Brief Report: Updated Data From IMscin001 Part 2, a Randomized Phase III Study of Subcutaneous Versus Intravenous Atezolizumab in Patients With Locally Advanced or Metastatic NSCLC.

INTRODUCTION: Subcutaneous atezolizumab is approved for the treatment of various solid tumors. Previous results from the IMscin001 study (NCT03735121) revealed that the pharmacokinetics, efficacy, immunogenicity, and safety of subcutaneous and intravenous atezolizumab were consistent (data cutoff: April 26, 2022). We present updated data from this trial (data cutoff: January 16, 2023). METHODS: Eligible patients aged above or equal to 18 years with locally advanced or metastatic NSCLC were randomized (2:1) to receive atezolizumab subcutaneously (1875 mg, n = 247) or intravenously (1200 mg, n = 124) every 3 weeks. Here, we present updated efficacy (overall survival [OS]; progression-free survival; objective response rate; duration of response), safety, and immunogenicity end points, alongside patient-reported outcomes and health care practitioner (HCP) perspectives. RESULTS: In this updated analysis, the median survival follow-up was 9.5 months. Median subcutaneous injection time was 7.1 minutes, with an average subcutaneous injection time of 4 to 8 minutes in most patients (75.7%). OS data were mature: median OS was similar between treatment arms, at 10.7 and 10.1 months in the subcutaneous and intravenous arms, respectively (hazard ratio: 0.88; 95% confidence interval: 0.67-1.16). Other efficacy end points, as well as immunogenicity, patient-reported outcomes, and safety, were similar between arms. Most HCPs found subcutaneous administration convenient (79.5%), easy to administer (89.7%), and were satisfied with the treatment (84.6%); 75.0% of HCPs agreed that administering atezolizumab subcutaneously compared with intravenously could save time. CONCLUSIONS: In this analysis, mature OS data were similar between treatments. The updated efficacy and safety profile of subcutaneous atezolizumab is consistent with previous findings and equivalent to intravenous atezolizumab.

Longitudinal Analyses of Circulating-Tumor DNA for Detection of EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer Progression During Treatment: Data From FLAURA and AURA3.

INTRODUCTION: Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-sensitizing and -resistance mutations may be detected in plasma via circulating tumor DNA (ctDNA). ctDNA level changes reflect alterations in tumor burden and could be a dynamic indicator of treatment effect. This analysis aimed to determine whether longitudinal EGFR-mutation ctDNA testing could detect progressive disease (PD) before radiologic detection. METHODS: This was a retrospective, exploratory ctDNA analysis in two phase 3 trials (FLAURA, NCT02296125; AURA3, NCT02151981). Patients had treatment-naïve (FLAURA) or EGFR-TKI pre-treated (AURA3) advanced non-small cell lung cancer (NSCLC) with EGFR mutations and on-study PD (RECIST), with a baseline ctDNA result and EGFR-mutation ctDNA monitoring beyond Cycle 3 Day 1. Patients received osimertinib versus comparator EGFR-TKIs (FLAURA) or chemotherapy (AURA3). Outcomes included time from ctDNA PD to RECIST PD, and to first subsequent treatment (FST; FLAURA only). RESULTS: ctDNA PD preceded/co-occurred with RECIST-defined PD in 93/146 (64%) patients in FLAURA and 82/146 (56%) in AURA3. Median time from ctDNA PD to RECIST-defined PD (months) was 3.4 and 2.6 in the osimertinib and comparator EGFR-TKI arms (FLAURA) and 2.8 and 1.5 in the osimertinib and chemotherapy arms (AURA3). In FLAURA, median time from ctDNA PD to FST (months) was 6.0 and 4.7 in the osimertinib (n = 51) and comparator EGFR-TKI arms (n = 70). CONCLUSIONS: Among patients with EGFR mutation-positive advanced NSCLC receiving EGFR-TKI or chemotherapy with ctDNA data and RECIST-defined PD, ctDNA PD preceded/co-occurred with RECIST-defined PD in approximately 60% of cases. Longitudinal ctDNA monitoring may detect PD before radiologic PD.

Small RNA Deep Sequencing of Circulating Small RNAs Discovers a Unique Panel of microRNAs as Feasible and Reliable Biomarkers of Non-Small Cell Lung Cancers in Northern Thailand.

