Purpose Exon 20 insertion mutations (E20ins) in epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) in non–small cell lung cancer (NSCLC) patients has become more important with emergence of novel agents targeting E20ins.
Materials and Methods Advanced/Metastatic NSCLC patients with E20ins were included. EGFR E20ins was identified by two methods, next-generation sequencing (NGS) or real-time polymerase chain reaction (PCR), while HER2 E20ins was done by NGS only.
Results Between December 2013 and July 2021, E20ins were identified in 107 patients at Asan Medical Center; 67 EGFR E20ins and 40 HER2 E20ins. Out of 32 patients with EGFR E20ins who had tested both PCR and NGS, 17 were identified only through NGS and the other 15 through both tests, giving a discordance rate of 53.1%. There was no clinically significant difference in clinicopathologic features between EGFR and HER2 E20ins; both were observed more frequently in adenocarcinoma, female and never-smokers. Brain metastases were evident at diagnosis in 31.8% of EGFR E20ins and 27.5% of HER2 E20ins, respectively. Platinum-based doublets demonstrated objective response rates (ORR) of 13.3% with a median progression-free survival (PFS) of 4.2 months for EGFR E20ins and 35.3% with 4.7 months for HER2 E20ins, respectively. In contrast, novel EGFR E20ins-targeted agents exhibited an ORR of 46.2% with a median PFS of 5.4 months, while HER2-targeted agents showed an ORR of 50% with that of 7.0 months.
Conclusion Identification of EGFR and HER2 E20ins is more important as their targeted therapies improved outcomes. Upfront NGS test as a comprehensive molecular approach is strongly warranted.
Jeong Yun Jang, Si Yeol Song, Young Seob Shin, Ha Un Kim, Eun Kyung Choi, Sang-We Kim, Jae Cheol Lee, Dae Ho Lee, Chang-Min Choi, Shinkyo Yoon, Su Ssan Kim
Cancer Res Treat. 2024;56(3):785-794. Published online January 16, 2024
Purpose This study aimed to assess the real-world clinical outcomes of consolidative durvalumab in patients with unresectable locally advanced non–small cell lung cancer (LA-NSCLC) and to explore the role of radiotherapy in the era of immunotherapy.
Materials and Methods This retrospective study assessed 171 patients with unresectable LA-NSCLC who underwent concurrent chemoradiotherapy (CCRT) with or without consolidative durvalumab at Asan Medical Center between May 2018 and May 2021. Primary outcomes included freedom from locoregional failure (FFLRF), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS).
Results Durvalumab following CCRT demonstrated a prolonged median PFS of 20.9 months (p=0.048) and a 3-year FFLRF rate of 57.3% (p=0.008), compared to 13.7 months and 38.8%, respectively, with CCRT alone. Furthermore, the incidence of in-field recurrence was significantly greater in the CCRT-alone group compared to the durvalumab group (26.8% vs. 12.4%, p=0.027). While median OS was not reached with durvalumab, it was 35.4 months in patients receiving CCRT alone (p=0.010). Patients positive for programmed cell death ligand 1 (PD-L1) expression showed notably better outcomes, including FFLRF, DMFS, PFS, and OS. Adherence to PACIFIC trial eligibility criteria identified 100 patients (58.5%) as ineligible. The use of durvalumab demonstrated better survival regardless of eligibility criteria.
Conclusion The use of durvalumab consolidation following CCRT significantly enhanced locoregional control and OS in patients with unresectable LA-NSCLC, especially in those with PD-L1–positive tumors, thereby validating the role of durvalumab in standard care.
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Therapeutic effect of induction therapy including nab-paclitaxel followed by surgical resection for the patients with locally advanced non-small-cell lung cancer Hidetaka Uramoto, Nozomu Motono, Shun Iwai Journal of Cardiothoracic Surgery.2024;[Epub] CrossRef
Songji Choi, Seyoung Seo, Ju Hyun Lee, Koung Jin Suh, Ji-Won Kim, Jin Won Kim, Se Hyun Kim, Yu Jung Kim, Keun-Wook Lee, Jwa Hoon Kim, Tae Won Kim, Yong Sang Hong, Sun Young Kim, Jeong Eun Kim, Sang-We Kim, Dae Ho Lee, Jae Cheol Lee, Chang-Min Choi, Shinkyo Yoon, Su-Jin Koh, Young Joo Min, Yongchel Ahn, Hwa Jung Kim, Jin Ho Baek, Sook Ryun Park, Jee Hyun Kim
Cancer Res Treat. 2024;56(2):404-413. Published online November 7, 2023
Purpose The female sex is reported to have a higher risk of adverse events (AEs) from cytotoxic chemotherapy. Few studies examined the sex differences in AEs and their impact on the use of medical services during adjuvant chemotherapy. This sub-study aimed to compare the incidence of any grade and grade ≥ 3 AEs, healthcare utilization, chemotherapy completion rate, and dose intensity according to sex.
