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BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) followed by radical esophagectomy is the standard treatment for locally advanced esophageal squamous cell cancer (LA-ESCC). However, various nCRT regimens have been used and their comparative efficacy and safety remain unclear. METHODS: Patients with histologically confirmed LA-ESCC who underwent nCRT followed by radical esophagectomy between January 2016 and February 2022 were enrolled in our study. Three different nCRT regimens were retrospectively compared: Conventional radiotherapy (RT) + cisplatin/5-fluorouracil (FP) (Conv-FP), hypofractionated RT + FP (Hypo-FP), and regimens from the CROSS trial (CROSS). The overall survival (OS), pathological complete response (pCR) rates, toxicities, and treatment compliance were analyzed. RESULTS: Among the 600 patients, 225 received Conv-FP, 255 received Hypo-FP, and 120 received the CROSS regimen. OS at 1 year were 78.7%, 83.9%, and 88.1% in the Conv-FP, Hypo-FP, and CROSS groups, respectively (p < 0.001). The pCR rates were 30.6%, 33.9%, and 35.0%, respectively (p = 0.653). The overall incidence of grade 3 toxicities was 10.2%. Hematologic and non-hematologic toxicities of grade ≥ 3 were observed in 8.4% and 11.4%, 0% and 7.6%, 5.5% and 0.8% in Conv-FP, Hypo-FP, and CROSS, respectively (p = 0.002 and 0.030). Weight loss > 5% was observed in 44.0%, 51.4%, and 32.5%, respectively (p < 0.001). In the multivariate analysis, clinical T-stage (p = 0.004), N-stage (p = 0.012), the use of FP chemotherapy regimen (p = 0.013), surgical resection (p < 0.001), hematologic toxicity (p = 0.001), and weight loss (p = 0.004) were significantly associated with poor OS. CONCLUSION: The choice of nCRT regimen did not significantly affect the pCR rates in patients with LA-ESCC. However, the CROSS regimen demonstrated better OS and lower toxicity, suggesting it may be the optimal treatment option among the groups. SYNOPSIS: This study compared three different neoadjuvant chemoradiotherapy (nCRT) regimens for locally advanced esophageal squamous cell cancer (LA-ESCC): Conventional radiotherapy (RT) + cisplatin/5-fluorouracil (FP), hypofractionated RT + FP, and regimens from the CROSS trial. The overall survival (OS), pathological complete response (pCR) rates, toxicities, and treatment compliance were analyzed. Results showed that the choice of nCRT regimen did not significantly affect pCR rates, but the CROSS regimen showed better OS and lower toxicity, suggesting it may be the optimal treatment option. DATA AVAILABILITY: Data availability is limited due to institutional data protection law and confidentiality of patient data.
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In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.
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Background: Since the emergence of coronavirus disease 2019 (COVID-19) across the globe, patients with cancer have been found to have an increased risk of infection with COVID-19 and are highly likely to experience a severe disease course. This study analyzed the clinical outcomes of COVID-19 in patients with non-small cell lung cancer (NSCLC) and identified the risk factors for adverse outcomes. Methods: The study included patients diagnosed with COVID-19 between January 2020 and April 2022 at the Samsung Medical Center in Seoul, Republic of Korea, who have a history of NSCLC. The case-fatality rate and risk factors for COVID-19 were analyzed using a machine-learning prediction method. Additionally, the study investigated the effect of COVID-19 on the systemic treatment of patients with advanced-stage NSCLC. Results: Overall, 1,127 patients were included in this study, with 10.3% of the patients being older than 75 years; of these patients, 51.8% were ex- or current smokers. Among the 584 patients cured after surgery, 91 had stable disease after concurrent chemo-radiotherapy, and 452 had recurrent or metastatic NSCLC. Among 452 patients with recurrent or metastatic NSCLC, 387 received systemic treatment in a palliative setting during COVID-19. Of these, 188 received targeted therapy, 111 received cytotoxic chemotherapy, 63 received immunotherapy +/- chemotherapy, and 26 received other agents. Among them, 94.6% of patients continued systemic treatment after the COVID-19 infection. Only one patient discontinued treatment because of complications of the COVID-19 infection, and 18 patients changed their systemic treatment because of disease progression. The case fatality rates were 0.86% for patients with early-stage NSCLC, 4.4% for patients with locally advanced NSCLC, and 9.96% for patients with advanced NSCLC. The factors associated with fatalities included palliative chemotherapy, type of palliative chemotherapy, age (≥75 years), diabetes, smoking history, history of lung radiotherapy, hypertension, sex, and chronic obstructive pulmonary disease (COPD). The predictive model using logistic regression and eXtreme Gradient Boosting (XGB) performed well [area under the curve (AUC) for logistic regression =0.84 and AUC for XGB =0.84]. Conclusions: The case fatality rate in patients with NSCLC was 4.8%, while most patients with advanced NSCLC continued to receive systemic treatment. However, patients with risk factors require careful management of COVID-19 complications.
