Lung Cancer Harboring Epidermal Growth Factor Receptor Mutations Research Articles

Abstract C025: Trial in progress: First-in-human study of BBT-207 in advanced non-small cell lung cancer harboring EGFR mutation after treatment with EGFR TKI

Abstract Background: There is a high unmet need for an effective therapy for the treatment of non-small cell lung cancer (NSCLC) following osimertinib or other 3rd generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) failure, especially when resistance is driven by the occurrence of the C797S mutation. BBT-207 is a fourth-generation EGFR inhibitor. Preclinically BBT-207 has shown activity against treatment-emergent complex EGFR mutations containing T790M and/or C797S as well as drug-naïve mutants providing a possibility to overcome resistance to prior TKIs. Activity to intracranial lesions is also anticipated from animal models. Methods: Study BBT207-ONC-001 is an open-label, phase 1/2 study evaluating safety, tolerability, pharmacokinetic profile, pharmacodynamic characterization, and preliminary antitumor activity of BBT-207 monotherapy in approximately 92 patients with EGFR-mutant NSCLC. It consists of 3 phases: Phase 1a (dose escalation), phase 1b (recommended phase 2 dose selection), and phase 2 (dose expansion). Key eligibility criteria include patients ≥18 years of age with advanced stage and refractory NSCLC with an activating EGFR mutation, documented partial response, complete response, or durable stable disease after treatment of an EGFR TKI, and previous treatment with all standard therapeutic options and at least one third-generation EGFR TKI. There is no limit on the number of previous treatments received. Phase 1a requires confirmation that the tumor harbors a classical EGFR mutation (19Del or L858R), and phase 1b and phase 2 require confirmation that the tumor or the blood harbors complex EGFR mutations containing C797S. Patients with asymptomatic brain metastases who are on stable dose of corticosteroid are eligible. Primary endpoints are to determine recommended dose range (RDR) which is defined between the minimal reproducibly active dose, and the maximum tolerated dose or maximum administered dose and to characterize the overall safety and tolerability of BBT-207 (phase 1a); to determine the recommended phase 2 dose (phase 1b); to evaluate preliminary antitumor activity with objective response rate (phase 2). Phase 1a dose escalation will be guided by Bayesian logistic regression model. The safety monitoring committee will determine RDR and two recommended dose levels (RDs) within the RDR to be explored in phase 1b. In phase 1b, up to 20 patients will be randomized to each of the two RDs. At the end of phase 1b, a futility test will be performed in the dose level to be treated with the RP2D using Bayesian analysis. Phase 2 will be a non-randomized, open-label phase with up to 20 patients. Patients may receive treatment until disease progression or unacceptable toxicity. Treatment continuation beyond progression will be allowed if potential benefits are justified. Investigational new drug application was cleared by the U.S. FDA. Patient enrollment will begin in approximately August 2023 in the U.S. and Republic of Korea. Clinical trial information: NCT05920135. Citation Format: NaEun Jeon, Alexander Spira, Douglas Orr, Lyudmila Bazhenova, Misako Nagasaka, Jin Seok Ahn, Dong-Wan Kim, Yu Jung Kim, Jimin Cho, Agnes Jung, Eunsoo Jung, Chul-Won Kim, Taiguang Jin, Yong-Hee Lee, Sang-Yoon Lee. Trial in progress: First-in-human study of BBT-207 in advanced non-small cell lung cancer harboring EGFR mutation after treatment with EGFR TKI [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C025.

A randomized phase II study of afatinib alone or combined with bevacizumab for treating chemo-naïve patients with non-small cell lung cancer harboring EGFR mutations

BackgroundAdding bevacizumab to first-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) prolonged the progression-free survival (PFS), but limited data are available for second-generation EGFR-TKIs. AfaBev-CS is a randomized, phase II trial comparing afatinib plus bevacizumab and afatinib alone as first-line treatment. Patients and methodsUntreated patients with non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations (Del19 or L858R) were enrolled and randomly assigned to receive either afatinib (30 mg) plus bevacizumab (AfaBev group) or afatinib (40 mg) monotherapy (Afa group). The primary endpoint was PFS. The power was >50% under the assumptions of a median PFS of 12 months for the Afa group and hazard ratio (HR) of 0.6 for the AfaBev group. ResultsBetween August 2017 and September 2019, 100 patients were enrolled. There was no significant difference in PFS between the groups. The median PFS was 16.3 and 16.1 months for the AfaBev and Afa groups, respectively, with an HR of 0.865 (95% confidence interval [CI], 0.539 to 1.388; p = 0.55). In terms of overall survival, there was no significant difference between the groups (HR, 0.84; 95% CI, 0.39 to 1.83; p = 0.67). The overall response rate was 82.6% and 76.6% in the AfaBev and Afa groups, respectively (p = 0.61). Grade ≥ 3 diarrhea, hypertension, acneiform rash, paronychia, and stomatitis were frequently observed in the AfaBev group. ConclusionsThis study failed to show efficacy of AfaBev over Afa for improving PFS in untreated patients with EGFR-mutated NSCLC.