Materials and Methods This is a sub-study of a multicenter cohort conducted in Korea that evaluated the impact of healthcare reimbursement on AE evaluation in patients who received adjuvant chemotherapy between September 2013 and December 2016 at four hospitals in Korea.
Results A total of 1,170 patients with colorectal, gastric, or non–small cell lung cancer were included in the study. Female patients were younger, had fewer comorbidities, and experienced less postoperative weight loss of > 10%. Females had significantly higher rates of any grade AEs including nausea, abdominal pain, stomatitis, vomiting, and neutropenia, and experienced more grade ≥ 3 neutropenia, nausea, and vomiting. The dose intensity of chemotherapy was significantly lower in females, and they also experienced more frequent dose reduction after the first cycle. Moreover, female patients receiving platinum-containing regimens had significantly higher rates of unscheduled outpatient visits.
Conclusion Our study found that females experienced a higher incidence of multiple any-grade AEs and severe neutropenia, nausea, and vomiting, across various cancer types, leading to more frequent dose reductions. Physicians should be aware of sex differences in AEs for chemotherapy decisions.
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Purpose We aimed to investigate the feasibility of four criteria on oligometastasis (OM) concerning clear survival benefits of local therapy (LT) during tyrosine kinase inhibitor (TKI) treatment in non–small cell lung cancer (NSCLC).
Materials and Methods This single-center, retrospective study included patients with advanced NSCLC who received LT because of OM during TKI treatment at Asan Medical Center from January 2011 to December 2020. At the application of LT OM was classified according to four criteria: TNM, European Organization for Research and Treatment of Cancer Lung Cancer Group (EORTC-LCG), National Comprehensive Network (NCCN), and ORGAN. We compared survival outcomes between patients with and without OM.
Results The median overall survival of the 117 patients included in the analysis was 70.8 months (95% confidence interval [CI], 56.6 to 85.1). The patients with OM meeting all four criteria (hazard ratio [HR] with 95% CI of TNM criteria 0.24 with 0.10-0.57; p=0.001, EORTC-LCG criteria 0.34 with 0.17-0.67; p=0.002, NCCN criteria 0.41 with 0.20-0.86; p=0.018 and ORGAN criteria 0.33 with 0.18-0.60; p < 0.001) had significantly longer survival compared with patients who did not after adjusting for confounding factors. Furthermore, increasing the number of extra-thoracic metastatic organs to two or more were independent predictive factors for worse survival outcomes (2 organs: HR, 3.51; 95% CI, 1.01 to 12.14; p=0.048; 3 organs: HR, 4.31; 95% CI, 0.94 to 19.73; p=0.060; 4 organs: HR, 24.47; 95% CI, 5.08 to 117.80; p < 0.001).
Conclusion Patients with OM defined by all four criteria showed prognostic benefits from LT during TKI therapy.
Radiation Oncologists’ Perspectives on Oligometastatic Disease: A Korean Survey Study Chai Hong Rim, Won Kyung Cho, Jong Hoon Lee, Young Seok Kim, Yang-Gun Suh, Kyung Hwan Kim, Ah Ram Chang, Eui Kyu Chie, Yong Chan Ahn Cancer Research and Treatment.2024; 56(2): 414. CrossRef
Oligometastasis: More Lessons to Be Learned Kyung Hwan Kim, Yong Chan Ahn Cancer Research and Treatment.2023; 55(1): 1. CrossRef
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Cancer Res Treat. 2022;54(3):767-781. Published online September 30, 2021
Purpose
Heat shock protein-90 (HSP90) remains an important cancer target because of its involvement in multiple oncogenic protein pathways and biologic processes. Although many HSP90 inhibitors have been tested in the treatment of KRAS-mutant non–small cell lung cancer (NSCLC), most, including AUY922, have failed due to toxic effects and resistance generation, even though a modest efficacy has been observed for these drugs in clinical trials. In our present study, we investigated the novel mechanism of resistance to AUY922 to explore possible avenues of overcoming and want to provide some insights that may assist with the future development of successful next-generation HSP90 inhibitors.
Materials and Methods
We established two AUY922-resistant KRAS-mutated NSCLC cells and conducted RNA sequencing to identify novel resistance biomarker.