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BACKGROUND: Lazertinib is a third-generation tyrosine kinase inhibitor of epidermal growth factor receptor (EGFR-TKI) that selectively inhibit common EGFR mutation and T790M mutation in non-small-cell lung cancer (NSCLC) patients. No previous studies have compared lazertinib to platinum-based chemotherapy. We have compared lazertinib with platinum-based chemotherapy in EGFR-mutated NSCLC patients after previous EGFR-TKI therapy. METHODS: We retrospectively compared 200 patients from LASER201, LASER301, and LASER-PMS studies to 334 patients who were treated with platinum-based chemotherapy after previous EGFR-TKI from the Samsung Medical Center. After propensity score matching (PSM), we selected 156 patients from each group. The primary outcome was progression-free survival (PFS), with overall survival (OS), objective response rate (ORR), and time to treatment discontinuation (TTD) as secondary outcomes. RESULTS: The median follow-up of PFS was 15.61 months in the lazertinib group and 21.67 months in the external control group. The PFS was significantly longer in patients who were treated with lazertinib than those treated with platinum-based chemotherapy (10.97 months vs. 5.10 months; adjusted hazard ratio (HR) 0.40; 95% confidence interval (CI), 0.29-0.55; p < 0.01) after PSM. Lazertinib showed superior OS (32.23 months vs. 18.73 months; adjusted HR 0.45; 95% CI, 0.29-0.69; p < 0.001), ORR (64.1% vs. 47.4%), and TTD (11.66 months vs. 6.73 months; adjusted HR 0.54; 95% CI, 0.39-0.75; p < 0.001) compared to platinum-based chemotherapy. CONCLUSION: Based on this retrospective, external control study, lazertinib has demonstrated significantly better efficacy compared with platinum-based chemotherapy. The external controls provide important context to evaluate efficacy in single-arm studies.
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Lazertinib is a recently developed third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors used for patients with advanced EGFR T790M-positive non-small-cell lung cancer. We evaluated the effectiveness of lazertinib compared with osimertinib using an external control. We obtained individual patient data for the lazertinib arm from the LASER201 trial and the osimertinib arm from registry data at the Samsung Medical Center. In total, 75 and 110 patients were included in the lazertinib and osimertinib groups, respectively. After propensity score matching, each group had 60 patients and all baseline characteristics were balanced. The median follow-up duration was 22.0 and 29.6 months in the lazertinib and osimertinib group, respectively. The objective response rate (ORR) were 76.7% and 86.7% for lazertinib and osimertinib, respectively (p = 0.08). The median progression-free survival (PFS) was 12.3 months (95% confidence interval [CI] 9.5-19.1) and 14.4 months (95% CI 11.8-18.1) for the lazertinib and osimertinib group, respectively (hazard ratio [HR] 0.97; 95% CI 0.64-1.45, p = 0.86). The median overall survival with lazertinib was not reached and that with osimertinib was 29.8 months (HR 0.44; 95% CI 0.25-0.77, p = 0.005). Our study suggests that lazertinib has an ORR and PFS comparable to those of osimertinib and has the potential for superior survival benefits.
Subject(s)
Acrylamides , Aniline Compounds , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Protein Kinase Inhibitors , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Carcinoma, Non-Small-Cell Lung/mortality , ErbB Receptors/genetics , ErbB Receptors/antagonists & inhibitors , Male , Female , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Aged , Middle Aged , Acrylamides/therapeutic use , Aniline Compounds/therapeutic use , Aniline Compounds/pharmacology , Protein Kinase Inhibitors/therapeutic use , Aged, 80 and over , Treatment Outcome , Progression-Free Survival , Mutation , Adult , Pyrimidines/therapeutic use , Indoles , Morpholines , PyrazolesABSTRACT
PURPOSE: Leptomeningeal metastases (LMs) exhibit a high incidence in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) post-treatment with first- or second-generation EGFR tyrosine kinase inhibitors (TKIs). This investigation evaluates the efficacy, safety, and pharmacokinetics of 80 mg once daily osimertinib in patients with LMs resistant to prior first- or second-generation EGFR TKIs. MATERIALS AND METHODS: In this phase II multicenter, open-label, single-arm study, 80 mg osimertinib was administered to patients with EGFR-mutated NSCLC who had developed LMs subsequent to treatment with prior EGFR TKIs. The primary end point was overall survival (OS), assessed alongside objective response rate by the blinded independent central review (BICR) and a pharmacokinetic analysis of plasma and cerebrospinal fluid (CSF) on the first day of cycles 3 and 6. RESULTS: A total of 73 patients diagnosed with LM were treated with osimertinib, including 64 patients evaluable for the LM efficacy set-T790M negative (n = 62) and T790M positive (n = 2). The median OS in the full-analysis set was 15.6 months (95% CI, 11.5 to 20.2). The objective response rate for LM was 51.6%, including a 15.6% complete response, and the disease control rate was 81.3% by BICR in the LM efficacy evaluable set. The median LM progression-free survival by BICR was 11.2 months (95% CI, 7.7 to 15.3), the duration of response was 12.6 months (95% CI, 7.6 to 17.7), and OS was 15.0 months (95% CI, 11.3 to 18.7). Pharmacokinetic analysis showed that the CSF to free plasma osimertinib ratio was 22%. Most safety profiles were grade 1 and 2. CONCLUSION: The study demonstrates significant intracranial efficacy and survival benefits of 80 mg once daily osimertinib in NSCLC patients with LMs. The data support considering daily 80 mg of osimertinib as a treatment option for EGFR-mutated NSCLC patients with LMs, irrespective of T790M mutation status.
