Treatment options and considerations for acquired resistance in EGFR mutation-positive non-small-cell lung cancer

Oncogene-addicted metastatic non-small-cell lung cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

13032 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been used to treat lung cancers, but resistance to these agents has been observed. This study was designed to investigate whether the insulin-like growth factor (IGF)-mediated signaling pathway induces resistance to the EGFR TKIs in lung cancer. Methods: The antitumor activities and action mechanisms of EGFR inhibitors (erlotinib, gefinitib, cetuximab), single or in combination with IGF-IR inhibitors, were assessed in vitro in a subset of non-small-cell lung cancer (NSCLC) cell lines by the MTT assay, flow cytometry-based TUNEL assay, soft agar, confocal microscopy, metabolic labeling, coimmunoprecipitation, and northern and western blot analyses, and in vivo in animal models. Correlation of EGFR and IGF-1R expression was assessed using lung tissues from patients with NSCLC. Results: EGFR TKI inhibited the proliferation and anchorage-dependent and -independent colony-forming ability of NSCLC cells, which induced apoptosis, only when IGF-1R signaling was blocked. Treatment with EGFR TKIs, but not with the EGFR antibody, induced EGFR:IGF-1R heterodimerization on cell surface and activation of the IGF-1R, resulting in the stimulation of PI3K/Akt/ mTOR pathway, promoting the de novo protein biosynthesis of survivin and EGFR, resulting in the survival of NSCLC cells. When IGF-IR and mTOR were blocked, treatment of EGFR-TKIs induced apoptosis in NSCLC cells, resulting in suppression of the NSCLC tumor growth. When we tested the expression of IGF-R and EGFR in human lung tissue, 9/14 tumor samples exhibited increased expression of EGFR and 7/9 samples showed a correlative increases in IGF-IR protein levels compared to their paired normal counterparts. Conclusions: These findings suggest that simultaneous targeting of EGFR and IGF-1R signaling pathways might be an effective therapeutic strategy against NSCLC. No significant financial relationships to disclose.

Dual Inhibition of Met Kinase and Angiogenesis to Overcome HGF-Induced EGFR-TKI Resistance in EGFR Mutant Lung Cancer

Meta-Analysis of EGFR Kinase Inhibitors: Not Always Greater Than the Sum of Its Parts

Objective: This study describes the symptom and economic burden associated with brain metastases (BM) in patients with non-small cell lung cancer (NSCLC) receiving epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs).Methods: This retrospective study included adults with ≥2 medical claims, within 90 days, for lung cancer and ≥1 administration of EGFR-TKIs. Based on ICD-9 codes, patients were stratified into cohorts by type of metastases (BM, other metastases [OM], or no metastases [NM]), and by when the metastasis diagnosis occurred (synchronous or asynchronous).Results: The population (synchronous BM [SBM] = 24, synchronous OM [SOM] = 23, asynchronous BM [ASBM] = 15, asynchronous OM [ASOM] = 49, NM = 85) was mostly female (57%), average age 69 years (SD = 11). SBM patients experienced more fatigue and nausea/vomiting compared with SOM and NM patients and more headaches and loss of appetite than NM patients. ASBM was associated with more fatigue, nausea/vomiting, headaches, pain/numbness, altered mental status, and seizures than NM, and more headaches and pain/numbness than ASOM. SBM patients experienced a greater increase in per-member-per-month all-cause total healthcare costs after diagnosis ($20,301) vs SOM ($9,131, p = .001) and NM ($2,493, p = .001). ASBM’s cost increase between baseline and follow-up ($7,867) did not differ from ASOM’s ($4,947, p = .195); both were larger than NM ($2,493, p = .001 and p = .009, respectively).Limitations: EGFR mutation status was inferred based on EGFR-TKI treatment, not by molecular testing. Patients were from US commercial insurance plans; results may not be generalizable to other populations.Conclusions: Among patients with EGFR-TKI-treated NSCLC, patients with BM experienced more symptoms and, when diagnosed synchronously, had significant increases in total medical costs vs patients with OM and NM. Therapeutic options with central nervous system activity may offer advantages in symptomatology and costs in EGFR-mutated patients with BM.

