OS), and central nervous system (CNS) efficacy. Results: Median total TOT in cohorts A, B, C, and D were 35.10 months [95% confidence interval (CI): 30.09-43.53 months], 18.80 months (95% CI: 16.92-20.20 months), 12.00 months (95% CI: 10.22-14.98 months), and 42.60 months (95% CI: 30.95-59.23 months), respectively. The ORR of patients given afatinib was 75.7%. In patients with initial brain metastasis without local treatment, the CNS response rate was 67.0% and CNS progression-free survival was 24.70 months (95% CI: 19.84-33.15 months). Conclusions: This study showed that sequential approach of afatinib followed by second line treatment is an effective therapeutic strategy for EGFR M+ NSCLC patients.ope

Treatment outcomes of sunitinib treatment in advanced renal cell carcinoma patients : a single cancer center experience in Korea

의과대학/석사Purpose : The retrospective study was performed to assess the efficacy and toxicity profiles of sunitinib in Korean patients with metastatic renal cell carcinoma (RCC). Materials and Methods : Between January 2005 and December 2008, 76 Korean patients with recurrent/metastatic RCC who received sunitinib were retrospectively reviewed. The primary end point was progression-free survival and the secondary end points were overall survival and response rate. We also assessed the toxicities associated with sunitinib treatment. Results : Of the 76 patients, 68 patients (89.5%) were diagnosed with clear cell RCC. The median progression-free survival and overall survival were 7.2 and 22.8 months, respectively in overall patients. Sixty-two patients (81.6%) received 50mg 4 week and 2 week off schedule, and 14 patients (18.4%) received 37.5mg daily on a daily continuous schedule. The objective response rate and disease control rate were 27.6% and 84.2%, respectively. A dose interruption or reduction in dose due to adverse events occurred in 76% of the patients, whereas 12% of these patients had discontinued treatment. Other common laboratory abnormalities were increased serum creatinine (75.6%), elevated alanine aminotransferase (71.0%), neutropenia (61.8%), anemia (69.7%), and increased aspartate aminotransferase (53.3%). Grade 3/4 toxicities occurred as follows: thrombocytopenia (38.2%), fatigue (10.5%), stomatitis (10.5%), and hand-foot syndrome (9.2%). Conclusion : Our results indicate that sunitinib treatment is effective and tolerable for recurrent/metastatic RCC patients in Korea. Further studies with prognostic or biochemical factors are needed to clarify the different toxicity profiles of this study.ope

Povidone-iodine for the management of oral mucositis during cancer therapy

Oral mucositis (OM) is a common and often dose-limiting side effect of cancer therapy. Povidone iodine (PVP-I) formulations have been shown to decrease the incidence and severity of OM, but the relevance of these findings remains unclear. The objective of the present study was to review evidence for the use of PVP-I for OM management. An algorithm identified relevant articles published online, and a panel of experts with experience in the management of OM reviewed the findings. Six studies fulfilled the criteria for full review. Two studies provided evidence of moderate quality. Two of the studies with negative findings were confounded by the use of PVP-I concentrations that are too low to be efficacious. The remaining two studies were found to have design flaws. There exists reasonable evidence to support a recommendation for the use of PVP-I in the management of cancer therapy-related OM.ope