Subject(s)
Acrylamides , Aniline Compounds , Carcinoma, Non-Small-Cell Lung , ErbB Receptors , Lung Neoplasms , Mutation , Humans , Acrylamides/therapeutic use , Acrylamides/pharmacokinetics , Acrylamides/administration & dosage , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Aniline Compounds/pharmacokinetics , Aniline Compounds/therapeutic use , Aniline Compounds/administration & dosage , Aniline Compounds/adverse effects , Male , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/pathology , Female , Middle Aged , ErbB Receptors/genetics , ErbB Receptors/antagonists & inhibitors , Aged , Adult , Aged, 80 and over , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Meningeal Carcinomatosis/secondary , Meningeal Carcinomatosis/drug therapy , Meningeal Carcinomatosis/genetics , Meningeal Neoplasms/secondary , Meningeal Neoplasms/drug therapy , Meningeal Neoplasms/genetics , Indoles , PyrimidinesABSTRACT
Purpose: Optimal treatment for stage IIIA/N2 non-small cell lung cancer (NSCLC) is controversial. We aimed to assess the efficacy and safety of adjuvant pembrolizumab for stage IIIA/N2 NSCLC completely resected after neoadjuvant concurrent chemoradiation therapy (CCRT). Materials and Methods: In this open-label, single-center, single-arm phase 2 trial, patients with stage IIIA/N2 NSCLC received adjuvant pembrolizumab for up to two years after complete resection following neoadjuvant CCRT. The primary endpoint was disease-free survival (DFS). Secondary endpoints included overall survival (OS) and safety. As an exploratory biomarker analysis, we evaluated the proliferative response of blood CD39+PD-1+CD8+ T cells using fold changes in the percentage of proliferating Ki-67+ cells from days 1 to 7 of cycle 1 (Ki-67D7/D1). Results: Between October 2017 and October 2018, 37 patients were enrolled. Twelve (32%) and three (8%) patients harbored EGFR and ALK alterations, respectively. Of 34 patients with programmed cell death ligand 1 assessment, 21 (62%), 9 (26%), and 4 (12%) had a tumor proportion score of <1%, 1-50%, and ≥50%, respectively. The median follow-up was 71 months. The median DFS was 22.4 months in the overall population, with a five-year DFS rate of 29%. The OS rate was 86% at two years and 76% at five years. Patients with tumor recurrence within six months had a significantly lower Ki-67D7/D1 among CD39+PD-1+CD8+ T cells than those without (p=0.036). No new safety signals were identified. Conclusion: Adjuvant pembrolizumab may offer durable disease control in a subset of stage IIIA/N2 NSCLC patients after neoadjuvant CCRT and surgery.
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OBJECTIVES: Advanced non-small cell lung cancer patients harboring EGFR mutation or ALK fusion have achieved significant survival benefit with targeted agents. In contrast, EGFR-wild type and ALK negative lung adenocarcinoma still have poor survival outcome. This study assessed the impact of participating in clinical trials on clinical outcomes in patients with EGFR-wild-type and ALK-negative lung adenocarcinoma. MATERIALS AND METHODS: This study included patients with advanced EGFR-wild-type and ALK-negative lung adenocarcinoma who received systemic treatment between March 2017 and June 2022. We compared clinical outcomes between patients who participated in clinical trials and those treated with standard-of-care (SOC) using propensity score matching (PSM). RESULTS: Overall, 1,686 patients with EGFR-wild-type and ALK-negative advanced lung adenocarcinoma were included in the final analysis. Of these, 1,380 (81.9 %) received SOC only and 306 (18.1 %) patients were enrolled in at least one clinical trial during their cancer journey. After PSM (1:1), 612 patients were matched to the SOC (n = 306) and clinical trial (n = 306) groups. Among those who participated in clinical trials, 27.8 % and 72.2 % were included in clinical trials involving targeted therapy and immunotherapy respectively. In the clinical trial group, more patients received targeted therapy (31.7 % vs. 5.5 %, p < 0.001) and immunotherapy (88.6 % vs. 62.8 %, p < 0.001) compared to the SOC group. The median overall survival was 17.1 months (95 % confidence interval [CI], 13.2-21.4) in the SOC group and 27.3 months (95 % CI, 22.1-32.4) in the clinical trial group (hazard ratio = 0.71, [95 % CI, 0.58-0.88, P = 0.002]). CONCLUSIONS: This study demonstrated that participating in clinical trials resulted in a survival benefit that reduced the risk of death by 29.6% compared to receiving SOC in EGFR-wild-type and ALK-negative lung adenocarcinoma.