Results
We identified novel two resistance biomarkers. We observed that both integrin Av (ITGAv) and β3 (ITGB3) induce AUY922-resistance via focal adhesion kinase (FAK) activation, as well as an epithelial-mesenchymal transition, in both in vitro and in vivo xenograft model. mRNAs of both ITGAv and ITGB3 were also found to be elevated in a patient who had shown acquired resistance in a clinical trial of AUY922. ITGAv was induced by miR-142 downregulation, and ITGB3 was increased by miR-150 downregulation during the development of AUY922-resistance. Therefore, miR-150 and miR-142 overexpression effectively inhibited ITGAvB3-dependent FAK activation, restoring sensitivity to AUY922.
Conclusion
The synergistic co-targeting of FAK and HSP90 attenuated the growth of ITGAvB3-induced AUY922-resistant KRAS-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome acquired AUY922-resistance in KRAS-mutant NSCLC.
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Purpose Ipilimumab improves survival in advanced melanoma patients. However, the efficacy and safety of ipilimumab has not been evaluated in Asian melanoma patients with a high frequency of mucosal and acral melanoma subtypes.
Materials and Methods Advanced melanoma patients treated with 3 mg/kg ipilimumab in a Korean multicenter named-patient program (NPP) were evaluated between September 2014 and July 2015. Baseline characteristics and blood parameters including neutrophil to lymphocyte ratio (NLR) were assessed, and outcome and adverse events were evaluated according to subtypes.
Results A total of 104 advanced melanoma patients were treated. The primary sites were acral (31.7%), mucosal (26%), cutaneous (26%), uveal (9.6%), and unknown (6.7%). Sixty-eight patients (65.4%) experienced adverse events, and the most common toxicity was skin rash (22.1%), 10 patients (9.6%) experienced adverse events of grade 3 or higher. The median progression-free survival (PFS) was 2.73 months (95% confidence interval, 2.67 to 2.85), and there was no difference in PFS according to subtypes. Poor performance status, liver metastasis, and NLR (≥5) were independent poor prognostic factors by multivariate analysis.
Conclusion In the Korean NPP cohort, ipilimumab showed similar efficacy and tolerability compared to Western patients, regardless of subtypes. All subtypes should benefit from ipilimumab with consideration of performance status, liver metastasis, and NLR.
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Advances in oncology research have led to identification of tumor-specific biomarkers, some of which are important predictive indicators and ideal targets for novel therapeutics. One such biomarker in non-small cell lung cancer (NSCLC) is the epidermal growth factor receptor (EGFR). Patients with NSCLC who harbor an activating EGFR mutation show a more favorable response to treatment with an EGFR inhibitor, such as gefitinib, erlotinib, or afatinib, than to chemotherapy. The prevalence of EGFR mutations in East Asian patients is higher than that in other populations, and in some clinical settings, patients have been treated with EGFR inhibitors based on clinicopathologic characteristics with no information on EGFR status. However, based on results from a series of studies in which East Asian patients with advanced non-squamous NSCLC were treated with EGFR inhibitors alone or in combination with standard chemotherapy, this may not be the best practice because EGFRmutation status was found to be a key predictor of outcome. Data from these studies highlight the necessity of EGFR testing in determining the most suitable treatment for patients with advanced or metastatic NSCLC.
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Purpose
This subgroup analysis of a phase II trial was conducted to assess possible ethnicity-based trends in efficacy and safety in East Asian (EA) and non-EA populations with nonsquamous non-small cell lung cancer (NSCLC).
Materials and Methods
Never-smoker patients (n=240) with locally advanced or metastatic nonsquamous NSCLC included 133 EA patients randomized to pemetrexed supplemented with dexamethasone, folic acid, and vitamin B12 plus erlotinib (pemetrexed-erlotinib) (n=41), erlotinib (n=49), or pemetrexed (n=43), and 107 non-EA patients randomized to pemetrexed-erlotinib (n=37), erlotinib (n=33), or pemetrexed (n=37). The primary endpoint, progression-free survival (PFS), was analyzed using a multivariate Cox model.
