Advanced EGFR-mutant Non-small Cell Lung Cancer Research Articles

PD-L1 expression and its effect on clinical outcomes of EGFR-mutant NSCLC patients treated with EGFR-TKIs.

Objective:Epidermal growth factor receptor (EGFR) activation was reported to upregulate programmed death-ligand 1 (PD-L1) expression in lung cancer cells and subsequently contribute to immune escape, indicating its critical role in EGFR-driven lung tumors. This study characterized PD-L1 expression in patients with surgically resected EGFR-mutant non-small cell lung cancer (NSCLC). The effect of PD-L1 expression on clinical outcomes was also investigated in advanced EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKIs).Methods:In total, 73 patients with surgically resected NSCLC and EGFR mutations were identified. PD-L1 expression and CD8+ tumor-infiltrating lymphocyte (TIL) density were assessed by immunohistochemistry. A literature review of publications that assessed the predictive and prognostic value of PD-L1 expression in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs was performed.Results:Nineteen (26.0%) patients were positive for PD-L1 expression, which was significantly associated with concomitant KRAS mutation (P = 0.020) and marginally associated with higher CD8+ TILs density (P = 0.056). Positive PD-L1 expression was associated with markedly inferior overall survival (OS) in multivariate analysis (P = 0.032). The combination of PD-L1 and CD8+ TILs expression could be used to stratify the population into three groups with distinct prognoses. A meta-analysis of six publications showed that positive PD-L1 expression was not associated with OS [hazard ratio (HR) = 0.90; 95% confidence interval (CI), 0.42–1.38] or progression-free survival (HR = 1.03; 95 CI, 0.73–1.33) in advanced EGFR-mutant NSCLC patients receiving EGFR-TKIs. Conclusions:PD-L1 expression tended to correlate with CD8+ TIL expression, concomitant KRAS mutation, and poor survival in surgically resected EGFR-mutant NSCLC. PD-L1 expression was neither the predictive nor the prognostic factor in advanced EGFR-mutant NSCLC patients treated with EGFR-TKIs.

Osimertinib for the treatment of patients with EGFR mutation-positive non-small cell lung cancer

Epidermal growth factor receptor (EGFR) mutations, mostly seen in exon 19 or exon 21, are present in roughly 50% of patients with advanced non-small cell lung cancer (NSCLC) of Asian ethnicity compared with 12% in Caucasians. EGFR-mutated NSCLC patients have an increased sensitivity to EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib, gefitinib or afatinib, showing superior response, progression-free survival and overall survival rates with EGFR-TKIs than with platinum doublet chemotherapy, which makes EGFR-TKIs the standard of care in this subgroup of NSCLC patients. This has been the most important step toward molecular-guided precision therapy for NSCLC. Despite the initial rapid and durable clinical responses, acquired resistance to EGFR-TKIs has been found to eventually develop in most cases, with disease progression observed mostly within 9-12 months after treatment. One of the most important mechanisms for resistance to EGFR-TKI therapy is the substitution of threonine to methionine (T790M) on exon 20 of the EGFR gene, which occurs in 49% to 60% of patients. Osimertinib mesylate (formerly AZD-9291) is a potent third-generation TKI which irreversibly inhibits mutated EGFR alleles, including T790M. This review summarizes osimertinib's pharmacology, pharmacokinetics, safety, side effects and clinical utility in the treatment of EGFR-mutated advanced NSCLC.

A phase I trial of afatinib and bevacizumab in chemo-naïve patients with advanced non-small-cell lung cancer harboring EGFR mutations: Okayama Lung Cancer Study Group Trial 1404