Subject(s)
Adenocarcinoma of Lung , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Anaplastic Lymphoma Kinase/genetics , ErbB Receptors/genetics , Adenocarcinoma of Lung/drug therapy , MutationABSTRACT
Purpose: BRAF mutations are detected in 30-80% of papillary thyroid cancer (PTC) cases. Dabrafenib and trametinib showed promising antitumor activity in patients with BRAFV600E-mutated metastatic melanoma and non-small cell lung cancer. This study aimed to evaluate the efficacy and safety of dabrafenib and trametinib in patients with metastatic BRAFV600E-mutated thyroid cancer. Materials and Methods: This was a retrospective study to evaluate the efficacy of dabrafenib and trametinib in patients with metastatic BRAFV600E-mutated PTC. The patients received dabrafenib 150 mg twice daily and trametinib 2 mg once daily at the Samsung Medical Center. This study evaluated the progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) overall survival (OS), and safety of dabrafenib and trametinib. Results: Between December 2019 and January 2022, 27 PTC patients including 8 patients with poorly differentiated or anaplastic transformation, received dabrafenib and trametinib. The median age was 73.0 years, and the median follow-up period was 19.8 months. The majority (81.5%) had undergone thyroidectomy, while 8 patients had received prior systemic treatments. ORR was 73.1%, with 19 partial responses, and DCR was 92.3%. Median PFS was 21.7 months, and median OS was 21.7 months. Treatment-related adverse events included generalized weakness (29.6%), fever (25.9%), and gastrointestinal problems (22.2%). Dose reduction due to adverse events was required in 81.5% of the patients. Conclusion: Dabrafenib and trametinib demonstrated a high ORR with promising PFS; however, most patients with BRAFV600E-mutated metastatic PTC required a dose reduction.
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BACKGROUND: Recent studies have reported the predictive and prognostic value of novel transcriptional factor-based molecular subtypes in small-cell lung cancer (SCLC). We conducted an in-depth analysis pairing multi-omics data with immunohistochemistry (IHC) to elucidate the underlying characteristics associated with differences in clinical outcomes between subtypes. METHODS: IHC (n = 252), target exome sequencing (n = 422), and whole transcriptome sequencing (WTS, n = 189) data generated from 427 patients (86.4% males, 13.6% females) with SCLC were comprehensively analysed. The differences in the mutation profile, gene expression profile, and inflammed signatures were analysed according to the IHC-based molecular subtype. FINDINGS: IHC-based molecular subtyping, comprised of 90 limited-disease (35.7%) and 162 extensive-disease (64.3%), revealed a high incidence of ASCL1 subtype (IHC-A, 56.3%) followed by ASCL1/NEUROD1 co-expressed (IHC-AN, 17.9%), NEUROD1 (IHC-N, 12.3%), POU2F3 (IHC-P, 9.1%), triple-negative (IHC-TN, 4.4%) subtypes. IHC-based subtype showing high concordance with WTS-based subtyping and non-negative matrix factorization (NMF) clusterization method. IHC-AN subtype resembled IHC-A (rather than IHC-N) in terms of both gene expression profiles and clinical outcomes. Favourable median overall survival was observed in IHC-A (15.2 months) compared to IHC-N (8.0 months, adjusted HR 2.3, 95% CI 1.4-3.9, p = 0.002) and IHC-P (8.3 months, adjusted HR 1.7, 95% CI 0.9-3.2, p = 0.076). Inflamed tumours made up 25% of cases (including 53% of IHC-P, 26% of IHC-A, 17% of IHC-AN, but only 11% of IHC-N). Consistent with recent findings, inflamed tumours were more likely to benefit from first-line immunotherapy treatment than non-inflamed phenotype (p = 0.002). INTERPRETATION: This study provides fundamental data, including the incidence and basic demographics of molecular subtypes of SCLC using both IHC and WTS from a comparably large, real-world Asian/non-Western patient cohort, showing high concordance with the previous NMF-based SCLC model. In addition, we revealed underlying biological pathway activities, immunogenicity, and treatment outcomes based on molecular subtype, possibly related to the difference in clinical outcomes, including immunotherapy response. FUNDING: This work was supported by AstraZeneca, Future Medicine 2030 Project of the Samsung Medical Center [grant number SMX1240011], the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number 2020R1C1C1010626] and the 7th AstraZeneca-KHIDI (Korea Health Industry Development Institute) oncology research program.