Prospective exosome-focused translational research for afatinib (EXTRA) study of patients with nonsmall cell lung cancer harboring EGFR mutation: an observational clinical study.

The exosome-focused translational research for afatinib (EXTRA) study is the first trial to identify novel predictive biomarkers for longer treatment efficacy of afatinib in patients with epidermal growth factor receptor (EGFR) mutation-positive nonsmall cell lung cancer (NSCLC) via a comprehensive association study using genomic, proteomic, epigenomic, and metabolomic analyses. We report details of the clinical portion prior to omics analyses. A prospective, single-arm, observational study was conducted using afatinib 40 mg/day as an initial dose in untreated patients with EGFR mutation-positive NSCLC. Dose reduction to 20 mg every other day was allowed. Progression-free survival (PFS), overall survival (OS), and adverse events (AEs) were evaluated. A total of 103 patients (median age 70 years, range 42-88 years) were enrolled from 21 institutions in Japan between February 2017 and March 2018. After a median follow-up of 35.0 months, 21% remained on afatinib treatment, whereas 9% had discontinued treatment because of AEs. The median PFS was 18.4 months, with a 3-year PFS rate of 23.3%. The median afatinib treatment duration in patients with final doses of 40 (n = 27), 30 (n = 23), and 20 mg/day (n = 35), and 20 mg every other day (n = 18) were 13.4, 15.4, 18.8, and 18.3 months, respectively. The median OS was not reached, with a 3-year OS rate of 58.5%. The median OS in patients who did (n = 25) and did not (n = 78) receive osimertinib during the entire course of treatment were 42.4 months and not reached, respectively (p = 0.654). As the largest prospective study in Japan, this study confirmed favorable OS following first-line afatinib in patients with EGFR mutation-positive NSCLC in a real-world setting. Further analysis of the EXTRA study is expected to identify novel predictive biomarkers for afatinib. UMIN-CTR identifier (UMIN000024935, https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_his_list.cgi?recptno=R000028688.

Sequential treatment in advanced non-small cell lung cancer harboring EGFR mutations.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are standard treatments for advanced EGFR-mutated non-small cell lung cancer (NSCLC) patients. Osimertinib is an effective therapy for NSCLC patients with acquired resistance due to T790M mutation after first- and second-generation EGFR-TKI treatment. This study aimed to analyze the clinical outcomes of sequential therapy following first-line EGFR-TKIs and the predictive factors of an acquired T790M mutation. Between January 2014 and December 2018, data from 2190 advanced NSCLC patients with common EGFR mutations (exon 19 deletion and L858R) receiving first- and second-generation EGFR-TKIs in Linkou, Kaohsiung, Chiayi and Keelung Chang Gung Memorial Hospitals were retrospectively retrieved and analyzed. Until August 2021, among 1943 patients who experienced progressive disease, 526 underwent T790M mutation tests, and their T790M-positive rate was 53.6%. Exon 19 deletion mutation and progression-free survival (PFS) of >12 months were positively associated with secondary T790M mutation. Different first-line first- and second-generation EGFR-TKI therapies did not affect the appearance of acquired T790M mutations. The median overall survival (OS) was 58.3 [95% confidence interval (CI): 49.0-67.5] months among the patients with T790M mutation who received second-line osimertinib therapy compared with 31.0 (95% CI: 27.5-34.5) months among the patients without T790M mutation who received chemotherapy alone. The multivariate analysis showed that a poor performance status (score: >2), nonadenocarcinoma histology, stage IV cancer, liver metastasis, brain metastasis, PFS while on first-line EGFR-TKIs, and subsequent chemotherapy without third-generation EGFR-TKIs were significant independent unfavorable prognostic factors for OS. This study demonstrated the efficacy of first-line EGFR-TKIs and sequential osimertinib therapy. The results of our study suggest that T790M mutation tests are important for the use of subsequent osimertinib, which yielded favorable survival outcomes.

Sequential treatment of afatinib and osimertinib or other regimens in patients with advanced non-small-cell lung cancer harboring EGFR mutations: Results from a real-world study in South Korea.

ObjectivesThe optimal sequence for the administration of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) for treating non‐small cell lung cancer (NSCLC) is still unclear. This study aimed to evaluate the efficacy of sequential afatinib and osimertinib treatment in patients with NSCLC harboring EGFR mutations.Materials and methodsElectronic records of patients with EGFR‐mutated NSCLC, who were administered afatinib and osimertinib (group A) or other chemotherapy (group B) between October 2014 and 2019, across 16 hospitals in South Korea were reviewed. The primary outcome, time on treatment (TOT), secondary outcome, and overall survival (OS) were estimated using the Kaplan–Meier method and log‐rank test. Multivariate analyses were performed using the Cox proportional hazards model.ResultsOf the 737 patients who received frontline afatinib treatment, 324 with complete records were selected (group A: 126, group B: 198). All patients in group A were T790M positive after afatinib, while patients in group B were all negative or unknown. The median TOT was 35.4 months (95% confidence interval [CI]: 27.7−45.6) in group A and 20.8 months (95% CI: 19.4−24.0) in group B. The median TOT with afatinib was 13.0 months (95% CI: 12.0−13.9) overall and 15.7 months (95% CI: 13.9−17.3) in group A. The 2‐ and 3‐year survival rates were 86.0 and 69.3% in group A and 75.9 and 55.3% in group B, respectively.ConclusionSequential afatinib and osimertinib treatment resulted in better survival rates than treatment with afatinib followed by other chemotherapies.