ObjectiveIn advanced epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC), treatment with afatinib, a second-generation EGFR-tyrosine kinase inhibitor (TKI), confers a significant survival benefit over platinum-based chemotherapy. The first-generation EGFR-TKIs gefitinib and erlotinib in combination with bevacizumab have improved progression-free survival. We hypothesized that the combination of afatinib with bevacizumab would further improve efficacy, and conducted a phase I trial to test this hypothesis. Materials and methodsUntreated patients with advanced EGFR-mutant NSCLC were enrolled. The primary endpoint was safety. Two doses of afatinib, 40mg/day (level 0) and 30mg/day (level −1), were evaluated in combination with 15mg/kg bevacizumab every 3 weeks. Optimal dosing was determined by dose-limiting toxicity (DLT), with the concentration at which ≤4 of 12 patients experienced toxicity considered the recommended dose. ResultsNineteen patients were enrolled (level 0:5, level −1:14). Three of the five patients at level 0 experienced a DLT, which indicated that this dose was unfeasible. Three patients at level −1 developed a DLT of grade 3 non-hematological toxicity, which was soon resolved. Grade 3 or worse adverse events were experienced by all five patients at dose level 0 (diarrhea in 2, skin rash in 1, hypoxia in 1, and paronychia in 1), and by three patients at level −1 (diarrhea in 2 and anorexia in 1). Among 16 evaluable patients, 1 had a complete response, 12 had partial responses, and 0 had progressive disease. ConclusionAfatinib plus bevacizumab (level −1) was well tolerated and showed evidence of favorable disease control. This combination therapy may represent a potent therapeutic option for patients with EGFR-mutant NSCLC.

P3.01-022 Prognostic Value of Clinical, Immune and Biochemical Markers in EGFR-Mutant NSCLC Patients Treated with First-Line EGFR TKIs

Sensitizing Epidermal Growth Factor Receptor (EGFR) mutations confers a better prognosis and predicts a favorable response to treatment with EGFR tyrosine kinase inhibitors (TKIs) in patients with advanced non-small cell lung cancer (NSCLC). We sought to determine the prognostic utility of a comprehensive panel of clinical, immune and biochemical markers in EGFR-mutant advanced NSCLC patients treated with first-line EGFR TKIs.

P3.01-007 Heterogeneous Resistance Mechanisms in Rebiopsies from EGFR-Mutated NSCLC: Transformation to SCLC; FGFR3 and T790M Mutations

Patients with epidermal growth factor receptor (EGFR) gene-mutated NSCLC initially show substantial clinical benefit from EGFR Tyrosine-Kinase Inhibitors (TKIs), but will ultimately develop resistance with a median progression-free survival of 9-15 months. However, the type and timing of TKI-resistance cannot be predicted and several mechanisms may occur simultaneously/subsequently during TKI-treatment. We present a patient case with advanced non-small cell lung cancer (NSCLC) of adenocarcinoma subtype (ADC) with EGFR-mutation and Erlotinib-treated Different mechanisms of TKI-resistance were detected in tumor biopsies during treatment time. The patient was a 49 year-old, previously healthy, Caucasian male with metastatic ADC. A diagnostic biopsy from hepatic metastasis, cytology from metastatic pleural effusion at first progression during TKI-therapy and a biopsy from new liver metastasis at second progression were analyzed by histology, immunohistochemistry and targeted next-generation sequencing (NGS) of hot-spot mutations in 50 cancer-related genes (Ion AmpliSeq Cancer Hotspot Panel v.2, Ion Torrent, Thermo Fisher Scientific). CT-scans revealed tumor in the right upper lobe with mediastinal infiltration and multiple pulmonary and hepatic metastases, stage T4N2M1b. Diagnostic liver biopsy revealed ADC (mucin-producing, CK7- and TTF1-positive epithelial acinar structures), which concomitantly harbored an EGFR exon 19-mutation (p.E746_A750delELREA) and a previously unreported 2 bp microdeletion in the fibroblast growth factor receptor 3 (FGFR3; p.D785fs*31) gene. The patient received first-line Erlotinib but progressed after 7 weeks with metastatic pleural effusion, in which transformation to small cell lung cancer (SCLC) and maintenance of EGFR-mutation and FGFR3-mutation was identified. The progression was treated with standard Carboplatin-Etoposide regimen for SCLC together with Erlotinib continuation. The second progression 7 months later was a new liver-metastasis with persistence of the original EGFR- and FGFR3-mutated ADC-phenotype and additional emergence of the Erlotinib-resistant T790M EGFR-mutation. The patient rapidly deteriorated and deceased. Thus, in this advanced EGFR-mutated NSCLC rapid onset and heterogeneous mechanisms of TKI-resistance occurred at different times of metastatic disease: 1. Concomitant FGFR3-mutation prior to and during TKI-treatment as potential intrinsic resistance-mechanism; 2. Transformation to SCLC at 1st progression during TKI-therapy; 3. Acquisition of T790M EGFR-mutation at 2nd progression. This suggests a continuous variation of TKI-resistant cells’ genetic and phenotypic behavior. Therefore, re-biopsies are important to provide the current status of the disease and better define subsequent treatment options. “Liquid biopsies” may potentially help identify heterogeneous genetic resistance-mechanisms; however assessment of mechanisms such as SCLC-transformation needs tissue biopsies.

