No benefit of chemotherapy in Osimertinib-treated postoperative non-small cell lung cancer patients.
Ontology highlight
ABSTRACT:
SUBMITTER: Li F
PROVIDER: S-EPMC8435392 | biostudies-literature | 2021 Aug
REPOSITORIES: biostudies-literature
Publications
No benefit of chemotherapy in Osimertinib-treated postoperative non-small cell lung cancer patients.
Li Feng F Zhao Yi Y Zhong Ran R Cai Xiuyu X Liu Jun J He Jianxing J Liang Wenhua W
Translational lung cancer research 20210801 8
Similar Datasets
Project description:The mutation status of tumor tissue DNA (n = 389) of resected stage II-III non-squamous non-small-cell lung cancer (Ns-NSCLC) was analyzed using targeted deep sequencing as an exploratory biomarker study (JIPANG-TR) for the JIPANG study, a randomized phase III study of pemetrexed/cisplatin (Pem/Cis) vs vinorelbine/cisplatin (Vnr/Cis). The TP53 mutation, common EGFR mutations (exon 19 deletion and L858R), and KRAS mutations were frequently detected. The frequency of the EGFR mutation was significant among female patients. Patients with an EGFR mutation-positive status had a significantly shorter recurrence-free survival (RFS) time (24 mo vs not reached) (HR, 1.64; 95% CI, 1.22-2.21; P = .0011 for EGFR mutation status). Multivariable analysis identified both the pathological stage and EGFR mutation status as independent prognostic factors for RFS (HR, 1.78; 95% CI, 1.30-2.44; P = .0003 for disease stage; and HR, 1.57; 95% CI, 1.15-2.16; P = .0050 for EGFR mutation status). This study demonstrated that the EGFR mutation has either a poor prognostic or predictive impact on a poor response to postoperative chemotherapy with platinum doublet chemotherapy for stage II-III Ns-NSCLC patients. This result supports a role for mandatory molecular diagnosis of early-stage Ns-NSCLC for precision oncology and signifies the importance of adjuvant for the 3rd generation tyrosine kinase inhibitor rather than platinum-based chemotherapy. This study is registered with the UMIN Clinical Trial Registry (UMIN 000012237).
| S-EPMC8748214 | biostudies-literature
Project description:ImportanceAlthough it has been reported that osimertinib mesylate provides better survival benefits compared with first- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), it remains unclear whether osimertinib is associated with more cancer therapy-related cardiac events (CTRCEs) compared with other EGFR TKIs, as does the extent of the association these adverse effects may have with overall survival. This issue is particularly critical due to the high prevalence of EGFR variants within Asian populations, including that of Taiwan.ObjectiveTo compare CTRCEs and their association with survival in patients treated with osimertinib vs other EGFR TKIs.Design, setting, and participantsThis cohort study was conducted at the National Cheng Kung University Hospital, a college hospital and tertiary academic referral center in Taiwan. The median follow-up duration was 23.2 (IQR, 15.2-31.5) months. A total of 401 patients with EGFR-mutant non-small cell lung cancer (NSCLC) beginning treatment with EGFR TKIs from September 1, 2019, to July 31, 2022, were retrospectively analyzed. CTRCEs included newly emerging arrhythmias, valvular heart diseases (moderate and more), myocardial infarction, and heart failure and were analyzed after adjusting for age, sex, smoking, alcohol consumption, body mass index, cardiovascular comorbidities, thoracic radiotherapy, and cardiovascular medications. Follow-up was completed January 31, 2024.ExposureOsimertinib.Main outcomes and measuresThe Cox proportional hazards model was used to estimate CTRCEs in patients treated with osimertinib or other EGFR TKIs. Considering that death can lower the incidence of CTRCEs, the competing risk method was used to calculate CTRCEs after adjusting for potential confounders. Multivariable Cox proportional hazard regression analysis for overall survival was used to explore whether CTRCEs were independently associated with overall survival.ResultsAmong the 401 patients (253 [63.1%] female; mean [SD] age, 69.2 [11.3] years), 195 (48.6%) treated with osimertinib were matched with 206 (51.4%) treated with other EGFR TKIs. Occurrence of CTRCEs in patients receiving osimertinib was significantly higher compared with patients treated with other EGFR TKIs (29 [14.9%] vs 9 [4.4%]; hazard ratio [HR], 3.37; 95% CI, 1.56-7.26; P = .002). After adjustment for relevant cardiovascular risk factors, the HR of CTRCEs was significantly higher in the group treated with osimertinib (adjusted subdistribution HR, 4.00; 95% CI, 1.81-8.85; P < .001). In addition, CTRCEs were independently associated with overall survival (HR, 4.02; 95% CI, 2.44-6.63; P < .001).Conclusions and relevanceIn this cohort study of patients with EGFR-mutant NSCLC, osimertinib was associated with a higher incidence of CTRCEs compared with other EGFR TKIs; CTRCEs were independently associated with overall survival. These findings highlight the need for ongoing cardiac monitoring in these patients, regardless of preexisting cardiac risk factors.