Subject(s)
Lung Neoplasms , Small Cell Lung Carcinoma , Male , Female , Humans , Transcription Factors/genetics , Lung Neoplasms/genetics , Lung Neoplasms/therapy , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Small Cell Lung Carcinoma/genetics , Small Cell Lung Carcinoma/therapy , PrognosisABSTRACT
Background: Limited disease (LD) small cell lung cancer (SCLC) treated with definitive concurrent chemoradiotherapy (CCRT) potentially experience disease recurrence. We investigated the feasibility of circulating-tumor DNA (ctDNA)-based genomic and fragmentome analyses to assess the risk of recurrence. Methods: Targeted sequencing was conducted using pre-treatment and on-treatment blood samples from definitive CCRT-treated patients with LD-SCLC (n=50). Based on 12-month recurrence-free survival (RFS), patients were categorized into persistent-response (PeR, n=29) and non-PeR (n=21) groups. Fragmentome analysis was conducted using ctDNA fragments of different lengths: P1 (100-155 bp) and P2 (160-180 bp). Results: Patients with TP53 (n=15) and RB1 (n=11) mutation in on-treatment samples demonstrated significantly shorter RFS than patients with wild-type (WT) (P=0.05, P=0.0014, respectively). Fragmentome analysis of all available on-treatment samples (n=26) revealed that the non-PeR group (n=10) had a significantly higher P1 range (P=0.003) and lower P2 range (P=0.002). The areas under the curves for P1, P2, and the fragmentation ratio (P1/P2) in distinguishing the PeR and non-PeR were 0.850, 0.725, and 0.900, respectively. Using optimal cut-off, longer RFSs were found with the low-fragmentation-ratio group than with the high-fragmentation-ratio group (not reached vs. 7.6 months, P=0.002). Patients with both WT RB1 and a low-fragmentation-ratio (n=10) showed better outcomes than patients with both mutated RB1 and a high-fragmentation-ratio (n=10; hazard ratio, 7.55; 95% confidence interval: 2.14-26.6; P=0.002). Conclusions: RB1 mutations and high fragmentation ratios correlated with early disease recurrence. Analyzing ctDNA could help in predicting early treatment failure and making clinical decisions for high-risk patients.
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Importance: Valuable evidence regarding clinical characteristics, treatments, and outcomes for non-small cell lung cancer (NSCLC) is limited to individual hospital databases or national-level registries. The common data and federated analysis framework developed through the Extensible Platform for Observational Research in Lung Cancer (EXPLORE-LC) initiative allows for research across multiple high-quality data sources, which may provide a deeper understanding of the NSCLC landscape and identification of unmet needs of subpopulations. Objective: To describe clinical characteristics, initial treatment patterns, subsequent treatment, and overall survival (OS) of patients with NSCLC in South Korea. Design, Setting, and Participants: This multicenter cohort study included patients aged 18 years and older who were diagnosed with NSCLC between 2014 and 2019 and followed up until March 2020 at 3 tertiary hospitals in South Korea. Clinical data were collected using a common data model and clinical data warehouse. Patients who had an initial diagnosis of nonsquamous (NSQ) or squamous (SQ) NSCLC and who had received at least 1 treatment for NSCLC were included in the study. Data were analyzed from June through November 2022. Main Outcomes and Measures: The primary outcome was clinical OS for patients with NSCLC. Secondary outcomes were clinical characteristics and treatment patterns subsequent to the diagnosis of NSCLC. Results: Among 22â¯101 patients with NSCLC who received anticancer treatment analyzed in this study, 17â¯350 patients (78.5%) had NSQ and 4751 patients (21.5%) had SQ NSCLC. Clinical characteristics and outcomes and treatment patterns were assessed for 13â¯084 patients with NSQ cancer who had known EGFR and ALK status (75.4%; mean [SD] 62.2 [10.5] years; 6552 males [50.1%]) and all 4751 patients with SQ cancer (mean [SD] age, 67.1 [8.6] years; 4427 males [93.2%]). More than half of patients with NSQ cancer were never smokers (7399 patients [56.6%]). Patients with SQ cancer were mostly males and former or current smokers (4235 patients [89.1%]) and were diagnosed at a later clinical stage than patients with NSQ cancer (eg, stage I: 1165 patients [24.5%] vs 5388 patients [41.2%]). Patients with EGFR-positive and ALK-positive NSQ cancer diagnosed between 2017 and 2019 had better median OS than similar patients diagnosed between 2014 and 2016 (EGFR-positive: not reached [95% CI, 35.9 months to not reached] vs 28.4 months [95% CI, 25.8 to 30.0 months]; P < .001; ALK-positive: not reached [95% CI, not reached] vs 49.5 months [95% CI, 35.1 months to not reached]; P < .001). No significant difference was observed in OS from first-line treatment for patients with SQ cancer. Conclusions and Relevance: This study, which pooled medical data from multiple clinical data warehouses to produce a large study cohort, may provide meaningful insights into the clinical practice of NSCLC and underscores the value of a common data model approach. The analyzable dataset may hold great promise for future comprehensive identification of subpopulations and unmet needs.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Carcinoma, Squamous Cell , Lung Neoplasms , Male , Humans , Aged , Female , Carcinoma, Non-Small-Cell Lung/therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Lung Neoplasms/epidemiology , Lung Neoplasms/therapy , Lung Neoplasms/diagnosis , Cohort Studies , Retrospective Studies , Receptor Protein-Tyrosine Kinases/therapeutic use , ErbB ReceptorsABSTRACT