Adjuvant gefitinib versus cisplatin/vinorelbine in Japanese patients with completely resected, EGFR-mutated, stage II-III non-small cell lung cancer (IMPACT, WJOG6410L): A randomized phase 3 trial.

8501 Background: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor is a standard of care for EGFR mutation-positive, untreated metastatic non-small cell lung cancer (NSCLC). However, the efficacy and safety of adjuvant gefitinib for patients with completely resected lung cancer harboring EGFR mutation over cisplatin-based adjuvant chemotherapy were not known in 2011 when this study was initiated. Methods: From September 2011 to December 2015, we randomly assigned 234 patients with completely resected, EGFR mutation-positive (exon 19 deletion or L858R), stage II–III NSCLC to receive either gefitinib (250 mg, once daily) for 24 months or cisplatin (80 mg/m2 on day 1) plus vinorelbine (25 mg/m2 on days 1 and 8) (cis/vin) every 3 weeks for four cycles. The primary endpoint was disease-free survival (DFS) according to a central review in the intent-to-treat (ITT) population. Results: Two patients in the gefitinib arm withdrew consent and were excluded from the ITT population. No treatment-related deaths were seen in the gefitinib arm, but three treatment-related deaths were reported in the cis/vin arm. Median duration of follow-up was 71 months. Median DFS was numerically longer in the gefitinib arm (36 months) than in the cis/vin arm (25.2 months). However, Kaplan-Meier curves began to overlap around 5 years after surgery, and no significant difference in DFS was seen, with a hazard ratio (HR) of 0.92 (95% confidence interval (CI), 0.67–1.28; P = 0.63). Overall survival was also not significantly different (median not reached in either arm). Five-year survival rates for gefitinib and cis/vin arms were 78.0% and 74.6%, respectively, with an HR for death of 1.03; 95%CI, 0.65–1.65; P = 0.89. Exploratory subset analysis revealed that patients ³70 years old in the gefitinib arm (n = 19/27 with G to cis/vin) survived longer than those in the cis/vin arm (HR 0.31; 95%CI, 0.10–0.98; P = 0.046). Conclusions: Adjuvant gefitinib appeared to prevent early relapse, but did not significantly prolong DFS or OS in patients with completely resected stage II–III, EGFR-mutated NSCLC. The apparent non-inferiority of DFS/OS may justify the use of adjuvant gefitinib in selected subset of patients, especially those deemed unsuitable for cis/vin adjuvant therapy. Clinical trial information: UMIN000006252.

N-glycosylated GPNMB ligand independently activates mutated EGFR signaling and promotes metastasis in NSCLC.

Lung cancer is the leading cause of cancer‐related death worldwide. As well as the identified role of epidermal growth factor receptor (EGFR), its association with driver mutations has improved the therapeutics for patients with lung cancer harboring EGFR mutations. These patients usually display shorter overall survival and a higher tendency to develop distant metastasis compared with those carrying the wild‐type EGFR. Nevertheless, the way to control mutated EGFR signaling remains unclear. Here, we performed membrane proteomic analysis to determine potential components that may act with EGFR mutations to promote lung cancer malignancy. Expression of transmembrane glycoprotein non‐metastatic melanoma protein B (GPNMB) was positively correlated with the status of mutated EGFR in non‐small‐cell lung cancer (NSCLC). This protein was not only overexpressed but also highly glycosylated in EGFR‐mutated, especially EGFR‐L858R mutated, NSCLC cells. Further examination showed that GPNMB could activate mutated EGFR without ligand stimulation and could bind to the C‐terminus of EGFR, assist phosphorylation at Y845, turn on downstream STAT3 signaling, and promote cancer metastasis. Moreover, we also found that Asn134 (N134) glycosylation of GPNMB played a crucial role in this ligand‐independent regulation. Depleting N134‐glycosylation on GPNMB could dramatically inhibit binding of GPNMB to mutated EGFR, blocking its downstream signaling, and ultimately inhibiting cancer metastasis in NSCLC. Clarifying the role of N‐glycosylated GPNMB in regulating the ligand‐independent activation of mutated EGFR may soon give new insight into the development of novel therapeutics for NSCLC.