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors for Non–Small-Cell Lung Cancer Patients with Leptomeningeal Carcinomatosis

Background: Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase inhibitor (TKI) can improve progression free survival in patients with treatment naive EGFR mutant metastatic non-small cell lung cancer (NSCLC) compared with platinum-based chemotherapy, but no statistically significant difference is observed in overall survival. The survival time of EGFR mutant NSCLC patients treated with at least two systemic chemotherapy regimens and one EGFR TKI was 34.8 months in a previous study. Objective: The present study was to determine the median survival time of advanced NSCLC patients who received EGFR-TKIs in Chulabhorn Hospital. Materials and Methods: We retrospectively reviewed the medical records of advanced NSCLC cases treated with EGFR TKIs in Chulabhorn Hospital during 2009 to 2011. Results: Among 243 advanced NSCLC cases, 72 patients received EGFR TKIs. EGFR mutation status was positive in 14 (19.17%) patients. The median overall survival time was 30.04 months (95% CI: 18.71 to 49.48 months) in all patients, compared with 49.49 months (95% CI: 15.93 to NR) in EGFR mutation-positive patients (n=14). No statistically significant difference of overall survival was noted between EGFR mutation status groups (p=0.51). Conclusion: The median survival time for Thai patients treated with EGFR TKIs was comparable to historical data and irrespective of EGFR mutation status. Keywords: Metastatic non-small cell lung cancer, EGFR TKIs, Survival

Gender Differences: Implications for Clinical Trials and Practice

Some but not all patients with non-small-cell lung cancer (NSCLC) respond to treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). We developed and tested the ability of a predictive algorithm based on matrix-assisted laser desorption ionization (MALDI) mass spectrometry (MS) analysis of pretreatment serum to identify patients who are likely to benefit from treatment with EGFR TKIs. Serum collected from NSCLC patients before treatment with gefitinib or erlotinib were analyzed by MALDI MS. Spectra were acquired independently at two institutions. An algorithm to predict outcomes after treatment with EGFR TKIs was developed from a training set of 139 patients from three cohorts. The algorithm was then tested in two independent validation cohorts of 67 and 96 patients who were treated with gefitinib and erlotinib, respectively, and in three control cohorts of patients who were not treated with EGFR TKIs. The clinical outcomes of survival and time to progression were analyzed. An algorithm based on eight distinct m/z features was developed based on outcomes after EGFR TKI therapy in training set patients. Classifications based on spectra acquired at the two institutions had a concordance of 97.1%. For both validation cohorts, the classifier identified patients who showed improved outcomes after EGFR TKI treatment. In one cohort, median survival of patients in the predicted "good" and "poor" groups was 207 and 92 days, respectively (hazard ratio [HR] of death in the good versus poor groups = 0.50, 95% confidence interval [CI] = 0.24 to 0.78). In the other cohort, median survivals were 306 versus 107 days (HR = 0.41, 95% CI = 0.17 to 0.63). The classifier did not predict outcomes in patients who did not receive EGFR TKI treatment. This MALDI MS algorithm was not merely prognostic but could classify NSCLC patients for good or poor outcomes after treatment with EGFR TKIs. This algorithm may thus assist in the pretreatment selection of appropriate subgroups of NSCLC patients for treatment with EGFR TKIs.

BackgroundIncreased focus surrounds identifying patients with advanced non-small cell lung cancer (NSCLC) who will benefit from treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI). EGFR mutation, gene copy number, coexpression of ErbB proteins and ligands, and epithelial to mesenchymal transition markers all correlate with EGFR TKI sensitivity, and while prediction of sensitivity using any one of the markers does identify responders, individual markers do not encompass all potential responders due to high levels of inter-patient and inter-tumor variability. We hypothesized that a multivariate predictor of EGFR TKI sensitivity based on gene expression data would offer a clinically useful method of accounting for the increased variability inherent in predicting response to EGFR TKI and for elucidation of mechanisms of aberrant EGFR signalling. Furthermore, we anticipated that this methodology would result in improved predictions compared to single parameters alone both in vitro and in vivo.ResultsGene expression data derived from cell lines that demonstrate differential sensitivity to EGFR TKI, such as erlotinib, were used to generate models for a priori prediction of response. The gene expression signature of EGFR TKI sensitivity displays significant biological relevance in lung cancer biology in that pertinent signalling molecules and downstream effector molecules are present in the signature. Diagonal linear discriminant analysis using this gene signature was highly effective in classifying out-of-sample cancer cell lines by sensitivity to EGFR inhibition, and was more accurate than classifying by mutational status alone. Using the same predictor, we classified human lung adenocarcinomas and captured the majority of tumors with high levels of EGFR activation as well as those harbouring activating mutations in the kinase domain. We have demonstrated that predictive models of EGFR TKI sensitivity can classify both out-of-sample cell lines and lung adenocarcinomas.ConclusionThese data suggest that multivariate predictors of response to EGFR TKI have potential for clinical use and likely provide a robust and accurate predictor of EGFR TKI sensitivity that is not achieved with single biomarkers or clinical characteristics in non-small cell lung cancers.