Analysis of Industrial Policy and the Product Space map in Colombia

학위논문 (석사)-- 서울대학교 국제대학원 : 국제학과(국제지역학전공), 2013. 8. 김종섭.본 연구는 콜롬비아의 저성장 및 경제발전의 뒤쳐짐 현상에 주목하였다. 1980년도부터 현재까지 콜롬비아는 상위 5위의 1인당 국민소득을 기록해왔으나 상위 4개국(멕시코, 칠레, 아르헨티나, 브라질)과의 격차가 점점 심해져 상위소득국가와 하위소득국가로 양분되는 양상이 나타났다. 콜롬비아가 상위 4개국의 발전 양상에 편입되지 못한 이유에 대한 규명은 다양한 방법에 의해 가능하다. 본 연구는 하우스만의 프로덕트 스페이스 맵을 통하여 1975년부터 2010년까지 콜롬비아의 프로덕트 스페이스 맵과 브라질, 멕시코의 사례의 차이점을 분석한다. 수출 품목의 기술적 숙련도와 수출 규모의 발전양상 비교를 통해 콜롬비아가 처한 문제를 1차적으로 분석하였다. 또한 콜롬비아의 산업정책을 분석하여 발전을 저해하는 요인을 조사하였다. 1950년부터 충실하게 산업정책을 수행해왔던 국가임에도 불구하고 발전이 제한되는 이유를 규명하며 프로덕트 스페이스 맵이 단편적인 생산 품목의 양상만을 다루는 것에 비해 심도 있게 접근 하고자 하였다. 위의 과정을 통해 콜롬비아의 수출 품목 변화 양상을 모범 사례 국가들과 비교하여 국가가 처한 상황에 대한 객관적인 인식 및 수출품목 및 규모 차원의 문제 진단이 가능하다. 또한 정책 분석을 통하여 오랜 산업정책 역사에서 콜롬비아가 극복하지 못하는 과제 분석에 기여하고자 하였다.The research focuses on lagging trend of economic development in Colombia. Since 1980, Colombia has ranked at 5th place in terms of GDP per capita. However the gap between Top 4 countries (Mexico, Chile, Argentina, and Brazil) and Colombia has increased and bisected region's economies into two groups. Analyzing the rationale for Colombia's failure in joining top 4 countries' economic performance is possible via various dimensions. This research applied Product Space Map by Hausmann et al. to analyze exporting structure of Colombia from 1975 to 2010 and compare the result with Brazil and Mexico's case. Product Space map allows analyzing sophistication level and volume of the product that has comparative advantage in export. In addition, the research studies Industrial Policies(IPs) of Colombia. Since the country pursued IPs from 1950, author analyzed the rationale behind stagnated growth despite having policy framework for an extensive period. Throughout the mentioned processes, this research executes objective as-is analysis of Colombia's export status by providing comparative cases.1. Introduction 1 2. Methodology 4 1) Product Space Map 4 2) Revealed Comparative Advantage 10 3. Product Space map analysis 11 4. Industrial Policies 17 1) Policy Shift in Latin America 17 2)Productive Development Policies (PDPs) in Colombia 22 5. Conclusion 27 References 29 Appendix 31 Korean Abstract 44Maste

Patient-Derived Cells to Guide Targeted Therapy for Advanced Lung Adenocarcinoma

Adequate preclinical model and model establishment procedure are required to accelerate translational research in lung cancer. We streamlined a protocol for establishing patient-derived cells (PDC) and identified effective targeted therapies and novel resistance mechanisms using PDCs. We generated 23 PDCs from 96 malignant effusions of 77 patients with advanced lung adenocarcinoma. Clinical and experimental factors were reviewed to identify determinants for PDC establishment. PDCs were characterized by driver mutations and in vitro sensitivity to targeted therapies. Seven PDCs were analyzed by whole-exome sequencing. PDCs were established at a success rate of 24.0%. Utilizing cytological diagnosis and tumor colony formation can improve the success rate upto 48.8%. In vitro response to a tyrosine kinase inhibitor (TKI) in PDC reflected patient treatment response and contributed to identifying effective therapies. Combination of dabrafenib and trametinib was potent against a rare BRAF K601E mutation. Afatinib was the most potent EGFR-TKI against uncommon EGFR mutations including L861Q, G719C/S768I, and D770_N771insG. Aurora kinase A (AURKA) was identified as a novel resistance mechanism to olmutinib, a mutant-selective, third-generation EGFR-TKI, and inhibition of AURKA overcame the resistance. We presented an efficient protocol for establishing PDCs. PDCs empowered precision medicine with promising translational values.ope

Lazertinib: on the Way to Its Throne

Lazertinib is an oral, irreversible, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that forms an irreversible covalent bond to the Cys797 residue in the ATP-binding site of the EGFR kinase domain and exhibits a high selectivity for sensitizing and T790M EGFR mutations. In January 2021, it was first approved for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) patients with EGFR T790M who had previously received EGFR TKI therapy based on LASER201, a phase I/II trial. At a recommended dose of 240 mg, lazertinib achieved an encouraging anti-tumor activity in both extra- and intracranial lesions. With a high half-maximal inhibitory concentration for EGFR wildtype tumors, it is anticipated to pose a lower risk of skin and cardiac adverse events compared to osimertinib. Lazertinib is currently being investigated as a monotherapy in first-line treatment and in combination with amivantamab under various settings. In this review, we systematically summarize the preclinical and clinical data of lazertinib and discuss future perspectives on the treatment of EGFR-mutant NSCLC.ope

The value of disease-free survival (DFS) and osimertinib in adjuvant non-small-cell lung cancer (NSCLC): an international Delphi consensus report

ope

High CD3 and ICOS and low TIM-3 expression predict favourable survival in resected oesophageal squamous cell carcinoma