Results
Consistent with the results of the overall study, a statistically significant difference in PFS among the three arms was noted in the EA population favoring pemetrexed-erlotinib (overall p=0.003) as compared with either single-agent arm (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29 to 0.79; p=0.004 vs. erlotinib; HR, 0.40; 95% CI, 0.23 to 0.70; p=0.001 vs. pemetrexed). The EA patients treated with pemetrexed-erlotinib achieved a longer median PFS (7.4 months) compared with erlotinib (4.5 months) and pemetrexed (4.0 months). The PFS results also numerically favored pemetrexed-erlotinib in the non-EA population (overall p=0.210) (HR, 0.62; 95% CI, 0.37 to 1.05; p=0.078 vs. erlotinib; HR, 0.75; 95% CI, 0.42 to 1.32; p=0.320 vs. pemetrexed) (median PFS: pemetrexed-erlotinib, 6.7 months; erlotinib, 3.0 months; pemetrexed, 4.4 months).
Conclusion
The PFS results from this subset analysis in both EA and non-EA populations are consistent with the results in the overall population. The PFS advantage for pemetrexed-erlotinib is significant compared with the single agents in EA patients.
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PURPOSE This study was designed to evaluate the efficacy of a combination treatment of S-1 plus either irinotecan or docetaxel for advanced/metastatic non-small cell lung cancer (NSCLC) patients who have already failed 3 or more lines of treatment. MATERIALS AND METHODS This was a prospective single center phase II study. The eligible patients received S-1 40 mg/m2 twice a day orally on days 1 though 14 combined with irinotecan 150 mg/m2on D1 only or docetaxel 35 mg/m2 on D1 and D8. The treatment was repeated every 3 weeks until disease progression, unacceptable toxicity, or patient refusal. The choice between the two regimens was made at the discretion of the treating physician. RESULTS A total of 14 patients participated in the study.
There were 3 patients with squamous cell carcinoma, 9 with adenocarcinoma, and 2 with NSCLC, NOS. Eight of the patients were male. There were 8 patients with an Eastern Cooperative Oncology Group (ECOG) of 1, and 6 patients with an ECOG of 2. All the patients had already been treated with platinum-based chemotherapy and epidermal growth factor receptor tyrosine kinase inhibitor therapy. Out of the 14 patients, 10 received irinotecan and S-1 and the other 4 received docetaxel and S-1. Twelve patients had also received pemetrexed. Disappointingly, there were no response from 2 patients with a stable disease, and therefore, as per the protocol, we stopped the study early. With a median follow-up time of 49 months, the median survival time was 5.6 months (95% confidence interval, 4.3 to 6.9 months). CONCLUSION S-1 containing doublets did not show activity in this population as a salvage treatment and further investigation cannot be recommended.
PURPOSE To evaluate the efficacy and toxicity of combination chemotherapy with low-dose paclitaxel and cisplatin in patients with advanced non-small cell lung cancer. MATERIALS AND METHODS Chemotherapy-naive patients with unresectable, pathologically proven non-small cell lung cancer were eligible for inclusion in the study. Patients received paclitaxel (145 mg/m2 iv 3 hour D1) and cisplatin (60 mg/m2 iv D1) every 3 weeks. RESULTS Forty-two patients were enrolled between February 2000 and February 2001. The median age was 53.5 years.
Patients with adenocarcinoma numbered 29, squamous cell carcinoma 7, large cell carcinoma 3, and undifferentiated carcinoma 3. Seventeen patients had stage IIIB, 19 had stage IV disease and the remaining 6 displayed recurred disease after previous surgical resection. Four patients terminated treatment early because of hypersensitivity (1) and severe emesis (3). Of the 38 evaluable patients, 14 had PR and the response rate was 36.8%. Among partial responders, 6 patients received additional chest radiation. The median duration of response was 47.9 weeks and the median overall survival was 54.0 weeks. Of the total 176 courses, 14 were delayed, 22 required dose reduction, and grade 3~4 neutropenia occurred in 5.6% of courses. Only one episode of neutropenic fever developed and there were no treatment- related mortalities. Other toxicities were generally mild. CONCLUSION The combination chemotherapy with low-dose paclitaxel and cisplatin was effective and tolerable in patients with advanced non-small cell lung cancer.
