Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Therapy Research Articles

Clinical Outcomes of Different Generations of EGFR Tyrosine Kinase Inhibitors in Advanced Lung Adenosquamous Carcinoma.

The role of targeted therapy in patients with lung adenosquamous carcinoma (ASC) has been controversial and it was unclear whether a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) could improve outcomes. This study was designed to evaluate the efficacy of different generations of EGFR TKI therapy in ASC patients with sensitive EGFR mutations. Patients with non-small cell lung cancer (NSCLC) diagnosed at the Shanghai Chest Hospital between January 2010 and December 2016 were retrospectively reviewed. A total of 10,037 NSCLC patients tested for EGFR mutations were screened, with primary ASC accounting for 1.4% (139/10,037). Positive EGFR mutations were found in 51.1% (71/139) of ASC patients, including 67 sensitive mutations (19del or 21L858R) and four uncommon mutations (19del + 20T790M, 21L858R + 20T790M, 19L747P + 20Q787Q, and 21L861Q). Sensitive EGFR mutations occurred more frequently in younger (62.0 vs 65.0, p = 0.010), non-smoking (83.6% vs 57.8%, p = 0.002) women (56.7% vs 34.4%, p = 0.014). Among the 36 ASC patients with eligible survival data for the first-generation TKIs, the median progression-free survival (PFS) was 9.3months (95% CI 6.7-11.9), which was rather similar to the data of adenocarcinoma (9.3 vs 11.4months, p = 0.294) in our institution as opposed to squamous cell carcinoma (9.3 vs 4.9months, p < 0.001). The objective response rate (ORR) was 37.9% (11/29), and the disease control rate (DCR) was 86.2% (25/29). After progression on the initial EGFR TKIs, 42.1% of the cases (8/19) had an EGFR T790M mutation detected. A median PFS of 10.2months (95% CI 5.8-14.5, n = 8) was achieved with treatment using the third-generation TKI. The ORR and DCR were 37.5% (3/8) and 100% (8/8), respectively. The median overall survival reached 38.3months (95% CI 13.7-62.9). Targeted therapy showed remarkable efficacy in ASC patients harboring sensitive EGFR mutations, comparable to adenocarcinoma. The application of the third-generation TKI provided an option to prolong survival.

P2.16-07 How to Manage Toxicities of EGFR-TKI for Extreme Elderly Lung Cancer Patients: Supportive Care for Patients Aged 85 and Older

In Japan, the population of extreme elderly individuals (85 years and older) was 5.75 million in 2018, and the number of elderly lung cancer patients is increasing. Recently, several elderly-specific trials showed that epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) is effective and feasible for elderly patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC). Nevertheless, there have been few reports on the efficacy and safety of EGFR-TKI therapy in patients aged 85 years and older with EGFR mutation-positive advanced NSCLC. We analyzed the efficacy and safety of EGFR-TKI therapy in patients with EGFR mutated NSCLC who were 85 years and older treated at our hospital, between 2014 and 2019. We assessed complications, prognosis, and supportive care needs. The median age was 87 years (range, 85-93 years) at last checkup, and only one patient was male. The study population included 12 patients with ECOG performance status 0-1 and all patients had adenocarcinoma. Four patients (33%) were diagnosed with cognitive impairment. Nine patients received gefitinib therapy. Treatment-related deaths were not observed in our analysis. Median progression free survival, overall survival from recent TKI therapy was 11.3 months, and 16.0 months. The response rate and disease control rate were 17%, and 100%. The common adverse events were diarrhea (25%), skin toxicities (25%), and liver dysfunction (25%). One patient (8%) experienced grade 2 EGFR-TKI-related interstitial lung disease. The dose of EGFR-TKI was reduced in 5 patients (42%) and EGFR-TKI therapy was discontinued in 3 patients (25%) due to toxicities, digestive disorders and interstitial lung disease. EGFR-TKI therapy is tolerable for extreme elderly patients with EGFR mutation-positive advanced NSCLC. Approximately half of the patients required a dose reduction or focused supportive care, but well tolerated and had similar efficacy compared to those of the younger. It is important for elderly patients to be treated with a personalized management plan and integrated supportive care.