With the increasing oncological potential of immunotherapy, several immune checkpoint modulators are being investigated. The value of immune markers, including programmed cell death ligand-1, programmed cell death-1 (PD-1), inducible co-stimulator (ICOS), lymphocyte activation gene-3, T-cell immunoglobulin, and mucin-dominant containing-3 (TIM-3), is not well known. Using tissue microarrays of 396 patients who underwent surgery for oesophageal squamous cell carcinoma (ESCC), infiltrated T-cell subsets (CD3, CD8, and Foxp3) and checkpoint protein expression were scored. With a median follow-up of 24.8 months, CD3+ TIL subsets (50.0%) had longer median recurrence-free survival (RFS, 55.0 vs 21.4 months) and overall survival (OS, 77.7 vs 35.8 months). Patients with high ICOS expression (46.5%) had longer median RFS (53.9 vs 25.3 months) and OS (88.8 vs 36.9 months). For PD-1, RFS (hazard ratio [HR] 0.67) and OS (HR 0.66) were significantly longer in the high-expression group (45.2%). In the multivariate analysis, high TIM-3 expression (50.8%) had a significant relationship with shorter RFS (HR = 1.52) and OS (HR = 1.60). High CD3+ TIL and T-cell ICOS expression were associated with favourable prognosis, whereas high TIM-3 expression suggested a poor prognosis. Our findings may confer new insights to improve ESCC outcomes beyond the application of PD-1 blockade.ope

A randomized Phase 2 study to compare erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation

Background: This study evaluated whether an addition of bevacizumab to erlotinib improves clinical outcomes in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). Methods: This is an open-label, multicenter, randomized Phase 2 study in South Korea. Chemonaive patients with Stage IIIB/IV NSCLC with EGFR 19 deletion or L858R mutation were eligible. Asymptomatic brain metastasis (BM) was enrolled without local treatment. Patients received either erlotinib plus bevacizumab or erlotinib. Results: Between December 2016 and March 2019, 127 patients were randomly assigned to receive erlotinib plus bevacizumab (n = 64) or erlotinib (n = 63). Fifty-nine (46.5%) patients had baseline BM. Fewer patients in the erlotinib plus bevacizumab arm received radiotherapy for BM than in the erlotinib arm (10.3% vs. 40.0%). A trend toward longer progression-free survival (PFS) was observed in the erlotinib plus bevacizumab arm compared with the erlotinib alone arm; however, it was not statistically significant (median PFS, 17.5 months vs. 12.4 months; hazard ratio [HR], 0.74; 95% CI, 0.51-1.08; p = .119). The unplanned subgroup analysis showed a longer PFS with erlotinib plus bevacizumab in patients with BM (median PFS, 18.6 months vs. 10.3 months; HR, 0.54; 95% CI, 0.31-0.95; p = .032). Grade 3 or worse adverse events occurred in 56.6% of the erlotinib plus bevacizumab arm and 20.6% of the erlotinib arm. Conclusions: Although it was not statistically significant, a trend to improvement in PFS was observed in patients with erlotinib plus bevacizumab compared to erlotinib alone. Plain Language Summary: A randomized Phase 2 study compared erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation. The erlotinib plus bevacizumab failed to improve median progression-free survival compared with the erlotinib alone. However, the progression-free survival benefit from erlotinib plus bevacizumab was found in patients with brain metastasis with no severe hemorrhagic adverse effects.ope

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer

Clinical benefit of ALK tyrosine kinase inhibitors (ALK-TKIs) in ALK-rearranged lung cancer has been limited by the inevitable development of acquired resistance, and bypass-molecular resistance mechanisms remain poorly understood. We investigated a novel therapeutic target through screening FDA-approved drugs in ALK-TKI-resistant models. Cerivastatin, the rate-limiting enzyme inhibitor of the mevalonate pathway, showed anti-cancer activity against ALK-TKI resistance in vitro/in vivo, accompanied by cytoplasmic retention and subsequent inactivation of transcriptional co-regulator YAP. The marked induction of YAP-targeted oncogenes (EGFR, AXL, CYR61, and TGFβR2) in resistant cells was abolished by cerivastatin. YAP silencing suppressed tumor growth in resistant cells, patient-derived xenografts, and EML4-ALK transgenic mice, whereas YAP overexpression decreased the responsiveness of parental cells to ALK inhibitor. In matched patient samples before/after ALK inhibitor treatment, nuclear accumulation of YAP was mainly detected in post-treatment samples. High expression of YAP in pretreatment samples was correlated with poor response to ALK-TKIs. Our findings highlight a crucial role of YAP in ALK-TKI resistance and provide a rationale for targeting YAP as a potential treatment option for ALK-rearranged patients with acquired resistance to ALK inhibitors.ope