BACKGROUND: The safety of immune-checkpoint inhibitors (ICIs) has not been thoroughly investigated in non-small cell lung cancer (NSCLC) patients with chronic hepatitis B (CHB) or occult hepatitis B infection (OBI). The authors analyzed the incidence of hepatitis B virus (HBV) reactivation, immune-related hepatitis and jaundice in NSCLC patients in a real-world setting. METHODS: A total of 1277 NSCLC patients treated with ICIs were analyzed. Among them, 52 patients were hepatitis B surface antigen (HBsAg) (+) (group A, CHB), 759 patients were HBsAg (-)/hepatitis B core antibody immunoglobulin G (anti-HBc IgG) (+) (group B, OBI), and 466 patients were HBsAg (-)/anti-HBc IgG (-) (group C). Among the 52 patients with CHB, 38 (73.1%) were receiving antiviral therapy. The primary end point was HBV reactivation, immune-related hepatitis, and jaundice. The secondary end points included other immune-related adverse events and efficacy. RESULTS: HBV reactivation was observed in two patients (0.2%) who were both in group A (CHB). Among CHB patients who were not receiving antiviral therapy, HBV reactivation was observed in 14.3% (2 of 14 patients). The incidences of immune-related hepatitis and jaundice were comparable among the three groups. The incidence of ≥grade 3 other immune-related adverse events and efficacy were all comparable among the three groups (p > .05 for all comparisons). CONCLUSIONS: In this large, real-world cohort study, the safety and efficacy of ICIs were comparable in patients with CHB and OBI. HBV reactivation was observed in patients with CHB without antiviral therapy indicating antiviral prophylaxis should be required for them. For patients with OBI, the risk of HBV reactivation was minimal.
Subject(s)
Carcinoma, Non-Small-Cell Lung , Hepatitis B, Chronic , Hepatitis B , Jaundice , Lung Neoplasms , Humans , Hepatitis B virus , Immune Checkpoint Inhibitors/adverse effects , Hepatitis B, Chronic/complications , Hepatitis B, Chronic/drug therapy , Hepatitis B, Chronic/epidemiology , Hepatitis B Surface Antigens/pharmacology , Hepatitis B Surface Antigens/therapeutic use , Incidence , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/epidemiology , Cohort Studies , Lung Neoplasms/complications , Lung Neoplasms/drug therapy , Lung Neoplasms/chemically induced , Antiviral Agents/adverse effects , Immunoglobulin G/pharmacology , Immunoglobulin G/therapeutic use , Jaundice/chemically induced , Jaundice/complications , Jaundice/drug therapy , Hepatitis B/complications , Virus Activation , DNA, ViralABSTRACT
BACKGROUND: Based on a high incidence of genomic alteration in the cell cycle and DNA damage and response (DDR)-related pathways in small cell lung cancer (SCLC), the clinical efficacy of the DDR-targeting agent olaparib (PARP inhibitor) as monotherapy and in combination with ceralasertib (ATR inhibitor) in relapsed or refractory SCLC was evaluated. METHODS: As part of a phase 2 biomarker driven umbrella study, patients with SCLC and predefined DDR gene alterations who failed to benefit from prior platinum-based regimens were allocated to the olaparib monotherapy arm and nonbiomarker-selected patients were allocated to the olaparib and ceralasertib combination arm. RESULTS: In the olaparib monotherapy arm (n = 15), the objective response rate was 6.7% (one partial response), and the disease control rate was 33.3%, including three patients with stable disease. The median progression-free survival was 1.3 months (95% CI, 1.2-NA). In the combination arm (n = 26), the objective response rate and disease control rate were 3.8% and 42.3%, respectively, with one partial response and 10 patients with stable disease. The median progression-free survival was 2.8 months (95% CI, 1.8-5.4). Treatment was generally well tolerated except for one fatal case of neutropenic fever in the combination arm. CONCLUSIONS: Targeting DDR pathways with olaparib as a single agent or in combination with ceralasertib did not meet the predefined efficacy end point. However, disease stabilization was more evident in the combination arm. Further investigation of the combination of olaparib in SCLC should be performed with diverse combinations and patient selection strategies to maximize efficacy.