OBJECTIVE: This study aimed to assess the practicality and reliability of utilizing microRNAs (miRNAs) as a potential screening and diagnosing tool for non-small cell lung cancers (NSCLCs) in Northern Thailand. METHODS: Small RNA sequencing and a literature review was performed to obtain a list of serum miRNA candidates. Serum levels of these selected miRNA candidates were measured in patients with NSCLC and healthy volunteers by real-time RT-PCR and receiver operating characteristic curve (ROC) were used to assess diagnostic performance. RESULTS: Sequencing data revealed 148 known miRNAs and 230 novel putative miRNAs in serum samples; 19 serum miRNAs were significantly downregulated and 242 were upregulated. Seven miRNAs selected according to sequencing data and 11 miRNAs according to previous reports were evaluated in training cohort (45 lung cancer patients, 26 controls) and 6 miRNAs were found differentially expressed (p < 0.05, Mann Whitney U test) and associated (p < 0.05, Chi-square test) with NSCLC development. Further analysis and verification identified an optimal combination of 4 miRNAs composed of hsa-miR23a, hsa-miR26b, hsa-miR4488 and novel-130 to provide the optimal AUC of 0.901±0.034. Detection of serum miRNA by real-time RT-PCR showed good reproducibility with the coefficient of variation (CV) ≤ 4%. The optimal screening miRNAs panel was primarily identified through sequencing data of local patient population, thus indicating that the etiology of NSCLCs may differ from one population to other and thus require a unique panel of miRNAs for their identification. CONCLUSION: Circulating miRNA is a feasible screening tool for NSCLCs. Nevertheless, populations with different lung cancer etiology may need to identify their own most suitable miRNA panel.

Efficacy of Combination Docetaxel and Nintedanib in Advanced Non-Small Cell Lung Cancer in Thailand: A Multicenter Study.

INTRODUCTION: The mainstay systemic treatment for non-oncogenic addictive advanced stage non-small cell lung cancer is chemotherapy. Anti-angiogenic agents are additive compounds that enhance disease control and lead to improvement of overall survival benefit. Recently PD-(L)1 blockage, a checkpoint inhibitor, has been adopted as another line of treatment. A sequential strategy to enhance the efficacy of combination docetaxel and nintedanib after immunotherapy, correlated with genomic mutation, has been explored. METHOD: A retrospective cohort study of 56 patients from 8 centers in Thailand who received combination docetaxel and nintedanib via the Thai nintedanib Named Patient Use program was conducted. Demographic characteristics, treatment details, and treatment responses were retrieved from medical records. RESULTS: The majority of patients were male (62.5%) with adenocarcinoma subtype (88%). Thirty-five percent had sensitizing EGFR mutation. Combination docetaxel and nintedanib was given as second to fourth line of treatment. Median PFS of docetaxel/nintedanib was 5.6 months [95% CI 4.8-6.9]. Median OS of the entire cohort was 22.5 months [95% CI 20.2-31.1]. Among them, only four patients received this combination after immunotherapy which limited the validity of efficacy analysis. Median PFS of those four patients was 7.9 months [range 5.2-9.1] which was slightly higher than the remaining cohort (median PFS 4.5 months, 95% CI: 4.0-6.0, p-value 0.09). Among the adenocarcinoma subtype, a relapse-time of platinum-doublet chemotherapy of more than 6 months was solely indicated as a benefit of combination docetaxel/nintedanib treatment compared to the relapse-time of platinum-doublet chemotherapy of less than 6 months by multivariate HR of PFS 0.32 [95% CI: 0.14-0.68, p-value 0.003]. CONCLUSION: Combination docetaxel and nintedanib provided more benefit in relapse-time of platinum-doublet chemotherapy of more than 6 months in advanced stage adenocarcinoma lung cancer. Neither EGFR nor ALK alteration influenced the outcome of treatment.

Effect of Insurance Type on Stage at Presentation, Surgical Approach, Tumor Recurrence and Cancer-Specific Survival in Resectable Non-Small Lung Cancer Patients.