EGFR gene mutations and increased EGFR copy number have been associated with favorable response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKI) in patients with non-small-cell lung cancer (NSCLC). In contrast, KRAS mutation has been shown to predict poor response to such therapy. We tested the utility of combinations of these three markers in predicting response and survival in patients with NSCLC treated with EGFR-TKIs. Patients with advanced NSCLC treated with EGFR-TKI with available archival tissue specimens were included. EGFR and KRAS mutations were analyzed using PCR-based sequencing. EGFR copy number was analyzed using fluorescence in situ hybridization. The study included 73 patients, 59 of whom had all three potential markers successfully analyzed. EGFR mutation was detected in 7 of 71 patients (9.8%), increased EGFR copy number in 32 of 59 (54.2%), and KRAS mutation in 16 of 70 (22.8%). EGFR mutation (P<0.0001) but not increased EGFR copy number (P=0.48) correlated with favorable response. No survival benefit was detected in patients with either of these features. KRAS mutation correlated with progressive disease (P=0.04) and shorter median time to progression (P=0.0025) but not with survival. Patients with both EGFR mutation and increased EGFR copy number had a >99.7% chance of objective response, whereas patients with KRAS mutation with or without increased EGFR copy number had a >96.5% chance of disease progression. KRAS mutation should be included as indicator of resistance in the panel of markers used to predict response to EGFR-TKIs in NSCLC.

The most common mechanism of resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is acquisition of the T790M gatekeeper mutation. Third-generation EGFR TKIs irreversibly inhibit EGFR mutants (EGFRm), especially T790M, while sparing wild-type EGFR. There are several third-generation EGFR TKIs under development, including osimertinib, CO-1686 (rociletinib), HM61713 (olmutinib), ASP8273, and EGF816. These third-generation EGFR TKIs have shown promising efficacy with favorable toxicity profiles in the management of advanced nonsmall cell lung cancer (NSCLC) with an acquired T790M mutation (EGFR). In the present review, we will discuss the evolving treatment landscape of EGFRm NSCLC. The LUX-Lung 7 study demonstrated superior progression-free survival, time-to-treatment failure, and objective response rate with afatinib versus gefitinib, but no significant overall survival improvement in TKI-naïve EGFRm NSCLC patients. In EGFRm NSCLC patients harboring T790M after treatment with first-generation or second-generation EGFR TKIs, third-generation EGFR TKIs showed robust efficacy with tolerable toxicity. The updated results of phase I studies have demonstrated encouraging activity of first-line osimertinib in patients with EGFRm NSCLC. Following progression with first-generation or second-generation EGFR TKIs, osimertinib was recently approved for the treatment of EGFR NSCLC. Encouraging early results with osimertinib have sparked interest in first-line treatment of EGFRm NSCLC, and head-to-head comparison studies of third-generation versus first-generation EGFR TKIs are being developed.