Subject(s)
Indoles , Lung Neoplasms , Morpholines , Ovarian Neoplasms , Piperazines , Pyrimidines , Small Cell Lung Carcinoma , Sulfonamides , Humans , Female , Small Cell Lung Carcinoma/drug therapy , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Lung Neoplasms/chemically induced , Treatment Outcome , Phthalazines/adverse effects , Ovarian Neoplasms/drug therapyABSTRACT
PURPOSE: Programmed death-1/programmed death-ligand 1 (PD-L1) inhibitors have shown efficacy in metastatic esophageal squamous cell carcinoma (ESCC) therapy. However, data is still limited regarding neoadjuvant immunotherapy for operable ESCC. MATERIALS AND METHODS: Patients with clinical stage T2 or T3 and N0 ESCC received three cycles of nivolumab therapy every two weeks before surgical resection. The primary endpoint is major pathologic responses (MPR) rate (≤ 10% of residual viable tumor [RVT]). RESULTS: Total 20 patients completed the planned nivolumab therapy. Among them, 17 patients underwent surgery as protocol, showing MPR in two patients (MPR rate, 11.8%), including one pathologic complete response, on conventional pathologic response evaluation. Pathologic response was re-evaluated using the immune-related pathologic response criteria based on immune-related RVT (irRVT). Three patients were classified as immunologic major pathologic response (iMPR; ≤ 10% irRVT, iMPR rate: 17.6%), five as pathologic partial response (> 10% and < 90% irRVT), and nine as pathologic nonresponse (≥ 90% irRVT). The combined positive score (CPS) for PD-L1 in the baseline samples was predictable for iMPR, with the probability as 37.5% in CPS ≥ 10 (3/8) and 0% in CPS < 10 (0/9). CONCLUSION: Although the efficacy of neoadjuvant nivolumab therapy was modest in unselected ESCC patients, further researches on neoadjuvant immunotherapy are necessary in patients with PD-L1 expressed ESCC.
Subject(s)
Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Humans , Neoadjuvant Therapy , B7-H1 Antigen , Nivolumab/therapeutic use , Esophageal Neoplasms/drug therapy , Esophageal Squamous Cell Carcinoma/drug therapy , Neoplasm, ResidualABSTRACT
PURPOSE: In the treatment of non-small-cell lung cancer (NSCLC) with a driver mutation, the role of anti-PD-(L)1 antibody after tyrosine kinase inhibitor (TKI) remains unclear. This randomized, open-label, multicenter, phase III study evaluates the efficacy of atezolizumab plus bevacizumab, paclitaxel, and carboplatin (ABCP ) in EGFR- or ALK-mutated NSCLC that progressed before TKI therapy. MATERIALS AND METHODS: We compared the clinical efficacy of ABCP followed by maintenance therapy with atezolizumab plus bevacizumab with pemetrexed plus carboplatin or cisplatin (PC) followed by pemetrexed maintenance. The primary end point was progression-free survival (PFS). RESULTS: A total of 228 patients with activating EGFR mutation (n = 215) or ALK translocation (n = 13) were enrolled from 16 sites in the Republic of Korea and randomly assigned at 2:1 ratio to either ABCP (n = 154) or PC arm (n = 74). The median follow-up duration was 26.1 months (95% CI, 24.7 to 28.2). Objective response rates (69.5% v 41.9%, P < .001) and median PFS (8.48 v 5.62 months, hazard ratio [HR], 0.62 [95% CI, 0.45 to 0.86]; P = .004) were significantly better in the ABCP than PC arm. PFS benefit increased as PD-L1 expression increased, with an HR of 0.47, 0.41, and 0.24 for PD-L1 ≥1%, ≥10%, and ≥50%, respectively. Overall survival was similar between ABCP and PC arm (20.63 v 20.27 months, HR, 1.01 [95% CI, 0.69 to 1.46]; P = .975). The safety profile of the ABCP arm was comparable with that previously reported, with no additional safety signals, but higher rates of treatment-related adverse events were observed compared with the PC arm. CONCLUSION: To our knowledge, this study is the first randomized phase III study to demonstrate the clinical benefit of anti-PD-L1 antibody in combination with bevacizumab and chemotherapy in patients with EGFR- or ALK-mutated NSCLC who have progressed on relevant targeted therapy.