P76.68 The Impact of Eligibility for Anti-Angiogenic Treatment to the Prognosis of Patients with Non-Small Cell Lung Cancer Harboring EGFR Mutations

Previous studies described the efficacy of erlotinib plus angiogenesis inhibitors (bevacizumab/ramucirumab) combination therapy compared with erlotinib monotherapy in epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC), regardless of EGFR activating mutation subtype. However, the impact of angiogenesis inhibitors’ eligibility criteria to progression free survival (PFS) and overall survival (OS) is still unclear. Hence, we evaluated the impact of angiogenesis inhibitors’ criteria in patients with NSCLC harboring EGFR activating mutation. We retrospectively collected data of patients with EGFR mutation positive NSCLC who were treated with EGFR tyrosine kinase inhibitor (EGFR-TKI) monotherapy at Shizuoka Cancer Center between 2002 and 2019. Patients whose performance status (PS) was over 3, and those with symptomatic brain metastasis, were excluded from this study. Angiogenesis inhibitors ineligibility was defined as having at least one following conditions; 1) a history of bloody sputum or an exposure of tumor in bronchus, 2) radiologically identified major vessel invasion, 3) a history of cardiovascular disease and 4) history of chemoradiotherapy prior to EGFR-TKI treatment. They were divided into two groups, angiogenesis inhibitors eligible group (AI fit group) and ineligible group (unfit group). A total of 452 patients with NSCLC harboring EGFR activating mutation were included in this study. Among 452 patients, 207 patients had L858R mutation, and 245 patients had exon19 deletion. Median age of all patients was 71 years old (range 31-92), 35.0% were male, 43.1% had history of smoking, and majority of the patients were treated with gefitinib or erlotinib as a first EGFR-TKI (60.3% and 18.8%). AI fit group included 339 patients; 152 patients (44.8%) had L858R and 187 patients (55.2%) had exon19 deletion. In baseline characteristics, patients with PS 2 were more frequently observed in AI unfit group compared with AI fit group. The median PFS of AI fit and unfit group were 12.9 month and 9.6 months (HR 0.72, 95%CI 0.57-0.92, p=0.007), and multivariate analysis indicated PS 2 and AI unfit were associated with shorter PFS. Also, OS was significantly longer in AI fit groups than in unfit group; median OS were 33.0 months and 18.5months, respectively (HR 0.58, 95%CI 0.45-0.74, p<0.001). Multivariate analysis indicated PS 2, AI unfit, EGFR exon 19 deletion, and age ≥75 as significant prognostic factors. Out of four AI eligibility definitions, bloody sputum or exposure of tumor in bronchus were significantly associated with poor PFS (HR 1.43, 95%CI 1.07-1.98 p=0.017) and OS (HR 1.67, 95%CI 1.18-2.36 p=0.004). There was no significant difference in PFS between EGFR mutation subtypes in AI fit group; median PFS were 11.5months in L858R mutation and 13.8months in exon19 deletion (HR 0.85, 95%CI 0.67-1.07 p=0.17). In EGFR mutation positive NSCLC patients, the eligibility of AI was associated with longer PFS and OS, and resulted in insignificance of PFS between L858R and exon19 deletion group. Since these selection bias may have affected previous clinical trials data showing the efficacy of AI plus EGFR-TKI, the results of clinical trials should be carefully considered of its benefits.

Phase I study of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer harboring EGFR mutations.

BackgroundAfatinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Combination therapies with first-generation EGFR-TKIs and bevacizumab have been reported to prolong progression-free survival (PFS). However, there are few data on the combination of afatinib and bevacizumab.MethodsIn this phase I trial, we evaluated the safety of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study consisted of two cohorts. In the dose-finding cohort, enrolled patients were treated with afatinib at a dose of 20, 30, or 40 mg/day (days 1–21) plus bevacizumab at a dose of 15 mg/kg (day 1) in 21-day cycles. This cohort was performed according to a 3 + 3 manner. In the expansion cohort, enrolled patients received the recommended dose (RD) based on the results of the dose-finding cohort. The serum trough concentration of afatinib was determined at the steady state.ResultsSeventeen patients were enrolled in this study (6 patients in the dose-finding cohort and 11 patients in the expansion cohort). There were no dose-limiting toxicities (DLTs) with afatinib at a dose of 30 mg/day. With afatinib at a dose of 40 mg/day, two of two patients experienced DLTs (grade 3 diarrhea) in cycle 1. With these results, afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg was determined as the RD. Eleven patients in the expansion cohort were treated with the RD. Common treatment-related adverse events (AEs) with the RD were diarrhea (79%), rash (71%), perionychia (64%), and stomatitis (50%). Grade 3 AEs with the RD were diarrhea (7%), perionychia (7%), and hypertension (7%). There were no grade 4/5 AEs or cases of interstitial lung disease. Dose-proportional increases in serum afatinib trough concentrations at steady state were not observed. The response rates (RRs) and disease control rates were 55% and 100% in EGFR-TKI-naïve patients. Re-biopsy was performed in eight patients after progressive disease following the study treatment, and three patients acquired a T790M mutation.ConclusionsAfatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg q3w is well tolerated.