| S-EPMC11621985 | biostudies-literature
Project description:IntroductionFirst-line osimertinib plus chemotherapy significantly prolonged progression-free survival of patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC) compared to osimertinib, according to the FLAURA2 trial.MethodsWe established a Markov model to compare the cost-effectiveness of osimertinib plus chemotherapy with that of osimertinib alone. Clinical data were obtained from the FLAURA and FLAURA2 trials, and additional data were extracted from online resources and publications. Sensitivity analyses were conducted to evaluate the robustness of the findings. We used A willingness-to-pay threshold of $150,000 per quality-adjusted life-years (QALYs) gained. The main outcomes were QALYs, overall costs, incremental cost-effectiveness ratio (ICER), incremental net monetary benefit, and incremental net health benefit. Subgroup analyses were conducted according to patients' mutation type and central nervous system (CNS) metastatic status.ResultsIn a 20-year time horizon, the ICER of osimertinib plus chemotherapy versus osimertinib alone was $223,727.1 per QALY gained. The sensitivity analyses identified the cost of osimertinib and the hazard ratio for overall survival as the top 2 influential factors and a 1.9% probability of osimertinib plus chemotherapy to be cost-effective. The subgroup analyses revealed ICERs of $132,614.1, $224,449.8, $201,464.1, and $130,159.7 per QALY gained for L858R mutations, exon 19 deletions, CNS metastases, and no CNS metastases subgroups, respectively.ConclusionsFrom the perspective of the United States health care system, osimertinib plus chemotherapy is not cost-effective compared to osimertinib alone for treatment-naïve patients with EGFR-mutated advanced NSCLC, but more favorable cost-effectiveness occurs in patients with L858R mutations and patients without baseline CNS metastases.
| S-EPMC11358701 | biostudies-literature
Project description:PurposeTo describe symptoms and side effects experienced by patients with advanced non-small cell lung cancer (NSCLC), assess how patients allocate sensations (i.e. symptoms or side effects) to either the disease or its treatment, and evaluate how patients balance side effects with treatment benefits.MethodsQualitative sub-studies were conducted as part of two clinical trials in patients treated for advanced NSCLC (AURA [NCT01802632]; ARCTIC [NCT02352948]).ResultsInterviews were conducted with 23 patients and 19 patients in the AURA and ARCTIC sub-studies, respectively. The most commonly experienced symptoms/side effects were respiratory (81% of patients), digestive (76%), pain and discomfort (76%), energy-related (71%), and sensory (62%). Patients identified a sensation as a treatment side effect if they had not experienced it before, if there was a temporal link between the sensation and receipt of treatment, and/or if their doctors consistently told or asked them about it in relation to side effects. Themes that emerged when patients talked about their cancer treatment and its side effects related to the serious nature of their advanced disease and their treatment expectations. Patients focused on treatment benefits, wanting a better quality of life, being hopeful, not really having a choice, and not thinking about side effects.ConclusionsIn these two qualitative sub-studies, patients with advanced NSCLC valued the benefits of their treatment regardless of side effects that they experienced. Patients weighed their options against the seriousness of their disease and expressed their willingness to tolerate their side effects in return for receiving continued treatment benefits.
| S-EPMC8800875 | biostudies-literature
Project description:Background: Osimertinib has shown greater efficacy than standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and fewer grade 3 or higher adverse drug reactions (ADRs) in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, the clinical outcomes of osimertinib treatment vary depending on the patient's ethnicity. Therefore, further research is necessary to evaluate the impact of single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP450) and drug transporters on the therapeutic outcomes and ADRs to osimertinib in Thai patients, to provide improved pharmacological treatments for cancer patients. Methods: This retrospective and prospective cohort study enrolled 63 Thai patients with NSCLC treated with 80 mg of osimertinib once daily as monotherapy. Seventeen SNPs in candidate genes related to drug metabolism and transport pathways were analyzed in each patient. Chi-square or Fisher's exact tests were used to evaluate the associations between SNPs and clinical outcomes, including ADR incidence and objective response rate (ORR). In addition, the correlation between the genotype and median time to treatment failure (TTF) or progression-free survival (PFS) was assessed using Kaplan-Meier analysis and a log-rank test. Results: We identified six SNPs (rs2231142 and rs2622604 in ABCG2, rs762551 in CYP1A2, rs1057910 in CYP2C9, rs28371759 in CYP3A4, and CYP2A6 deletion polymorphism (CYP2A6*4)) that significantly increased the incidence of ADRs. In addition, we found two SNPs (rs2069514 in CYP1A2 and rs1057910 in CYP2C9) that significantly decreased the median TTF, and two SNPs (rs28399433 in CYP2A6 and rs1057910 in CYP2C9) that significantly decreased the median progression-free survival (PFS). Specifically, we found that one of these SNPs (rs1057910 in CYP2C9) influenced ADRs, TTF, and PFS. Additionally, SNPs in the CYP2A6 heterozygous variant (non4/*4) significantly increased ADR incidence, leading to a high frequency of dose reduction (27.0%). Conclusion: Our study demonstrated significant SNPs associated with increased ADR incidence, decreased PFS, and decreased TTF in Thai patients with NSCLC treated with osimertinib. The CYP2C9 (*3) and CYP2A6 (*4) allele frequencies differed between ethnicities and were associated with an increased incidence of ADRs. These findings highlight the importance of considering genetic factors in NSCLC treatment and may facilitate personalized medicine approaches. Moreover, our study showed a higher incidence of ADRs than the previous trials, including FLAURA and AURA2, and a higher frequency of dose reduction than reported in the AURA 3 trial, possibly due to genetic differences among the study populations.