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Phase II Study of Low-dose Paclitaxel and Cisplatin as a Second-line Therapy after 5-Fluorouracil/Platinum Chemotherapy in Gastric Cancer Keun-Wook Lee, Jee Hyun Kim, Tak Yun, Eun Kee Song, Im il Na, Hyunchoon Shin, So Yeon Oh, In Sil Choi, Do-Youn Oh, Dong-Wan Kim, Seock-Ah Im, Tae-You Kim, Jong Seok Lee, Dae Seog Heo, Yung-Jue Bang, Noe Kyeong Kim Journal of Korean Medical Science.2007; 22(Suppl): S115. CrossRef
Phase II Trial of Low-dose Paclitaxel and Cisplatin in Patients with Advanced Gastric Cancer Keun-Wook Lee, Seock-Ah Im, Tak Yun, Eun Kee Song, Im il Na, Hyunchoon Shin, In Sil Choi, Do-Youn Oh, Jee Hyun Kim, Dong-Wan Kim, Tae-You Kim, Jong Seok Lee, Dae Seog Heo, Yung-Jue Bang, Noe Kyeong Kim Japanese Journal of Clinical Oncology.2005; 35(12): 720. CrossRef
PURPOSE We investigated the effectiveness and safety of DA-3030 for prophylatic use in patients receiving chemotherapy for malignant disease. MATERIALS AND METHODS Seventy cancer patients were randomized to receive chemotherapy alone (36 patients) or with DA-3030 administered (34 patients) after stratified block randomization according to chemotherapeutic regimen.
DA-3030 was subcutaneously administered at the dose of 100 pg/m/day for 10 days from 24 hours after the completion of chemotherapy. RESULTS Of the 70 enrolled patients, 62 patients were evaluable. The neutropenia (absolute neutrophil count [ANC] <1,000/mm) occurred in 9 of 32 (28.1%) of the DA-3030 group and 21 of 30 (90.0%) of the control group, giving relative risk for control group of 0.154 (95% confidence interval [CI], 0.05 to 0.45; p-0.0001). Severe neutropenia (ANC 500/mm') occurred in 4 of 32 (12.5%) of the DA-3030 group and in 20 of 30 (66.7%) of the control group (relative risk for control group of 0.316 [95% CI, 0,18 to 0.55]; p=0.0001). The mean duration of neutropenic period (+/-standard error) was 1.13+/-0.34 days in the DA-3030 group and 6.73+/-0.69 days in the control group respectively, and was significantly shorter in the DA-3030 group (p<0.0001). And, there was higher nadir ANC in the OA-3030 group than that in the control group (p=0.0001); the mean nadir ANC was 2,547+/- 343/mm and 442+/-120/mm, respectively. The DA-3030 group had significantly higher incidence of myalgia in comparison to the control group (43.8% compared with 3.3%; p=0.001). However, it was tolerable and was easily managed by conservative therapy CONCLUSION: The use of DA-3030 was effective in preventing chemotherapy-induced neutropenia.
Min Hee Ryu, Young Iee Park, Hark Kyun Kim, Dae Ho Lee, Joo Young Jeong, Dong Wan Kim, Im Il Na, Ji Hyun Kim, Se Hoon Lee, Dae Seog Heo, Yung Jue Bang, Seon Yang Park, Byoung Kook Kim, Noe Kyeong Kim
PURPOSE International Prognostic Index Model (IPIM) in aggressive non-Hodgkin's lymphoma was published and accepted generally as a better predictive model for prognosis. This study was undertaken to identify prognostic factors of aggressive non- Hodgkin's lymphoma and usefulness of IPIM in Korea. MATERIALS AND METHODS Previously untreated, pathologically proven 226 aggressive non-Hodgkin's lymphoma patients who were treated with CHOP or COP-BLAM V between 1986 and 1995 in Seoul National University Hospital were evaluated for clinical features predictive of overall survival. RESULTS Complete response (CR) was reached in 76% of all patients. With a median follow-up of 62 months, 5-year disease free survival of complete reponders was 67% and 5-year overall survival of all patients was 54%. In a univriate analysis, age, ECOG performance status, Ann Arbor stage, histologic subtype, bone marrow involvement, bulkiness, serum LDH level and number of extranodal involvement were significant prognostic factors for CR and survival (p<0.05). Of these, by multivariate analysis, age(RR 0.4, 95% CI 0.2~0.9) alone was a independent prognostic factor for CR. For disease free survival, no independent prognostic factor was found. For overall survival, Ann Arbor stage (RR 1.7, 95% CI 1.1~2.8), age (RR 1.7, 95% CI 1.1~2.6), Histologic subtype (RR 1.7, 95% CI 1.1~2.8), serum LDH level (RR 1.7, 95% CI 1.1~2.6) and bone marrow involvement (RR 1.8, 95% CI 1.0~3.1) were independent prognostic factors. According to risk group of IPIM, 5-year overall survival rate was 72% in low risk group, 46% in low intermediate risk group, 32% in high intermediate risk group, respectively, and median survival of high risk group was 12 months (RR 1, 2.3, 4.3, 6.4 respectively). CONCLUSION IPIM is a useful model for identifying poor prognostic groups in aggressive non-Hodgkin's lymphoma.