Potential influence of interleukin-6 on the therapeutic effect of gefitinib in patients with advanced non-small cell lung cancer harbouring EGFR mutations

Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are a key therapy used for patients with EGFR-mutant non-small cell lung cancer (NSCLC), some of whom do not respond well to its therapy. Cytokine including IL-6 secreted by tumour cells is postulated as a potential mechanism for the primary resistance or low sensitivity to EGFR-TKIs. Fifty-two patients with advanced EGFR-mutant NSCLC who had received gefitinib were assessed retrospectively. The protein expression of IL-6 in the tumour cells was assessed by immunostaining and judged as positive if ≥ 50 of 100 tumour cells stained positively. Of the 52 patients, 24 (46%) and 28 (54%) were defined as IL-6-postitive (group P) and IL-6-negative (group N), respectively. Group P had worse progression-free survival (PFS) than that of group N, which was retained in the multivariate analysis (hazard ratio: 2.39; 95 %CI: 1.00–5.68; p < 0.05). By contrast, the PFS after platinum-based chemotherapy did not differ between groups P and N (p = 0.47). In cell line-based model, the impact of IL-6 on the effect of EGFR-TKIs was assessed. The combination of EGFR-TKI and anti-IL-6 antibody moderately improved the sensitivity of EGFR-TKI in lung cancer cell with EGFR mutation. Interestingly, suppression of EGFR with EGFR-TKI accelerated the activation of STAT3 induced by IL-6. Taken together, tumour IL-6 levels might indicate a subpopulation of EGFR-mutant NSCLC that benefits less from gefitinib monotherapy.

Gefitinib: an “orphan” drug for non-small cell lung cancer

ABSTRACTIntroduction: The discovery of sensitizing mutations in epidermal growth factor receptor (EGFR) and the rapid development of EGFR tyrosine kinase inhibitors (TKIs) have substantially changed the management of non-small-cell lung cancer (NSCLC), leading to a tailored therapeutic approach for patients with advanced EGFR-mutant NSCLC. Gefitinib is an EGFR-directed TKI, approved by U.S. Food and Drug Administration (FDA) for the first-line treatment of patients with metastatic NSCLC whose tumors harbor specific EGFR gene mutations, as detected by an FDA-approved test.Areas covered: Here, we will focus on the approval of gefitinib as an effective EGFR-directed TKI option, describing the drug development to its currently established use. In parallel, based on the latest evidence, we will present its efficacy and its toxicity profile on selected NSCLC patients harboring specific EGFR driver mutations and we will try to reply to all open questions about gefitinib administration.Expert opinion: Gefitinib in NSCLC is an example of a more personalized approach to cancer therapeutics, where understanding of the molecular background of the cancer led to the appropriate evaluation of the drug into a selected patient population.

DNA amount comparison between cytologic and histologic samples for epithelial growth factor receptor (EGFR) testing in non-small-cell lung cancer (NSCLC) patients: a single institution experience

Background: In EGFR-mutated advanced NSCLC patients (pts) the identification of the specific mutation is mandatory to design the proper therapeutic algorithm. Abundant histologic tumour specimens are usually preferred for mutational analyses in regarding small and cytologic specimens. Unfortunately, these ones still represent the only available material for several patients. We aim to compare the DNA amount extracted from cytologic and histologic samples for EGFR tests performed in a single Institution. Methods: Positive EGFR tests performed at San Luigi Hospital from 2008 to 2015 were included. Information about pts’ characteristics, type of mutation, sample details and DNA amount for EGFR test were collected. The comparison of median DNA amount was performed using the independent T test, while the chi-square test was used for the evaluation of cytological sample ratio over time. Results: We collected 152 tests performed on 136 EGFR mutated pts. The median age was 66 yrs [range 32 – 86], 80 (58.8%) were females, 135 (99.3%) adenocarcinoma, 120 (88.2%) never or former smokers, 95 (69.8%) presented a metastatic disease at diagnosis while 41 pts presented a localized or locally advanced disease. Eighty-five pts (62.5%) harboured a mutation in exon 19; 39 (28.7%) in exon 21, 4 (2.9%) in exon 20 and 1 (0.7%) in exon 18; 7 pts (5.2%) presented a double mutation and in 3 pts (2.1%) a de novo T790M mutation was detected. Thirty-six pts performed at least one re-biopsy at EGFR TKI progression and 15 cases showed the acquired T790M mutation. In the overall population, the proportion of cytologic samples was equal to 50.7%, with a significant increase from before 2011 to 2015 (p = 0.004). Any significant difference in extracted DNA amount neither between cytologic and histologic samples (61.25 ng/ml ± 52.97 vs 71.42 ng/ml ± 75.47, p = 0.348) nor between specimens derived from bronchoscopy and thoracic biopsy (64.07 ng/ml ± 57.53 vs 52.31 ng/ml ± 42.39, p = 0.233) was detected. Conclusions: In this retrospective evaluation, no difference in DNA amount availability for EGFR analysis was detectable in cytologic or histologic specimens. This result supports previous data showing a similar sensibility in EGFR detection in both types of samples, confirming the indication to perform the less invasive procedure in specimen obtaining. Our institution progressively increased the number of cytologic samples over time, showing to get more confident with this analysis over time.

Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy.

The discovery of epidermal growth factor receptor (EGFR) mutations and subsequent demonstration of the efficacy of genotype-directed therapies with EGFR tyrosine kinase inhibitors (TKIs) marked the advent of the era of precision medicine for non-small-cell lung cancer (NSCLC). First- and second-generation EGFR TKIs, including erlotinib, gefitinib and afatinib, have consistently shown superior efficacy and better toxicity compared with first-line platinum-based chemotherapy and currently represent the standard of care for EGFR-mutated advanced NSCLC patients. However, tumors invariably develop acquired resistance to EGFR TKIs, thereby limiting the long-term efficacy of these agents. The T790M mutation in exon 20 of the EGFR gene has been identified as the most common mechanism of acquired resistance. Osimertinib is a third-generation TKI designed to target both EGFR TKI-sensitizing mutations and T790M, while sparing wild-type EGFR. Based on its pronounced clinical activity and good safety profile demonstrated in early Phase I and II trials, osimertinib received first approval in 2015 by the US FDA and in early 2016 by European Medicines Agency for the treatment of EGFR T790M mutation-positive NSCLC patients in progression after EGFR TKI therapy. Recent results from the Phase III AURA3 trial demonstrated the superiority of osimertinib over standard platinum-based doublet chemotherapy for treatment of patients with advanced EGFR T790M mutation-positive NSCLC with disease progression following first-line EGFR TKI therapy, thus definitively establishing this third-generation TKI as the standard of care in this setting. Herein, we review preclinical findings and clinical data from Phase I–III trials of osimertinib, including its efficacy in patients with central nervous system metastases. We further discuss currently available methods used to analyze T790M mutation status and the main mechanisms of resistance to osimertinib. Finally, we provide an outlook on ongoing trials with osimertinib and novel therapeutic combinations that might continue to improve the clinical outcome of EGFR-mutated NSCLC patients.

Significance of neutrophil-to-lymphocyte ratio in Western advanced EGFR-mutated non-small cell lung cancer receiving a targeted therapy.

Lung cancer is one of the leading causes of cancer-related death worldwide and, although targeted therapy with tyrosine kinase inhibitors has dramatically improved the rates of response and survival in advanced EGFR-mutated adenocarcinoma, the overall outcome remains unsatisfactory. Therefore, new prognostic factors, preferably simple, inexpensive, and easy to reproduce on a large scale, are needed. We performed a retrospective analysis of our database including 63 western Caucasian patients with advanced EGFR-mutated lung adenocarcinoma and receiving gefitinib, erlotinib, or afatinib as first- or second-line therapy. Several studies demonstrated a strong link between elevated neutrophil-to-lymphocyte ratio (NLR) and poor prognosis both in early and advanced stages of non-small-cell lung cancer (NSCLC). From January 2011 to December 2015, 63 consecutive elegible patients with advanced EGFR-mutated NSCLC were included in this analysis from 5 institutions. The NLR was derived from the absolute neutrophil and the absolute lymphocyte counts of a full blood count and the cutoff value was determined according to the mean NLR level. Despite the small sample analyzed, we found that NLR has a prognostic role for progression-free survival (PFS) and overall survival (OS), reaching a statistically significant difference with a better PFS and OS in the lower NLR group. Pretreatment NLR seems to represent a reliable, simple, and easy to reproduce laboratory tool to predict outcome and response to cancer therapies in this setting of Western Caucasian patients with EGFR-mutated NSCLC.

