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Evaluation of Drug-Drug Interactions in EGFR-Mutated Non-Small-Cell Lung Cancer Patients during Treatment with Tyrosine-Kinase Inhibitors.

ABSTRACT: (1) Background. The onset of a drug-drug interaction (DDI) may affect treatment efficacy and toxicity of advanced non-small-cell lung cancer (aNSCLC) patients during epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) use. Here we present the use of Drug-PIN® (Personalized Interactions Network) software to detect DDIs in aNSCLC patients undergoing EGFR-TKIs. (2) Methods. We enrolled patients with Stage IV aNSCLC already treated with or candidates to receive EGFR-TKIs, in any line; ECOG PS 0-2; taking at least one concomitant drug. Cancer treatments, concomitant drugs, and clinical and laboratory data were collected and inserted in Drug-PIN®. (3) Results. Ninety-two patients, median age of 68.5 years (range 43-89), were included. In total, 20 clinically relevant DDIs needing medical intervention in a total of 14 patients were identified; the 14 major DDIs were related to a high-grade interaction between TKIs and SSRIs, antipsychotics, antiepileptics, H2-receptor antagonist and calcium antagonists. A negative association between statin intake and PFS was identified (p = 0.02; HR 0.281, 95% CI 0.096-0.825). (4) Conclusions. This is the first retrospective study assessing the prevalence of DDIs, the clinical need for medical intervention and the impact of concomitant drugs on EGFR-TKIs survival in aNSCLC.

SUBMITTER: Occhipinti M

PROVIDER: S-EPMC8157378 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Evaluation of Drug-Drug Interactions in EGFR-Mutated Non-Small-Cell Lung Cancer Patients during Treatment with Tyrosine-Kinase Inhibitors.

Occhipinti Mario M Brambilla Marta M Galli Giulia G Manglaviti Sara S Giammaruco Maristella M Prelaj Arsela A Ferrara Roberto R De Toma Alessandro A Proto Claudia C Beninato Teresa T Zattarin Emma E Lo Russo Giuseppe G Gelibter Alain Jonathan AJ Simmaco Maurizio M Preissner Robert R Garassino Marina Chiara MC De Braud Filippo F De Braud Filippo F Marchetti Paolo P

Journal of personalized medicine 20210518 5

(1) Background. The onset of a drug-drug interaction (DDI) may affect treatment efficacy and toxicity of advanced non-small-cell lung cancer (aNSCLC) patients during epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor (TKI) use. Here we present the use of Drug-PIN<sup>®</sup> (Personalized Interactions Network) software to detect DDIs in aNSCLC patients undergoing EGFR-TKIs. (2) Methods. We enrolled patients with Stage IV aNSCLC already treated with or candidates to receive EGFR-TK ...[more]