Postoperative adjuvant epidermal growth factor receptor (EGFR) inhibitor osimertinib is the standard care for stage IB-IIIB non-small-cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R mutation, following complete tumour resection, with or without prior platinum-based adjuvant chemotherapy. However, the role of EGFR tyrosine kinase inhibitors (TKIs) in this setting is debated, particularly concerning long-term curative effects versus recurrence delay. Uncertainties persist around treatment duration, harms, and effectiveness across disease stages, prior chemotherapy, or EGFR-sensitising mutation types. To assess the effectiveness and harms of adjuvant EGFR tyrosine kinase inhibitors (TKIs) in people with resected stage I to III non-small-cell lung cancer (NSCLC) harbouring an activating EGFR mutation. We searched major databases (CENTRAL, MEDLINE, Embase) to 9 December 2024, along with conference proceedings (from 2019) and clinical trial registries. We included randomised controlled trials (RCTs) reporting benefits or harms of adjuvant EGFR TKIs in adults with resected stage I-III NSCLC. Trials compared EGFR TKIs with platinum-based chemotherapy, placebo/best supportive care (BSC), or second-and/or third-generation EGFR TKIs versus first- and/or second-generation EGFR TKIs. Participants were adults with histologically confirmed stage I-III NSCLC. Three review authors independently assessed search results, resolving disagreements with a fourth author. Primary outcomes were overall survival (OS), disease-free survival (DFS), and adverse events (AEs); secondary outcomes included health-related quality of life (HRQoL), relapse risk during drug-off time, and brain relapse risk. We conducted meta-analyses using random-effects and fixed-effect models with hazard ratios (HRs) or risk ratios (RRs) and 95% confidence intervals (CIs). We assessed heterogeneity with the I² statistic. We included nine RCTs involving 2603 participants, and identified six ongoing trials. Five trials compared EGFR TKIs with placebo/BSC, and four compared them with chemotherapy. We found no trials comparing second-and/or third-generation to first- and/or second-generation EGFR TKIs. Six trials had low selection bias risk; most had unclear or high risk for detection or performance bias; and four were high risk for other biases. The certainty of the evidence (GRADE) ranged from moderate to very low, depending on the outcome. First-, second-, and/or third-generation EGFR TKIs versus placebo/BSC EGFR TKIs probably improve overall survival compared to placebo/BSC (HR 0.54, 95% CI 0.40 to 0.73; 3 studies, 864 participants; moderate-certainty evidence). TKIs may improve disease-free survival compared to placebo/BSC, but the evidence is very uncertain (HR 0.34, 95% CI 0.28 to 0.41; 5 studies, 1153 participants). We are uncertain if there is a difference between groups in serious adverse events (≥ grade 3) as the evidence is very uncertain, with wide confidence intervals spanning both potential harm and no effect (RR 2.52, 95% CI 0.44 to 14.37; 4 studies, 1134 participants). Mild-to-moderate adverse events (grades 1 and 2) may be more frequent with EGFR TKIs compared to placebo/BSC, but the evidence is very uncertain (RR 1.57, 95% CI 1.08 to 2.29; 4 studies, 1134 participants). One study assessed HRQoL, with no clinically meaningful decline compared to placebo/BSC (592 participants; moderate-certainty evidence). First-, second-, and/or third-generation EGFR TKIs versus chemotherapy Overall survival was similar between EGFR TKIs and chemotherapy (HR 0.79, 95% CI 0.52 to 1.18; 4 studies, 878 participants; moderate-certainty evidence). TKIs may have improved disease-free survival compared to chemotherapy (HR 0.54, 95% CI 0.35 to 0.83; 4 studies, 878 participants; low-certainty evidence). TKIs may have reduced serious adverse events (≥ grade 3) compared to chemotherapy (RR 0.31, 95% CI 0.18 to 0.52; 4 studies, 811 participants; low-certainty evidence). TKIs may have increased mild-to-moderate adverse events (grades 1 and 2) (RR 2.13, 95% CI 1.20 to 3.78; 4 studies, 811 participants; low-certainty evidence). Two studies assessed HRQoL, showing no clear difference compared to chemotherapy, as assessed with the Functional Assessment of Cancer Therapy-Lung instrument (2 studies, 399 participants) and the Lung Cancer Symptom Scale (2 studies, 400 participants), both with moderate-certainty evidence. Adjuvant EGFR TKIs may improve disease-free survival compared to both placebo/BSC and chemotherapy. There is moderate-certainty evidence that EGFR TKIs increase overall survival compared to placebo/BSC. However, they likely result in little to no difference in overall survival compared to chemotherapy. We could not rule out a potential survival benefit of adjuvant chemotherapy in people with EGFR-mutant NSCLC. Approximately 50% of participants experienced relapse or death within one year of stopping TKI therapy, indicating that the disease-free survival benefit may wane after withdrawal. This raises the possibility that prolonged adjuvant TKI therapy could be associated with improved long-term outcomes, although further research is needed to clarify this.

Update on afatinib-based combination regimens for the treatment of EGFR mutation-positive non-small-cell lung cancer.

Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are an effective treatment for non-small-cell lung cancer (NSCLC) harbouring EGFR mutations. The development of isolated central nervous system (CNS) metastases is a relevant clinical problem in patients who respond well to EGFR-TKIs. Methods: We present a patient with isolated progression of brain metastases during treatment of EGFRmutated NSCLC with an EGFR-TKI and review the treatment options in this setting, including the evidence for and toxicity of treatment with high-dose TKIs. Results: Oligometastatic CNS progression during TKI therapy may be treated locally. Both whole brain radiotherapy (WBRT) and stereotactic brain irradiation are well tolerated and effective in this setting. The use of high-dose pulsed TKIs is intended to increase the concentration of TKI in the brain and has been reported to be effective and without significant toxicity in case reports and small case series. These therapeutic options are illustrated in the case of a 44-year-old NSCLC patient who developed CNS progression after WBRT during second-line erlotinib and was treated locally with stereotactic radiosurgery (SRS) and, upon further CNS progression, with high-dose pulsed erlotinib. This resulted in intracerebral response; however, significant haemorrhage also occurred. Severe haemorrhage has not previously been described as a complication of high-dose pulsed erlotinib. Conclusion: Possible explanations for isolated CNS progression during TKI treatment include inadequate dosing across the blood—brain barrier and longer survival on TKIs. The efficacy and tolerability of high- dose pulsed TKIs for CNS metastases has been previously reported. None of the cases reported showed the severe haemorrhage and cerebral oedema that developed in our patient. Simultaneous anticoagulation as well as previous SRS may have predisposed our patient to haemorrhage and may prove to be relative contraindications to high-dose pulsed erlotinib. Most centres only see a few patients in this clinical situation, and co-operative efforts are needed to collect and analyse similar cases and to develop appropriate treatment strategies.