| S-EPMC10657898 | biostudies-literature
Project description:The aim of this article is to summarise the published data on prognostic and predictive biomarkers for early-stage non-small cell lung cancer (NSCLC), and discuss how to integrate them into clinical trials. Large phase III trials have been published in resected NSCLC with biomarkers identifying subsets of patients benefitting from perioperative chemotherapy. Initial findings of predictive implications for the DNA repair protein, ERCC1, were not confirmed in a larger series of patients due to the versatility of the commercially available monoclonal ERCC1 antibody. Prediction of survival by RRM1 tumour expression was not confirmed in a prospective phase III trial in 275 patients with stage IV disease, precluding its use in early-stage NSCLC. BRCA1 mRNA tumour content also failed to predict platinum resistance in 287 stage IV NSCLC patients included in a phase II trial, and the results of a similar trial in early-stage patients are still pending. Of the several cDNA gene expression studies in early-stage NSCLC with non-overlapping prognostic signatures, few have been replicated in independent cohorts for prognostic value, and none received external validation for predictive value. Therefore, use of biomarkers predicting chemotherapy efficacy still needs additional validation before becoming routine practice in oncogene-driven pan-negative NSCLC patients.
| S-EPMC9639177 | biostudies-literature
Project description:BackgroundImproved methods are needed for predicting prognosis and the benefit of delivering adjuvant chemotherapy (ACT) in patients with non-small-cell lung cancer (NSCLC).MethodsA novel prognostic algorithm was identified using genomic profiles from 332 stage I-III adenocarcinomas and independently validated on a separate series of 264 patients with stage I-II tumors, compiled from five previous studies. The prognostic algorithm was used to interrogate genomic data from a series of patients treated with adjuvant chemotherapy. Those genes associated with outcome in the adjuvant treatment setting, independent to prognosis were used to train an algorithm able to classify a patient as either a responder or non-responder to ACT. The performance of this signature was independently validated on a separate series of genomic profiles from patients enrolled in a randomized controlled trial of cisplatin/vinorelbine vs. observation alone (JBR.10).ResultsNSCLC patients exhibiting the high-risk, poor-prognosis form of the 160-gene prognosis signature experienced a 2.80-times higher rate of 5-year disease specific death (log rank P < 0.0001) compared to those with the low-risk, good prognosis profile, adjusted for covariates. The prognosis signature was found to especially accurate at identifying early stage patients at risk of disease specific death within 24 months of diagnosis when compared to traditional methods of outcome prediction.Separately, NSCLC patients with the 37-gene ACT-response signature (n = 70, 64 %), benefited significantly from cisplatin/vinorelbine (adjusted HR: 0.23, P = 0.0032). For those patients predicted to be responders, receiving this form of ACT conferred a 25 % improvement in the probability of 5-year-survival, compared to observation alone and adjusted for covariates. Conversely, in those patients predicted to be non-responders, ACT was observed to offer no significant survival benefit (adjusted HR: 0.55, P = 0.32).The two gene signatures overlap by one gene only SPSB3, which interacts with the oncogene MET. In this study, higher levels of SPSB3 which were associated with favorable prognosis and benefit from ACT.ConclusionsThese complimentary prognostic and predictive gene signatures may assist physicians in their management and treatment of patients with early stage lung cancer.