PURPOSE: The aim of this study was to identify the association between Thailand's insurance types and stage at presentation, surgical approach, tumor recurrence and cancer-specific survival in resectable non-small cell lung cancer (NSCLC) patients in northern Thailand. PATIENTS AND METHODS: Medical records of patients with NSCLC who underwent pulmonary resection at Chiang Mai University Hospital from January 2007 through December 2015 were retrospectively reviewed. Patients were divided into two groups: patients with the Universal Coverage Scheme (UCS) or Social Security Scheme (SSS) and patients with the Civil Servant Medical Benefit Scheme (CSMBS) or private insurance (PI). Patient characteristics were assessed. The primary outcome was cancer-specific survival while the secondary outcome was tumor recurrence. Cox's regression and matching propensity score analysis was used to analyze data. RESULTS: This study included 583 patients: 344 with UCS or SSS and 239 with CSMBS or PI. Patients with UCS or SSS were more likely to be active smokers, have a lower percent predicted FEV1, present with higher-stage tumors and worse differentiated tumors, present with tumor necrosis, and undergo an open surgical approach than those with CSMBS or PI. At multivariable analysis of all patients cohort, there were no significant differences in terms of early stage at presentation (adjusted odds ratio (ORadj) = 0.94, 95% confidence interval (CI) = 0.65-1.37), undergoing lobectomy (ORadj = 0.59, 95% CI = 0.24-1.46), and recurrent-free survival (adjusted hazard ratio (HRadj) =1.20, 95% CI = 0.88-1.65) between groups (UCS/SSS versus CSMBS/PI). However, patients with UCS or SSS had shorter cancer-specific survival (HRadj = 1.61, 95% CI = 1.22-2.15). The results from the propensity score matched patient cohort were not different from those analyses on the full patient cohort. CONCLUSION: Thai insurance types have an effect on cancer-specific survival. The Thai government should recognize the importance of these differences, and further multi-center studies with a larger sample size are warranted to confirm this result.

Outcomes of pulmonary resection in non-small cell lung cancer patients older than 70 years old.

BACKGROUND: An appropriate treatment of older lung cancer patients has become an important issue. The aim of this study is to evaluate the short and long-term surgical outcomes in lung cancer patients using 70 years as a cut-point, and to identify prognostic factors of cancer-specific mortality in patients older than 70 years. METHODS: Medical records of non-small cell lung cancer (NSCLC) patients who underwent pulmonary resection at Chiang Mai University Hospital from January 2002 through December 2016 were retrospectively reviewed. Patients were divided into age less than 70 years (control group) and 70 years or more (study group). Primary outcomes were major post-operative complications and in-hospital death (POM); secondary outcome was long-term survival. Multivariable regression analysis was used. RESULTS: This study included 583 patients, 167 for study group, and 416 for control group. There were no differences in POM, both at univariable and multivariable analyses, however, for long-term cancer-specific mortality, the study group was more likely to die (HRadj = 1.40, 95%CI = 1.03-1.89). Adverse prognostic factors for long-term mortality in study group were having universal coverage scheme (HRadj = 1.70, 95%CI = 1.03-2.79), the presence of intratumoral lymphatic invasion (HRadj = 2.83, 95%CI = 1.28-6.29), perineural invasion (HRadj = 2.80, 95%CI = 1.13-6.94), underwent lymph node sampling (HRadj = 2.23, 95%CI = 1.16-4.30) and higher stage of disease (HRadj = 2.02, 95%CI = 1.06-3.85 for stage III, HRadj = 3.40, 95%CI = 1.29-8.94 for stage IV). CONCLUSIONS: In-hospital mortality and composite post-operative complications are acceptable in pulmonary resection for NSCLC patients older than 70 years. However, these patients had shorter long-term survival, especially who have some adverse prognostic factors. Further studies with larger sample size are warranted.

Osimertinib versus Standard of Care EGFR TKI as First-Line Treatment in Patients with EGFRm Advanced NSCLC: FLAURA Asian Subset.

INTRODUCTION: Here we report efficacy and safety data of an Asian subset of the phase III FLAURA trial (NCT02296125), which compares osimertinib with standard of care (SoC) EGFR tyrosine kinase inhibitors (TKIs) in patients with previously untreated advanced NSCLC with tumors harboring exon 19 deletion (Ex19del)/L858R EGFR TKI-sensitizing mutations. METHODS: Eligible Asian patients (enrolled at Asian sites) who were at least 18 years of age (≥20 years in Japan) and had untreated EGFR-mutated advanced NSCLC were randomized 1:1 to receive osimertinib (80 mg, orally once daily) or an SoC EGFR TKI (gefitinib, 250 mg, or erlotinib, 150 mg, orally once daily). The primary end point was investigator-assessed progression-free survival (PFS). The key secondary end points were overall survival, objective response rate, central nervous system efficacy, and safety. RESULTS: The median PFS was 16.5 versus 11.0 months for the osimertinib and SoC EGFR TKI groups, respectively (hazard ratio = 0.54, 95% confidence interval: 0.41-0.72, p < 0.0001). The overall survival data were immature (24% maturity). The objective response rates were 80% for osimertinib and 75% for an SoC EGFR TKI. The median central nervous system PFS was not calculable for the osimertinib group and was 13.8 months for the SoC EGFR TKI group (hazard ratio = 0.55, 95% confidence interval: 0.25-1.17, p = 0.118). Fewer adverse events of grade 3 or higher (40% versus 48%) and fewer adverse events leading to treatment discontinuation (15% versus 21%) were reported with osimertinib versus with an SoC EGFR TKI, respectively. CONCLUSION: In this Asian population, first-line osimertinib demonstrated a clinically meaningful improvement in PFS over an SoC EGFR TKI, with a safety profile consistent with that for the overall FLAURA study population.