Subject(s)
Antibodies, Monoclonal, Humanized , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Bevacizumab , Carboplatin , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , B7-H1 Antigen/therapeutic use , Pemetrexed/therapeutic use , ErbB Receptors/genetics , Receptor Protein-Tyrosine Kinases/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
PURPOSE: Alectinib and brigatinib are second-generation anaplastic lymphoma receptor tyrosine kinases (ALKs) that are widely used as first-line therapy for treating ALK-positive advanced non-small cell lung cancer (NSCLC). Given the lack of a head-to-head comparison of these drugs as first-line therapies, this retrospective observational study aimed to compare the real-world efficacy and safety of alectinib and brigatinib. MATERIALS AND METHODS: Patients who received alectinib or brigatinib as the first-line treatment for ALK-positive advanced NSCLC were evaluated for clinical outcomes of objective response rate (ORR), intracranial ORR, time to next treatment (TTNT), progression-free survival (PFS), overall survival (OS), and safety profiles. RESULTS: Of 208 patients who received either alectinib or brigatinib as a first-line treatment, 176 received alectinib and 32 received brigatinib. At the data cutoff point, the median follow-up duration was 16.5 months (95% confidence interval [CI], 14.7 to 18.3) in the brigatinib group and 27.5 months (95% CI, 24.6 to 30.4) in the alectinib group. The ORR was 92.5% with alectinib and 93.8% for brigatinib. The intracranial ORR rates were 92.7% (38/41) and 100% (10/10), respectively. The rate of PFS at 12 months was comparable between the alectinib group and the brigatinib groups (84.4% vs. 84.1%, p=0.64), and the median TTNT, PFS, and OS were not reached in either group. Treatment-related adverse events were usually mild, and treatment discontinuation due to adverse events was rare (alectinib 4.5% vs. brigatinib 6.25%). CONCLUSION: Alectinib and brigatinib had similar clinical benefits when used as the first-line treatment of NSCLC patients with ALK rearrangement in the real world.
Subject(s)
Carbazoles , Carcinoma, Non-Small-Cell Lung , Lung Neoplasms , Organophosphorus Compounds , Pyrimidines , Humans , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/genetics , Lung Neoplasms/drug therapy , Lung Neoplasms/genetics , Piperidines/adverse effects , Protein Kinase Inhibitors/adverse effectsABSTRACT
In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.
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INTRODUCTION: While the efficacy of immune checkpoint inhibitors (ICIs) in treating non-small cell lung cancer (NSCLC) patients with actionable genetic alterations (AGAs) is modest, certain patients demonstrate improved survival. Thus, this study aimed to evaluate the benefits of ICIs in NSCLC patients with diverse AGAs and verify the predictive biomarkers of ICI efficacy. METHODS: From January 2018 to July 2022, this study compared the progression-free survival (PFS) of NSCLC patients with different AGAs treated with ICI monotherapy as second- or later-line therapy at Samsung Medical Center. To ascertain the predictors of ICIs efficacy, we adjusted ICIs' effects on PFS in terms of clinical and molecular biomarkers. RESULTS: EGFR (46.0%) was the most prevalent mutation in 324 patients. In multivariate analysis, PD-L1 positivity (tumor proportion score (TPS) ≥ 1%) (HR = 0.41) and the use of steroids for immune-related adverse events (HR = 0.46) were positive factors for ICI therapy in the AGAs group. Co-existing mutation of STK11 with KRAS mutation (HR = 4.53) and TP53 with MET mutation (HR = 9.78) was negatively associated with survival. CONCLUSIONS: The efficacy of ICI treatment varied across AGA subtypes, but patients with KRAS, MET, and BRAF mutations demonstrated relatively long-duration benefits of ICI therapy. PD-L1 was a significant positive predictive biomarker in all AGA groups.
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Background: Lazertinib is a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) designed to overcome EGFR T790M mutation. Currently, lazertinib is approved for usage in the acquired EGFR T790M mutation population based on promising clinical and safety profiles. In this study, we evaluated the clinical outcomes of lazertinib in acquired EGFR T790M mutated non-small cell lung cancer (NSCLC) patients in a real-world clinical setting. Methods: Clinical outcomes of 103 patients treated with lazertinib, from July 2021 to August 2022, for NSCLC with acquired EGFR T790M mutation were retrospectively analyzed. EGFR T790M mutation was confirmed using either a cell-free EGFR test (48.5%) or a tissue-based test (51.5%). Results: The median follow-up duration was 11.4 months [95% confidence interval (CI): 10.4-13.1], and 58.3% of patients remained on treatment at the time point of data analysis. The objective response rate was 72.8%. The median progression-free survival (PFS) was not reached, and the PFS rates at 6 and 12 months were 81.7% and 65.1%, respectively. The median PFS in a subgroup treated with lazertinib based on T790M-positive tissue was significantly longer than that in a subgroup treated based on T790M-positive plasma (not reached vs. 14.5 months) (hazard ratio, 0.43; 95% CI: 0.21-0.87). Related to adverse events, there was no treatment-related mortality. However, the lazertinib dose was adjusted in 39 patients (37.9%), including 10 patients (9.7%) with permanent discontinuation. Peripheral sensory-motor related adverse events were observed in 65 patients (63.1%) (paresthesia: n=58; muscle cramping: n=24), leading to dose reduction and permanent discontinuation in 17 (16.5%) and 5 (4.9%) patients, respectively. There was no difference in PFS between the groups with and without dose-adjustment (P=0.40). Conclusions: Our result demonstrates the real-world clinical efficacy of lazertinib in acquired EGFR T790M mutation. Although dose reduction due to adverse events was not uncommon, it did not impair clinical efficacy of lazertinib.