Optimal Adjuvant Therapy in Resected Stage IIIA-N2 Non-Small-Cell Lung Cancer Harboring EGFR Mutations

Background: Some non-small-cell lung cancer (NSCLC) patients are unexpectedly diagnosed with stage IIIA-N2 disease at the time of thoracoscopy or thoracotomy. Because of the limited statistical evidence of induction chemotherapy for these patients, it is necessary to develop more profound treatment strategies. Methods: The demographic and clinical characteristics of patients with stage IIIA-N2 NSCLC harboring epidermal growth factor receptor (EGFR) mutations after radical resection were retrospectively reviewed. The patients were divided into 3 groups based on treatment: EGFR tyrosine kinase inhibitors (EGFR-TKIs, erlotinib or gefitinib), adjuvant chemotherapy (docetaxel plus cisplatin), and combination treatment (chemotherapy plus EGFR-TKIs). The effect of adjuvant therapy on survival rate was assessed using univariate and Cox regression analyses. Results: Patients receiving EGFR-TKIs alone showed significantly improved disease-free survival (DFS; p = 0.025) when compared to those receiving chemotherapy alone. Compared to chemotherapy alone, the combination of chemotherapy and EGFR-TKIs resulted did not significantly improve DFS (p < 0.001) and overall survival (OS p < 0.001). The combination of EGFR-TKIs with chemotherapy as adjuvant therapy led to improvements in both DFS (p = 0.116) and OS (p = 0.039) compared to patients receiving a EGFR-TKI monotherapy. Toxicities were mild in the 3 treatment groups. Conclusions: Our study demonstrated that adjuvant EGFR-TKI treatment significantly increased the DFS of patients with stage IIIA-N2 NSCLC when compared with cisplatin-based chemotherapy. The use of EGFR-TKIs and chemotherapy is recommended in the setting of combined-modality therapy.

The Clinical Prognostic Value of the Neutrophil-to-Lymphocyte Ratio in Brain Metastases from Non-Small Cell Lung Cancer-Harboring EGFR Mutations.

PurposeSeveral studies have explored the correlation between the neutrophil-to-lymphocyte ratio (NLR) and the prognosis of patients with lung cancer. However, little is known about the correlation between the pretreatment NLR and the prognosis of patients with brain metastases from non–small cell lung cancer (NSCLC)-harboring mutations in the epidermal growth factor receptor (EGFR) gene. We sought to evaluate the predictive values in brain metastasis from lung adenocarcinoma with EGFR mutations.MethodsWe retrospectively examined 133 patients with brain metastases (BMs) from lung adenocarcinoma with EGFR mutations. NLR was calculated using N/L, where N and L, respectively, refer to peripheral blood neutrophil (N) and lymphocyte (L) counts. The cut-off value of NLR was assessed by the area under the curve (AUC). The Log rank test and Cox proportional hazard model were used to confirm the impact of NLR and other variables on survival.ResultsAn NLR value equal to or less than 2.99 was associated with prolonged survival in this cohort of patients in both variable and multivariable analysis.ConclusionWe concluded that NLR is an independent prognostic factor in BMs from lung adenocarcinoma with EGFR mutations. This could serve as a useful prognostic biomarker and could be incorporated in the clinical prognostic index specific to patients with BMs.

Serum C-Reactive Protein Level Predicts Clinical Outcomes in Patients With Non-Small Cell Lung Cancer Harboring EGFR Mutations

The aim of this study was to assess the association of serum C-reactive protein (CRP) levels with outcomes in 81 patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). Patients with high serum CRP levels had lower therapeutic responses to EGFR-tyrosine kinase inhibitors (43.8%), and shorter time to treatment failure (TTF; 5.8 months) and overall survival (OS; 14.2 months) than those with low CRP levels. In multivariate analysis, serum CRP level was associated with TTF (hazard ratio [HR] 4.86) and OS (HR 49.42). High serum CRP levels may predict poor outcomes in patients with EGFR-mutated NSCLC.

P1.14-30 Phase I Study of Afatinib Plus Bevacizumab in Patients with Advanced Non-Small Cell Lung Cancer Harboring EGFR Mutations