PMID: 34069851

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Project description:BackgroundThis study aimed to investigate the efficacy of immunotherapy, as monotherapy or in combination, comparing to chemotherapy with or without anti-angiogenesis for advanced non-small cell lung cancer (NSCLC) patients progressing to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs).MethodsWe retrospectively analyzed patients with advanced NSCLC harboring EGFR mutations who received immune checkpoint inhibitors (ICI) and/or chemotherapy after EGFR-TKIs failure at Shanghai Chest Hospital between Aug 2016 and Oct 2022. According to the subsequent immunotherapy regimen, the patients were assigned to ICI monotherapy (IM), IO plus anti-angiogenesis (IA), ICI plus chemotherapy (IC), ICI plus chemotherapy plus anti-angiogenesis (ICA). Eligible patients undergoing standard chemotherapy were assigned to chemotherapy plus anti-angiogenesis (CA) and chemotherapy alone (CM). Efficacy was evaluated according to the RECIST 1.1version, and calculated the objective response rate (ORR) and disease control rate (DCR). Survival curves were plotted using the Kaplan-Meier method, and the median progression-free survival (PFS) was calculated. Differences among survival curves of the six groups were assessed using the log-rank test.ResultsA total of 237 advanced NSCLC patients with EGFR mutations were included in this study. Of the 160 patients who received immunotherapy, 57 received ICI monotherapy, 27 received ICI plus anti-angiogenesis therapy, 43 received ICI plus chemotherapy, and 33 received ICI plus anti-angiogenesis plus chemotherapy. 77 patients received standard chemotherapy, of which 30 received chemotherapy plus anti-angiogenesis and 47 received chemotherapy alone. Patients in ICA group showed significant longer PFS than IM (7.2 vs 1.9 months, P=0.011), IA (7.2 vs 4.8 months, P=0.009) and CM group (7.2 vs 4.4 months, P=0.005). There was no significant difference in PFS between the ICA and IC (7.2 vs 5.6 months, P=0.104) or CA (7.2 vs 6.7 months, P=0.959) group. Meanwhile, the ICA group showed the highest ORR and DCR (36.4% and 90.9%) compared to the other five groups. The IC group had a higher ORR than the IA and CA group (32.6% vs 7.4% vs 10.0%, respectively), but the DCR was comparable (79.1% vs 74.1% vs 76.7%, respectively). The ORR of the CM group was 6.4% and the DCR was 66.0%. IM group showed the lowest ORR and DCR (1.8% and 36.8%). Treatment-related adverse events (TRAEs) of grade 3 or worse occurred in 9 (27.3%) patients in the ICA group, 6 (20.0%) in the CA group, 7 (14.9%) in the CM group, 5 (11.6%) in the IC group, 5 (8.8%) in the IM group, and 2 (7.4%) in the IA group.ConclusionNSCLC patients with positive EGFR mutations after EGFR-TKIs failure received subsequent immunotherapy plus anti-angiogenesis and chemotherapy are likely to have more benefits in ORR, DCR and mPFS.

Project description:BackgroundNon-small-cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. In Asian populations, epidermal growth factor receptor (EGFR) mutations are particularly prevalent, leading to the development of EGFR tyrosine kinase inhibitors (TKIs) to improve patient outcomes. While extensive research has been conducted on the prognosis of patients receiving EGFR-TKIs, the estimation of 5-year survival in this population remains an underexplored area.ObjectivesThis study aimed to provide real-world evidence and conduct a comprehensive analysis of the determinants influencing the 5-year survival rate in patients with EGFR-mutated NSCLC. Considering the factors identified in this study, a scoring system was developed to predict the likelihood of patients achieving this goal.DesignA retrospective cohort study utilizing a training cohort of 1,873 patients and a validation cohort of 484 patients.MethodsA logistic regression model was constructed to evaluate the weighting of factors and develop a scoring system. The Kaplan-Meier model estimated the overall survival probability, and patients were categorized into four risk groups based on their likelihood of five-year survival. The prediction performance of both the training and validation cohorts was evaluated using the area under the curve (AUC), accuracy, precision, sensitivity, specificity, and F1-score.ResultsResults indicated that age > 65 years; performance score of 2-4; metastasis to the liver, brain, bone, or pleura; and poor disease control were associated with a decreased likelihood of 5-year survival. The estimated 5-year survival rate was 23.4% (odds ratio [OR]: 20.56; 95% confidence interval [CI]: 9.06-46.64; p < 0.0001), 16.1% (OR: 12.88; 95% CI: 5.82-28.49; p < 0.0001), 7.2% (OR: 5.23; 95% CI: 2.36-11.60; p < 0.0001), and 1.5% (OR: reference) for the low-risk, intermediate-risk, high-risk, and very-high-risk groups, respectively. The validation cohort further confirmed these findings, showing survival probabilities of 52.6% (OR: 96.67; 95% CI: 11.07-844.23; p < 0.0001), 21.3% (OR: 23.49; 95% CI: 3.13-176.46; p = 0.002), 14.9% (OR: 15.21; 95% CI: 2.03-114.25; p = 0.008), and 1.1% (OR: reference) for the low-risk, intermediate-risk, high-risk, and very-high-risk groups, respectively. The training cohort demonstrated an AUC of 0.79 (95% CI: 0.75-0.82) and a model quality score of 0.75, indicating good predictive performance. Calibration plots demonstrated a good fit for the scoring system. For the external validation cohort, the AUC, precision, sensitivity, and specificity were 0.71, 0.74, 0.35, 0.33, respectively. The model achieved an F1-score of 0.47, reflecting adequate performance in predicting 5-year survival probabilities.ConclusionThis study identified critical prognostic factors and developed a validated scoring system for estimating 5-year survival in patients with EGFR-mutated NSCLC receiving EGFR-TKIs. While the model demonstrated robust predictive performance within the study cohort, broader applicability beyond Taiwan may require further refinements and alternative study designs.