Gefitinib in combination with pemetrexed in patients with advanced non-small cell lung cancer harboring EGFR mutations: is there any difference in acquired resistance mechanism between gefitinib monotherapy and the combination treatment?

Somatic mutations within the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) are the most reliable predictors of efficacy of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in patients with non-small cell lung cancer (NSCLC). In randomized phase III trials, EGFR-TKIs in patients with advanced EGFR mutant NSCLC were associated with longer progression-free survival (PFS) and higher radiographic response rates than the standard first-line platinum-based chemotherapy (1-7). Based on these results, three types of EGFR-TKIs, gefitinib, erlotinib and afatinib have been approved for treatment of advanced EGFR-mutant NSCLC as a first-line setting. Despite an initially marked response, almost all patients treated with EGFR-TKIs eventually acquire resistance to these drugs, with an average PFS of around 1 year. To improve these results, several combinations of EGFR-TKIs and other drugs, such as targeted drugs and chemotherapy, have been developed.

Osimertinib for EGFR T790M positive non-small cell lung cancer—making it happen, turning good idea into great results

Epidermal growth factor receptor (EGFR) activating mutations account for approximately 50% of non-small cell lung cancer (NSCLC) in Asian population and about 20% in Caucasians (1-4). Several famous phase III clinical trials have demonstrated the superior efficacy and quality of life of the first or second generation EGFR tyrosine kinase inhibitors (TKIs) including gefitinib, erlotinib, icotinib and afatinib in patients with EGFR-mutant advanced NSCLC when compared to first-line standard platinum-based chemotherapy (5-8). To date, EGFR-TKIs have been extensively accepted for the first choice for patients with untreated advanced NSCLC and EGFR activating mutation. Despite the substantial benefit of EGFR-TKIs, the vast majority of patients would experience disease relapse so called acquired resistance within about 1–2 years (2,3,9). Previously, a large number of studies have revealed the mechanism of acquired resistance against first-generation EGFR-TKIs and they can be summarized into four parts: (I) second mutations in EGFR; (II) histological transformation; (III) bypass signaling pathway activation and (IV) other mechanisms. Among them, the most common mechanism was the gatekeeper mutation involving the substitution of threonine at position 790 with methionine of EGFR exon 20, known as EGFR T790M mutation (10).

Prognostic value of neutrophil-to-lymphocyte ratio in advanced EGFR-mutated non-small cell lung cancer (NSCLC) treated with a tyrosine-kinase inhibitors: A retrospective analysis in a series of western patients.

e23045 Background: Several studies demonstrated that an elevated neutrophil-to-lymphocyte ratio (NLR) correlate with a poor prognosis both in early and advanced stage of NSCLC. The aim of this retrospective analysis was to investigate the correlation between NLR and prognosis in caucasian patients diagnosed with advanced EGFR-mutated NSCLC and treated with tyrosine kinase inhibitors (TKIs). Methods: A retrospective database was used to identify consecutive patients diagnosed with advanced EGFR-mutated NSCLC and treated with TKIs. From January 2011 to December 2015, 63 patients from five Institutions were enclosed in our series. NLR was derived from the absolute neutrophil and the absolute lymphocyte counts of a full blood count.Survival curves were calculated with Kaplan-Meier method and data were compared by log-rank test. Prognostic significance of NLR were assessed using a Cox regression analysis. Results: Sixty-three eligible patients were stratified according to the mean pretreatment NLR value (3.57 ± 2.42). The chosen cut-off for NLR was 3.5. Forty patients had NLR &lt; 3.5 while 23 patients had a value of NLR &gt; 3.5.A statistical significant difference, both in PFS and OS, was found in the NLR &lt; 3.5 group compared with the higher NLR group (PFS: p &lt; 0.01, OS: p &lt; 0.05). According to univariate analysis, histological type (adenocarcinoma vs non-adenocarcinoma) and NLR value correlate significantly with PFS and OS. In Cox multivariate analysis, only NLR ³ 3.5 resulted significantly associated as independent prognostic factor for worse PFS (HR 2.275, 95% CI 1.257-4.116, p &lt; 0.01) and OS (HR 2.699, 95% CI 1.187-6.137, p &lt; 0.05). Conclusions: Pre-treatment NLR seems to represent a reliable, simple, and easy to reproduce, laboratory tool to predict survival and outcome to therapies in western caucasian EGFR-mutated NSCLC patients. Further prospective trials are needed to definitively confirm its prognostic and predictive role.