| S-EPMC3407714 | biostudies-literature
Project description:AimsOsimertinib is a third-generation, irreversible, central nervous system-active, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with efficacy in EGFR-mutated non-small cell lung cancer (NSCLC). We assessed the relationship between plasma osimertinib levels and its efficacy and safety events.MethodsComprehensive pharmacokinetics exposure-response (E-R) modelling was performed utilizing steady state area under the curve (AUCss) data from first-line, ≥second-line and adjuvant studies from the osimertinib clinical development programme (20-240 mg once-daily dosing; N = 1689 patients). Analyses were conducted for survival using a proportional hazard model; for interstitial lung disease (ILD) and left ventricular ejection fraction (LVEF) events using a penalized logistic regression model and graphical analysis of potential confounding factors; and for rash and diarrhoea events using descriptive analysis.ResultsE-R modelling analyses indicated no clear trend of increasing efficacy with increasing osimertinib AUCss; efficacy in all exposure quartiles was significantly better than the control arm (comparator EGFR-TKI, chemotherapy or placebo) irrespective of treatment line. Model-based analysis suggested a potential relationship between increased osimertinib exposure and increased probability of ILD events, predominantly in Japanese patients. Additionally, there were increased probabilities of rash or diarrhoea with increasing osimertinib exposure. The probability of LVEF events showed overlapping confidence intervals for osimertinib ≤80 mg and control.ConclusionsE-R modelling in patients with EGFR-mutated NSCLC demonstrated that increased osimertinib exposure was unlikely to increase efficacy but may increase occurrence of certain adverse events. Hence, long-term treatment with doses ≥80 mg was not expected to provide additional benefit.
| S-EPMC11602960 | biostudies-literature
Project description:The activation of lymphocytes by gefitinib treatment has been described. In this phase II pilot trial, we explored the possible synergism between IL-2 and gefitinib for non-small cell lung cancer (NSCLC) treatment. From September, 2003, to November, 2006, 70 consecutive patients with advanced, progressive NSCLC, previously treated with chemotherapy, received oral gefitinib 250 mg daily. The first 39 patients received gefitinib alone (G group). The other 31 also received subcutaneous IL-2 (GIL-2 group): 1 MIU/m2 (Million International Unit/m2)twice a day on Days 1 and 2, once a day on Days 3, 4, 5 every week for four consecutive weeks with a four-week rest period. Median follow-up was 25.2 months. Grade 3-4 toxicity of gefitinib was represented by skin rash (7%), asthenia/anorexia (6%) and diarrhea (7%); patients treated with IL-2 showed grade 2-3 fever (46%), fatigue (21%) and arthralgia (13%). In the GIL-2 group and G-group, we respectively observed: an overall response rate of 16.1% (6.4% complete response) and 5.1% (only partial response); a disease control rate of 41.9% and 41%; a median time to progression of 3.5 (CI 95% = 3.2-3.8) and 4.1 (CI 95% = 2.6-5.7) months; a median overall survival of 20.1 (CI 95% = 5.1-35.1) and 6.9 (CI 95% = 4.9-8.9) months (p = 0.002); and an actuarial one-year survival rate of 54% and 30%. Skin toxicity (p < 0.001; HR = 0.29; CI 95% = 0.16-0.54) and use of IL-2 (p < 0.001; HR = 0.33; CI 95% = 0.18-0.60) were independently associated with improvement of survival. In this consecutive, non-randomized, series of advanced NSCLC patients, the use of IL-2 increased the efficacy of gefitinib.
| S-EPMC4276955 | biostudies-other
Project description:BackgroundThe immunotherapy plus chemotherapy combination is one of the most promising treatments in advanced non-small-cell lung cancer (NSCLC). Immunotherapy often causes immune-related adverse events (irAEs), which have been reported to be associated with the good clinical outcomes. However, the effects of immunotherapy plus chemotherapy remain unknown. In this study, we investigated the association between irAEs caused by immunotherapy plus chemotherapy and clinical efficacy in patients with advanced NSCLC.Materials and methodsWe retrospectively analyzed the data of patients with advanced NSCLC, who received a combination of immunotherapy plus chemotherapy at six institutions in Japan between January 2019 and September 2019. We examined the effect of irAEs on various clinical outcomes.ResultsWe included 70 patients with advanced NSCLC. Patients were divided into two groups: patients with irAEs and patients without irAEs. Patients with irAEs had significantly longer progression-free survival than those without irAEs on univariate (hazard ratio 0.53, 95% confidence interval 0.30-0.93, p = 0.026) and multivariate (hazard ratio 0.53, 95% confidence interval 0.29-0.97, p = 0.041) analyses. In addition, patients with grade 1-2 irAEs (mild irAEs) had significantly longer progression-free and overall survival than those with grade 3-5 irAEs (severe irAEs) or without irAEs on univariate (398 days versus 189 days, respectively; p = 0.0061) and multivariate (not reached versus 412 days, respectively; p = 0.021) analyses.ConclusionPatients with NSCLC who experienced mild irAEs showed better response to treatment with immunotherapy plus chemotherapy than those with severe irAEs or without irAEs. Further large-scale research is warranted to confirm these findings.
| S-EPMC8021904 | biostudies-literature