Afatinib, a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), is one of the standard therapies for patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations. The first-generation EGFR-TKIs in combination with bevacizumab have been reported to improve progression-free survival (PFS). However, data on afatinib plus bevacizumab are limited. In this phase I study, we examined the safety and the efficacy of afatinib plus bevacizumab in patients with advanced non-squamous NSCLC harboring EGFR mutations. This study comprised two cohorts. In the dose-finding cohort, eligible patients received afatinib 20, 30, or 40 mg/day (days 1–21) plus bevacizumab 15 mg/kg (day 1) in 21-day cycles. This cohort was designed and conducted in a 3 + 3 manner. In the expansion cohort, the patients were treated with the recommended dose (RD) based on the findings in the dose-finding cohort, and we evaluated the preliminary efficacy of this combination therapy. The serum trough concentration of afatinib was assessed at the steady state. Sixteen patients were enrolled in this study (5 patients in the dose-finding cohort and 11 patients in the expansion cohort). No dose-limiting toxicities (DLTs) occurred with afatinib 30 mg/day. With afatinib 40 mg/day, 2 out of 2 patients had DLTs (grade 3 diarrhea) in cycle 1. From these results, afatinib 30 mg/day plus bevacizumab 15 mg/kg was decided as the RD. Additionally, 11 patients in the expansion cohort were treated with RD. Common treatment-emergent adverse events (AEs) with the RD were diarrhea (79%), rash (71%), perionychia (64%), and stomatitis (50%). Grade 3 AEs with the RD were diarrhea (7%), perionychia (7%), and hypertension (7%). There were no grade 4/5 AEs and interstitial lung disease. The response rates and median PFS were 56% and 16.8 months in EGFR-TKI naïve patients, and 0% and 4.9 months in patients pretreated with EGFR-TKIs. The median serum concentration at the steady state was 13.7 ng/mL (range: 8.1–38.1 ng/mL) in the patients treated with the RD. Rebiopsy was conducted in eight patients after disease progression with afatinib plus bevacizumab, and three patients acquired an exon 20 T790M mutation. Afatinib 30 mg/day plus bevacizumab 15 mg/kg was well tolerated. Large-scale studies are warranted to evaluate the efficacy of this combination therapy.

EGFR-TKI acquired resistance in lung cancers harboring EGFR mutations in immunocompetent C57BL/6J mice

ObjectivesLung cancers harboring epidermal growth factor receptor (EGFR) mutations inevitably develop resistance to EGFR tyrosine-kinase inhibitors (EGFR-TKIs). Therefore, we sought to establish clinically relevant lung-cancer mouse models to achieve deep remission of cancers. Materials and methodsWe previously established two transgenic lung-cancer mouse models harboring human EGFR exon 21 L858R substitution (hLR) and mouse Egfr exon 19 deletion (mDEL) in the C57BL/6 J background. Lung tumors from these two transgenic mouse strains were transplanted subcutaneously into BALB/c-nunu mice or C57BL/6 J mice. ResultsThe transplanted tumors developed the ability to grow on the subcutaneous tissue, peritoneum, or lung of C57BL/6 J mice. While hLR tumors could grow only in C57BL/6 J mice carrying the transgene, mDEL tumors could grow in wild-type C57BL/6 J mice. The tumors maintained EGFR-dependency, and, thus, the EGFR-TKI gefitinib inhibited tumor growth; however, similar to human lung cancers, hLR and mDEL tumors acquired resistance in 60 and 200 days, respectively, following gefitinib administration. Secondary EGFR T790 M mutation in hLR tumors and secondary Egfr T792I mutation in mDEL tumors developed; however, no MET activation was detected. Accordingly, the third-generation EGFR-TKI osimertinib effectively inhibited gefitinib-resistant tumors in vivo. Furthermore, gefitinib-resistant tumors developed resistance to osimertinib in 100 days. ConclusionThese syngeneic lung-cancer mouse models harboring EGFR mutations are suitable for studying the drug-resistance mechanisms and the role of the tumor microenvironment. Further investigation with these mouse models is warranted for developing next-generation treatment strategies for lung cancer.

EGFR inhibitors as adjuvant therapy for resected non-small cell lung cancer harboring EGFR mutations

ObjectivesCisplatin-based chemotherapy as an adjuvant therapy for resected non-small cell lung cancer (NSCLC) has reached its plateau, and it is limited by a high risk of recurrence and significant toxicities. The clinical value of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in resected NSCLC harboring EGFR mutations remains controversial. In this study, we performed a meta-analysis to evaluate the role of EGFR inhibitors as an adjuvant therapy for targeted patients. Materials and methodsStudies were identified via electronic search. The pooled odds ratio (OR) for disease-free survival (DFS) and overall survival (OS) were calculated for the meta-analysis. ResultsThere were 11 trials (1,152 resected NSCLC patients with EGFR sensitive mutations) in this meta-analysis. The results showed that adjuvant treatment with EGFR-TKIs can prolong both the OS and DFS when compared to treatment without TKIs as an adjuvant therapy (OS: OR, 0.63; 95% CI, 0.46 to 0.87, P = 0.004; heterogeneity I2 = 61%, P = 0.008; DFS: OR, 0.56; 95% CI, 0.43 to 0.72, P < 0.00001; heterogeneity I2 = 37%, P = 0.10). The results of the predefined subgroup analyses in this meta-analysis suggested a greater DFS with the mono EGFR-TKIs compared with chemotherapy, whereas the OS benefit failed to show a similar difference between the two arms (p = 0.30). We also found that treatment with EGFR-TKIs plus chemotherapy was associated with a significantly longer DFS and OS compared to mono chemotherapy in patients with completely resected EGFR-mutant NSCLC (DFS: OR, 0.48; 95% CI, 0.34-0.68; P < 0.0001; heterogeneity I2 = 47%, P = 0.07; OS: OR, 0.50; 95% CI, 0.31-0.78; P = 0.003; heterogeneity I2 = 57%, P = 0.05). Additionally, less severe adverse events (SAEs) were observed in the TKIs group (OR, 0.22; 95% CI, 0.14 to 0.37, P < 0.00001; heterogeneity I2 = 22%, P = 0.28). ConclusionThe addition of EGFR-TKIs to adjuvant chemotherapy can prolong the OS and PFS for resected NSCLC. Adjuvant EGFR-TKIs may be a potential treatment option compared to adjuvant chemotherapy in completely resected patients with EGFR mutation-positive NSCLC. Statement of significanceThe clinical value of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in resected non-small cell lung cancer (NSCLC) harboring EGFR mutations remains controversial. This study demonstrates that EGFR-TKIs as an adjuvant therapy could prolong the DFS and potentially prolong the OS in postoperative patients. Therefore, this therapy paves the way for EGFR-TKIs to be an adjuvant treatment for NSCLC.