ΔCT value of amplified refractory mutation system (ARMS) to predict efficacy of EGFR-TKIs in non-small cell lung cancer: A multicenter retrospective study.

e20573 Background: This multi-center retrospective study was to determine whether the ΔCt value of Amplified Refractory Mutation System (ARMS) in EGFR mutated detection in tumors predicts the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small-cell lung cancer (NSCLC). Methods: A total of 108 NSCLC patients harbored an exon 19 deletion (19Del) or exon 21 L858R mutation detected by ARMS were enrolled. We identified patients with ΔCt&lt;1(Group L) harbored a high proportion of EGFR mutation but the patients with ΔCt≥1 (Group H) harbored a low proportion of EGFR mutation in the tumor sample. The progression-free survival (PFS), objective response rates (ORRs) and overall survival (OS) between the groups were analyzed. Results: In the 108 patients we enrolled, 63 were in group L and 45 were in group H. Patients’ demographics and clinical characteristics including age, sex, smoking history, pathology, mutation sites, TNM stage, line of TKIs therapy were not significantly difference between group L and group H. The Median PFS was 331 days (95%CI: 311.8 to 350.2) in group L and 206 days (95%CI, 157.2 to 254.8) in group H and the difference showed statistically significant (P &lt; 0.001). Moreover, the ORRs in group L was significant higher than the group H (60.0% vs 34.9%, P = 0.011). The median OS was 744 days (95%CI, 635.5 to 852.5) in group L and 596 days in group H (95%CI, 491.7 to 700.0) but showed not statistically significant ( P = 0.098). Conclusions: ΔCt value of ARMS in EGFR mutated detection could be an efficacy predictor for EGFR-TKIs treatment in advanced EGFR-mutant NSCLC.

Osimertinib benefit inEGFR-mutant NSCLC patients withT790M-mutation detected by circulating tumour DNA

Approximately 50% of epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) patients treated with EGFR tyrosine kinase inhibitors (TKIs) will acquire resistance by the T790M mutation. Osimertinib is the standard of care in this situation. The present study assesses the efficacy of osimertinib when T790M status is determined in circulating cell-free tumour DNA (ctDNA) from blood samples in progressing advanced EGFR-mutant NSCLC patients. ctDNA T790M mutational status was assessed by Inivata InVision™ (eTAm-Seq™) assay in 48 EGFR-mutant advanced NSCLC patients with acquired resistance to EGFR TKIs without a tissue biopsy between April 2015 and April 2016. Progressing T790M-positive NSCLC patients received osimertinib (80 mg daily). The objectives were to assess the response rate to osimertinib according to Response Evaluation Criteria in Solid Tumours (RECIST) 1.1, the progression-free survival (PFS) on osimertinib, and the percentage of T790M positive in ctDNA. The ctDNA T790M mutation was detected in 50% of NSCLC patients. Among assessable patients, osimertinib gave a partial response rate of 62.5% and a stable disease rate of 37.5%. All responses were confirmed responses. After median follow up of 8 months, median PFS by RECIST criteria was not achieved (95% CI: 4-NA), with 6- and 12-months PFS of 66.7% and 52%, respectively. ctDNA from liquid biopsy can be used as a surrogate marker for T790M in tumour tissue.

P3.02b-095 Tracing Spatiotemporal T790M Heterogeneity in Patients with EGFR-Mutant Advanced NSCLC after Acquired Resistance to EGFR TKIs: Topic: EGFR RES