Efficacy according to blind independent central review: Post-hoc analyses from the phase III, randomized, multicenter, IPASS study of first-line gefitinib versus carboplatin/paclitaxel in Asian patients with EGFR mutation-positive advanced NSCLC.

OBJECTIVE: The Phase III, randomized, open-label IPASS study (NCT00322452) of first-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) gefitinib versus carboplatin/paclitaxel for Asian patients with advanced non-small-cell lung cancer (NSCLC) showed that investigator-assessed progression-free survival (PFS) and objective response rate (ORR) were significantly prolonged in patients with EGFR mutation-positive NSCLC who received gefitinib versus patients with EGFR mutation-negative NSCLC. We report post-hoc analyses of IPASS data by blind independent central review (BICR), performed at the request of the US FDA, in a subset of patients with EGFR mutation-positive NSCLC. PATIENTS AND METHODS: Eligible patients (aged ≥18 years; histologically/cytologically confirmed Stage IIB/IV adenocarcinoma NSCLC; non- or former light-smokers; treatment-naïve) were randomly assigned 1:1 to gefitinib (250mg/day) or carboplatin (dose calculated to produce an area under the curve of 5 or 6 mg/mL/minute)/paclitaxel (200mg/m2). Primary endpoint: PFS. BICR analyses included PFS, ORR, and duration of response (DoR). RESULTS: Scans from 186 IPASS patients (gefitinib n=88, carboplatin/paclitaxel n=98) with EGFR mutation-positive NSCLC were available for BICR. Consistent with investigator-assessed results, in patients with EGFR mutation-positive NSCLC: PFS (hazard ratio 0.54; 95% confidence interval [CI] 0.38, 0.79; p=0.0012) and ORR (odds ratio 3.00; 95% CI 1.63, 5.54; p=0.0004) were significantly longer with gefitinib versus carboplatin/paclitaxel. The median DoR by BICR was 9.6 months with gefitinib and 5.5 months with carboplatin/paclitaxel. CONCLUSION: BICR analysis of IPASS data support the original, investigator-assessed results. EGFR mutation-positive status remains a significant predictor of response to first-line TKI therapy.

A phase II study of docetaxel and carboplatin in Thai patients with advanced non-small-cell lung cancer.

OBJECTIVE: This phase II study aimed to assess the effectiveness of the docetaxel plus carboplatin combination in chemotherapy-naive Thai patients with advanced non-small-cell lung cancer (NSCLC). MATERIAL AND METHOD: Forty patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-1, stage IIIB/IV NSCLC were enrolled in a phase H study between August 2001 and April 2003. Docetaxel 75 mg/m2 and Carboplatin AUC = 6 were given every 3 weeks. Response to treatment and toxicity were graded using standard WHO criteria. The Thai Functional Living Index Cancer (T-FLIC) scale was used to assess the Quality of Life (QoL) of all treated patients. RESULTS: Forty patients (median age: 55 years, range, 39-68 years; PS:0-1) were enrolled: one had stage IIIB disease with effusion, while thirty-nine had stage IV disease. Five patients were non-evaluable due to death within the first cycle; two dying of febrile neutropenia and sepsis, two of pulmonary infection, and one of unknown etiology. Partial response (PR) was seen in 28.6% patients, stable disease (SD) in 25.7%, and progressive disease (PD) in 45.7%. The median survival time was 32 weeks and the 1-year survival rate was 30.7%. Body mass index (BMI) was the only factor associated with survival time (univariate analysis: p = 0.006; multivariate analysis: p = 0.004). Other factors (gender, age, histology, ECOG PS, and glomerular filtration rate) were not predict for survival. The major treatment-related toxicities were neutropenia (from 152 treatment cycles there were grade 4: 19.7%; grade 3: 23.7%), febrile neutropenia (from 152 treatment cycles there was 3.95%), and diarrhea (grades 3/4: 0.66%). The QoL scores improved significantly throughout the treatment period. CONCLUSION: The regimen of docetaxel and carboplatin is active in advanced NSCLC and may be considered for first-line therapy.