Mutation Profile of Resected EGFR-Mutated Lung Adenocarcinoma by Next-Generation Sequencing.

The efficacy of adjuvant targeted therapy for operable lung cancer is still under debate. Comprehensive genetic profiling is needed for detecting co-mutations in resected epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (ADC), which may interfere the efficacy of adjuvant tyrosine kinase inhibitor (TKI) treatment. Mutation profiling of 416 cancer-relevant genes was conducted for 139 resected stage I-IIIa lung ADCs with EGFR mutations using targeted next-generation sequencing. Co-mutation profiles were systematically analyzed. Rare EGFR alterations other than exon 19 deletion and L858R, such as L861Q (∼3%) and G719A (∼2%), were identified at low frequencies. Approximately 10% of patients had mutations in EGFR exon 20 that could confer resistance to first-generation TKIs. Ninety-one percent of patients harbored at least one co-mutation in addition to the major EGFR mutation. TP53 was the top mutated gene and was found more frequently mutated at later stage. Markedly, NF1 mutations were found only in stage II-III ADCs. Conversely, RB1 mutations were more frequent in stage I ADCs, whereas APC mutations were observed exclusively in this group. Thirty-four percent of patients with EGFR TKI-sensitizing mutations had genetic alterations involving EGFR downstream effectors or bypass pathways that could affect the response to EGFR TKIs, such as PIK3CA, BRCA1, and NOTCH1. Operable lung ADCs with EGFR TKI-sensitizing mutations are associated with a high proportion of co-mutations. Mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy. The efficacy of adjuvant epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy for lung cancer harboring EGFR mutation after surgical resection is still under debate. Next-generation sequencing of 416 cancer-relevant genes in 139 resected lung cancers revealed the co-mutational landscape with background EGFR mutation. Notably, the study identified potential EGFR TKI-resistant mutations in 34.71% of patients with a drug-sensitizing EGFR mutation and who were naive in terms of targeted therapy. A comprehensive mutation profiling of these resected tumors could facilitate in determining the applicability and efficacy of adjuvant EGFR TKI therapeutic strategy for these patients.

Phase I study of TAS-121, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in patients with non-small-cell lung cancer harboring EGFR mutations

SummaryPurpose We investigated the safety, tolerability, pharmacokinetics, and efficacy of TAS-121, a novel, potent, and highly selective third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in Japanese patients with advanced EGFR mutation-positive non-small-cell lung cancer (NSCLC) previously treated with EGFR-TKI. Methods This was an open-label, non-randomized, multi-center, dose escalation, phase I study conducted in three phases (dose escalation, expansion, and extension phases). TAS-121 was administered orally once daily (QD) or twice daily (BID) under fasting conditions in a 21-day treatment cycle. The primary endpoint was dose-limiting toxicities (DLTs) during Cycle 1 of the dose escalation phase. Results In total, 134 patients received treatment. Five and three patients presented a DLT with the QD and BID regimens, respectively. The DLTs were drug-induced liver injury, platelet count decreased, urticaria, interstitial lung disease, and left ventricular failure. The maximum tolerated dose (MTD) was 10 mg/day QD and 8 mg/day BID in the dose escalation phase. The most common adverse drug reactions (ADRs) were dermatological toxicity (89.6%), platelet count decreased (67.2%), and pyrexia (44%) among all patients. Rate of discontinuations due to ADRs at the MTD level were 11.1% with TAS-121 10 mg/day QD and 7.9% with TAS-121 8 mg/day BID. Among 86 T790M-positive patients (confirmed by blood serum sampling in most patients), the objective response rate (ORR) was 28% and highest at 8 mg/day BID (39%). Among 16 T790M-negative patients, the ORR was 19%. Conclusions TAS-121 was well tolerated up to the MTD and demonstrated antitumor activity in Japanese T790M-positive NSCLC patients. Clinical trial registration: JapicCTI-142651.

Re-challenge of afatinib after 1st generation EGFR-TKI failure in patients with previously treated non-small cell lung cancer harboring EGFR mutation.