With the marketing of osimertinib, epidermal growth factor receptor (EGFR) T790M mutation has become a clinically significant biomarker for advanced EGFR-mutant non-small-cell lung cancer (NSCLC) after acquired resistance to previous EGFR TKIs. However, T790M status might vary spatiotemporally and consequently hinder the initiation and clinical efficacy of third generation EGFR TKIs. Till now, the spatiotemporal traces of T790M under treatment pressure have not been fully elucidated. We retrospectively reviewed T790M status and clinical courses of 93 patients who underwent multiple (≥2) rebiopsies after acquired resistance to first or second generation EGFR TKIs from 2010 to 2015 in Guangdong General Hospital. Patients underwent synchronous rebiopsies at the same lesion or paired tissue and plasma rebiopsies were enrolled to evaluate the spatial T790M heterogeneity. Patients received heterochronous rebiopsies at the same lesion or different lesions were enrolled to evaluate the temporal and spatiotemporal T790M heterogeneity respectively.Tissue EGFR detection was performed by SNAPSHOT or Amplification Refractory Mutation System (ARMS). Plasma EGFR was detected by ARMS. A total of 99 evaluations were performed with 6 of 93 enrolled patients underwent both synchronous and heterochronous rebiopsies. Among 20 patients who underwent synchronous rebiopsies at the same lesion, 13 revealed T790M heterogeneity. Among 17 patients who had paired tissue and plasma rebiopsies, 8 showed T790M heterogeneity. Spatial T790M heterogeneity ratio was 57% (21/37) in general. 33% (10/30) patients who received heterochronous rebiopsies at the same lesion revealed temporal T790M heterogeneity. Spatiotemporal T790M heterogeneity was observed in 53% (17/32) of patients who received heterochronous multiple sites rebiopsies. Of abovementioned patients with heterochronous T790M heterogeneity, T790M status in 67% (18/27) switched from negative to positive after chemotherapy or continuation of EGFR TKIs and in 33% (9/27) switched from positive to negative after chemotherapy or combined regimens of chemotherapy and EGFR TKIs. T790M status could vary spatiotemporally at a ratio of 33-57% in patients with acquired resistance to previous EGFR TKIs. Repeated rebiopsies both at the same lesion and various lesions might be valued particularly in T790M-negative cases in this subset of patients.

P3.02b-052 Afatinib with or without Cetuximab for First-Line Treatment of EGFR-Mutant NSCLC: Interim Safety Results of SWOG S1403: Topic: EGFR Clinical

Afatinib is used as first-line therapy for EGFR-mutant non-small cell lung cancer (NSCLC), however resistance invariably develops. To attempt to delay resistance and improve survival, we are conducting a randomized Phase II/III trial of afatinib plus cetuximab versus afatinib alone in treatment-naïve patients with advanced EGFR-mutant NSCLC (NCT02438722). Previously untreated patients with EGFR exon 19 deletion or L858R point mutation are randomized to afatinib 40mg PO daily plus cetuximab 500mg/m2 IV every 2 weeks (afat/cetux) or afatinib 40mg PO daily (afat). Dose reductions are performed for grade 3-4 or intolerable or medically concerning grade 2 adverse events (AEs) per CTCAE v4.0. The Phase II primary endpoint is progression-free survival and the Phase III primary endpoint is overall survival. Here we review the safety data after enrollment of the first 53 patients. 53 patients were registered as of June 30, 2016, and safety has been assessed in 47 (23 treated with afat/cetux and 24 with afat, see Table). Grade 1-2 rash occurred in 71% of patients receiving afat/cetux and 63% of patients on afat. Grade 3 rash was noted in 22% of patients on afat/cetux. Fatigue was more common in the combination arm; all occurrences were grade 1-2. Grade 1-2 diarrhea and other gastrointestinal AEs were comparable between the two arms. There were similar numbers of dose reductions for AEs on each arm. Three patients discontinued treatment due to AEs: 2 on the afat/cetux arm due to hyperglycemia and accumulated side effects and 1 on the afat arm due to weight loss and diarrhea. In this randomized trial of afat/cetux versus afat, treatment was tolerable in both arms of the study. Skin toxicity appears to be worse with the combination however other AEs are similar between the two groups. Enrollment to this trial is ongoing.

P3.02b-069 To Assess Efficacy of First Line TKIs in EGFR Mutant Advanced NSCLC Patients from North India: Topic: EGFR Clinical