Project description:ObjectiveCirculating tumor DNA (ctDNA) monitoring proves to be a promising approach to assess response and predict survival in epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors (TKIs). However, whether the dynamic changes in ctDNA EGFR mutation status have the same predictive value as ctDNA remains unknown. This study aims to explore the predictive value of dynamic changes in both ctDNA and ctDNA EGFR status.MethodsA retrospective analysis was performed using 91 ctDNA samples from a cohort of 28 patients who were diagnosed with EGFR-mutated NSCLC and treated with EGFR-TKIs, including 14 patients treated with first-/second-generation TKIs and 14 treated with osimertinib. Blood samples at baseline (BL), within 4 weeks after TKI initiation (Week4), within 12 weeks before progression (pre-PD), and at progression were collected. The relationship alternatives in ctDNA status, ctDNA EGFR status and response to EGFR-TKIs as well as progression-free survival (PFS) were analyzed.ResultsWe categorized 20 BL-ctDNA positive patients with available Week4-ctDNA into two groups: ctDNA-clearance (N = 7, 35%) and ctDNA-non-clearance (N = 13, 65%). The ctDNA-clearance group had better PFS than the ctDNA-non-clearance group (ctDNA-clearance vs. ctDNA-non-clearance, p = 0.091, hazard ratio [HR] = 0.42, 95% confidence interval [CI] = 0.15-1.19). According to Week4-EGFR status, we observed that PFS was significantly longer in EGFR-clearance patients than EGFR-non-clearance groups, (p = 0.011, HR = 0.23, 95% CI = 0.08-0.72). We then categorized patients into three subgroups according to Week4-ctDNA and Week4-EGFR status: non-clearance (N = 9), only-EGFR-clearance (concomitant alterations non-clearance) (N = 4), and all-clearance (N = 7). The nonclearance group had a significantly worse PFS than the all-clearance group (median PFS = 5.07 vs. 11.40 months, p = 0.029, HR = 3.45, 95% CI = 1.05-11.49). The only-EGFR-clearance group had a similar PFS to the all-clearance group (p = 0.607), which was longer than that of the non-clearance group (median PFS = 9.20 vs. 5.07 months, p = 0.060, HR = 0.25, 95% CI = 0.05-1.18). We found that the all-clearance group had a similar objective response rate (ORR) to the only-EGFR-clearance group (p = 1.000) and a higher ORR than the non-clearance group (p = 0.012).ConclusionMonitoring of EGFR clearance in ctDNA is promising and cost-effective in assessing response and predicting survival in EGFR-mutated NSCLC patients treated with EGFR-TKIs, with similar predictive value to ctDNA surveillance.

Dataset Information

Evaluation of Drug-Drug Interactions in EGFR-Mutated Non-Small-Cell Lung Cancer Patients during Treatment with Tyrosine-Kinase Inhibitors.

Publications

Evaluation of Drug-Drug Interactions in EGFR-Mutated Non-Small-Cell Lung Cancer Patients during Treatment with Tyrosine-Kinase Inhibitors.

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