Re-challenge of erlotinib after gefitinib failure is reported to yield some benefit in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation. However, little is known about the re-challenge of afatinib after 1st generate on EGFR tyrosine kinase inhibitor (TKI) failure. From May 2015 to August 2018, 62 patients with advanced NSCLC harboring sensitive EGFR mutation received afatinib after gefitinib and/or erlotinib failure at our institution was included in our retrospective study. The overall response rate (ORR) and disease control rate (DCR) of afatinib as re-challenge were 17.0% and 79.2%, respectively. The median time on treatment of 1st generation EGFR-TKI (1st TKI) was 14months. By multivariate analysis, smoking, performance status (PS), and time on treatment of 1st TKI with more than 10months were confirmed to be independent prognostic factors predicting a worse progression-free survival (PFS), and significant prognostic markers for overall survival (OS) were PS and time on treatment of 1st TKI with more than 10months, especially in patients with exon 19 deletion. Re-challenge of afatinib was identified as one of the therapeutic options after 1st TKI failure in the patients with advanced NSCLC harboring EGFR mutation when the time of treatment by prior 1st TKI is more than 10 months.

Phase 2 Study of Afatinib Alone or Combined With Bevacizumab in Chemonaive Patients With Advanced Non–Small-Cell Lung Cancer Harboring EGFR Mutations: AfaBev-CS Study Protocol

Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), has demonstrated a significant survival benefit over platinum-based chemotherapy in a first-line setting in advanced non–small-cell lung cancer (NSCLC) harboring EGFR exon 19 deletion. In addition, we and other groups have shown there to be favorable progression-free survival (PFS) outcomes, with acceptable toxicity profiles, with bevacizumab and first-generation EGFR-TKI combination therapy. On the basis of the above, we hypothesized that a combination of bevacizumab and afatinib could potentially improve efficacy. In our phase 1 study, a daily 30 mg dose of afatinib and 15 mg/kg intravenous bevacizumab every 3 weeks was well tolerated and was defined as the recommended dose. We have initiated a randomized phase 2 trial comparing afatinib (30 mg daily) and bevacizumab (15 mg/kg every 3 weeks) with afatinib (40 mg daily) alone for nonsquamous NSCLC harboring EGFR common mutations as a first-line therapy. A total of 100 patients will be enrolled onto this study and randomized in a 1:1 ratio. Patients will continue to receive treatment until disease progression or unacceptable toxicity. The primary end point is PFS, and the secondary end points are overall survival, tumor response, and time to treatment failure. The power is greater than 50% under the assumptions of a median PFS of 12 months for the afatinib group and a hazard ratio of 0.6 for the combination group (2-sided α = 0.05). We hypothesize that the combination therapy will be more efficacious than standard therapies for EGFR-mutant NSCLC patients.

Afatinib versus gemcitabine/cisplatin for first-line treatment of Chinese patients with advanced non-small-cell lung cancer harboring EGFR mutations: subgroup analysis of the LUX-Lung 6 trial.

IntroductionNon-small-cell lung cancer (NSCLC) is the leading cause of cancer death in China. Four epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors – afatinib, erlotinib, icotinib, and gefitinib – are available for first-line treatment of NSCLC in China; however, there are few data to guide treatment choice. The Phase III LUX-Lung 6 trial compared afatinib with platinum-based chemotherapy for first-line treatment of patients from Southeast Asia with EGFR mutation-positive advanced NSCLC. This post hoc analysis assessed the findings from LUX-Lung 6 in Chinese patients.Clinical trial registrationClinicalTrials.gov: NCT01121393.Materials and methodsPreviously untreated patients with EGFR mutation-positive stage IIIB/IV lung adenocarcinoma were randomized 2:1 to receive afatinib or ≤6 cycles of gemcitabine/ cisplatin. The key outcomes were progression-free survival (PFS; primary), objective response rate, disease control rate, overall survival (OS), duration of response and disease control, patient-reported outcomes, and safety. Three hundred and twenty-seven patients from mainland China were treated (89.8% of overall LUX-Lung 6 population; afatinib 217, gemcitabine/cisplatin 110).ResultsPFS was significantly longer with afatinib than gemcitabine/cisplatin (median 11.0 versus 5.6 months; hazard ratio [HR], 0.30 [95% CI, 0.21, 0.43]; P,0.0001). Overall, there was no significant difference in OS between treatment arms; however, in a subgroup analysis, afatinib significantly improved OS versus gemcitabine/cisplatin in patients with an EGFR Del19 mutation (median 31.6 versus 16.3 months; HR, 0.61 [95% CI, 0.41, 0.91]; P=0.0146). Afatinib was well tolerated, with most treatment-related adverse events (TRAEs) being of grade 1 or 2 severity. The most common grade 3/4 TRAEs with afatinib were rash/acne (15.9%/0.5%), stomatitis (6.1%/0%), and diarrhea (5.6%/0%). TRAEs leading to permanent discontinuation were reported in 12 patients (5.6%) receiving afatinib and 43 (41.7%) receiving gemcitabine/cisplatin. Afatinib significantly improved PFS compared with standard first-line chemotherapy in Chinese patients with EGFR mutation-positive NSCLC and demonstrated a manageable safety profile.ConclusionThe findings support the rationale for using afatinib as a first-line treatment option for this patient population.