The reversible EGFR tyrosine kinase inhibitors gefitinib and erlotinib are approved for first-line treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC). However, here is paucity of data on their efficacy from the Indian subcontinent. This is a retrospective analysis including 43 patients. These patients were treated at a tertiary care center in north India. Advanced NSCLC patients (stage IV) having sensitive EGFR mutation who were treated with gefitinib (250 mg per day) or erlotinib (150 mg per day) were analyzed for their outcome. Subgroup analysis by EGFR mutation (18, 19, 20, 21), sex and status according to brain metastasis was also done using SPSS. 43 patients with stage IV non-squamous NSCLC with EGFR sensitive mutation were treated with first line TKI. There were 16 male and 27 female patients with mean age of 62.5 years (ranging from 43 to 85 years). Mean PFS for all the patients on first line TKI was 11.63 months Mean PFS for male patients was 9.93 months and for female patients it was 12.7 month. There were 26 patients with exon 19 deletions and 16 with exon 21 mutation and 1 with exon 18 mutation. Mean PFS in patients with exon 19 deletions was 11.11 months and 10.44 months in patients with exon 21 mutation. Mean PFS in patients on erlotinib was 12.27 months (CI 6.2-18.3) and 11.4 months in patients on gefitinib. Twelve patients (27.9%) out of 43 had brain metastases. PFS of these 12 patients was 10.33 months and 12.08 months for patients without brain metastases. Erlotinib and gefitinib significantly improves PFS in patients with sensitive EGFR mutations. PFS is better in female patients, exon 19 mutation/deletion and without brain metastases in North Indian population.

The association between clinical prognostic factors and epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) efficacy in advanced non-small-cell lung cancer patients: a retrospective assessment of 94 cases with EGFR mutations.

ObjectiveThis study aimed to examine the association of clinical prognostic factors with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) efficacy in advanced non-small-cell lung cancer (NSCLC) patients.MethodsThe demographic and clinical characteristics of 94 patients with stage IV NSCLC were retrospectively reviewed, and the association between clinical factors and EGFR-TKIs efficacy was evaluated.ResultsOf the 94 stage IV NSCLC patients enrolled in this study, a 74.5% objective response rate (ORR) and 97.9% disease control rate (DCR) were observed for EGFR-TKIs treatment, and a higher ORR was seen in patients with 0 and 1 ECOG scores than those with 2 or greater scores (P = 0.049). The subjects had a median PFS of 11 months and a median OS of 31 months after EGFR-TKIs treatment. ECOG score and timing of targeted therapy were factors affecting PFS, and ECOG score, smoking status and brain metastasis were factors affecting OS. In addition, ECOG score was an independent prognostic factor for PFS in stage IV NSCLC patients, and the patients with EGFR 19del mutation had a longer PFS than those with exon 21 L855R mutation (P = 0.003), while ECOG score and brain metastasis were independent prognostic factors for OS.ConclusionsThe results of this study demonstrate that EGFR-TKI therapy results in survival benefits for EGFR-mutant advanced NSCLC patients, regardless of gender, smoking history, pathologic type, type of EGFR mutations, brain metastasis and timing of targeted therapy. ECOG score is an independent prognostic factor for PFS, and ECOG score and brain metastasis are independent prognostic factors for OS in advanced NSCLC patients.

EGFR kinase inhibitors and gastric acid suppressants in EGFR-mutant NSCLC: a retrospective database analysis of potential drug interaction.

BackgroundErlotinib and gefitinib are weak base drugs whose absorption and clinical efficacy may be impaired by concomitant gastric acid suppressive (AS) therapy, yet proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2As) are widely indicated in non-small cell lung cancer (NSCLC) patients for the prevention and treatment of erlotinib-induced gastrointestinal injury and corticosteroid-associated gastric irritation. We assessed the clinical relevance of this potential drug-drug interaction (DDI) in a retrospective cohort of EGFR-mutant NSCLC patients.ResultsThe AS usage rate was 35%. In the overall cohort, AS users did not experience poorer OS (HR: 1.47, 95% CI: 0.92 – 2.35, P = 0.10; median, 11.4 versus 17.5 months) or PFS (HR = 1.37, 95% CI: 0.89 – 2.12, P = 0.16; median, 7.6 versus 8.7 months) compared with non-users in multivariate Cox regression analysis. However, subgroup analyses indicated that AS usage was associated with significantly poorer OS and PFS in patients who had fewer or milder comorbidities (Charlson comorbidity index ≤ 2), those with Karnofsky performance status < 90, and never-smokers.Materials and MethodsA retrospective database analysis of 157 patients given erlotinib or gefitinib for EGFR-mutant advanced NSCLC from two institutions was conducted. Patients were classified as AS-users if the periods of AS and anti-EGFR therapy overlapped by ≥ 30%. Overall survival (OS) and progression-free survival (PFS) were assessed according to AS usage.ConclusionsConcomitant AS therapy did not have an adverse impact on OS and/or PFS in the overall cohort. Our subgroup findings should be regarded exploratory and require replication in a large prospective cohort.