P1.01-100 Effect of Osimertinib in Non-Small Cell Lung Cancer Patients with Brain Metastases After Progression Following Front-Line EGFR-TKI Therapy

Osimertinib has been adopted as the standard of care for T790M-mediated acquired epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. In this study, we aim to investigate the effect of osimertinib in advanced NSCLC with brain metastases after the failure of first-line therapy. We retrospectively studied 43 NSCLC patients with BM received osimertinib after progression following front-line EGFR-TKI therapy from January 2013 to December 2016 at our institution. Overall survival (OS) was measured from the date of brain metastases. Among the 43 patients, 25(58.1%) received EGFR-TKIs as first-line therapy, 15(34.9%) were treated with EGFR-TKIs therapy after the progression of chemotherapy, and there’re also 3(7.0%) received the combination of EGFR-TKIs and chemotherapy as first-line therapy. 16(37.2%) were EGFR T790M positive, 4(9.3%) were EGFR T790M negative and 23(53.5%) were unknown T790M status. 34(79.1%) patients had received local radiation therapies (RT). The median overall survival (OS), and the median intracranial progression free survival (iPFS) was 32.0 months, 14 months, respectively. Patients with EGFR T790M mutation had the median OS of 24.7 months, these without T790M mutation had the median OS of 17.0 months, and the patients with unknown status of T790M showed the longest OS of 34.4months, although it did not reach statistical significance (P =0.727). There was also no difference in iPFS among the T790M-positive group, T790M-negetive group and the unknown status group (5.0 vs. 7.0 vs. 18.0 months, P=0.195). Similar results in OS were found among the first line TKIs group, chemotherapy followed by EGFR-TKI therapy group and the combination of TKIs and chemotherapy group (P=0.491). Three patients had leptomeningeal metastasis (LM), showed to have a worse iPFS of 12 months compared to 14 months of these without LM (P=0.991). Osimertinib had a good efficacy in patients with brain metastasis of advanced non–small-cell lung cancer in whom disease had progressed following front-line EGFR-TKIs.

Nivolumab + chemotherapy vs chemotherapy in EGFR-mutated NSCLC after 1L or 2L EGFR-TKIs (CheckMate 722)

Abstract Background Although osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) is approved for first-line (1L) treatment of EGFR-mutated metastatic non-small cell lung cancer (NSCLC) and second-line (2L) treatment of pts who acquired the EGFR T790M mutation during 1L therapy with other TKIs, treatment options after progression on TKIs are limited; platinum-doublet chemotherapy (PT-DC) remains the standard therapy, including for pts with no T790M mutation. Nivolumab (NIVO), a fully human IgG4 programmed death-1 immune checkpoint inhibitor antibody, is approved worldwide for the treatment of advanced NSCLC on or after prior chemotherapy. CheckMate 722 (NCT02864251) will compare the efficacy and safety of NIVO + PT-DC vs PT-DC alone in pts with EGFR-mutated metastatic or recurrent NSCLC progressed on 1L or 2L EGFR TKI therapy. Methods This open-label phase 3 trial is enrolling ∼500 adults with confirmed stage IV or recurrent EGFR-mutated NSCLC progressed on prior EGFR TKI therapy. Patients are eligible if they progressed on 1L first- or second-generation TKIs with no T790M mutation or 1L or 2L osimertinib regardless of T790M status. Pts with CNS metastases that are adequately controlled and/or treated during screening are eligible. Pts are randomized 1:1 to NIVO (360 mg Q3W) + PT-DC (pemetrexed 500 mg/m2 Q3W + cisplatin 75 mg/m2 or carboplatin AUC 5 or 6 Q3W), or PT-DC alone; pts without disease progression after 4 cycles will receive NIVO + pemetrexed or pemetrexed, respectively, until disease progression or unacceptable toxicity. Randomization is stratified by programmed death ligand-1 status (≥ 1% or Results The estimated primary completion date is September 2019.

1415P - Feasibility study of a ctEGFR prototype assay on the fully automated Idylla™ platform

BackgroundTo predict the response to EGFR tyrosine kinase inhibitor (TKI) therapy in non-small cell lung cancer (NSCLC) patients, formalin-fixed paraffin-embedded (FFPE) tumor tissue is routinely tested for the presence of somatic mutations in the epidermal growth factor receptor (EGFR) gene. Sufficient tumor tissue is not always available and ctEGFR testing from plasma is an alternative approach for the detection of EGFR mutations. Therefore, a fast and fully automated ctEGFR assay with minimal hands-on time should allow laboratories to quickly generate EGFR testing results. MethodsIdyllaTM (Biocartis) is a fully integrated molecular diagnostics platform that combines speed and ease of use with high sensitivity and high multiplexing capabilities. In terms of ctDNA testing, it overcomes the time-consuming step of ctDNA extraction from plasma. After insertion of 2ml of plasma into the cartridge, the complete process of ctDNA extraction, real-time PCR, data analysis and reporting is fully automated. The ctEGFR prototype assay allows the detection of 49 mutations including insertions and deletions in exons 18, 19, 20 and 21. The results obtained by the ctEGFR prototype assay were compared with NGS (sensitivity 2-5%). ResultsSixty-four NSCLC samples were tested with both assays. Overall, 34 mutations were detected by NGS and confirmed by the ctEGFR prototype assay. In 33 samples, NGS detected no mutation. The ctEGFR prototype assay detected 7 additional mutations in this cohort. Retesting with the cobas EGFR Mutation Test v2 confirmed the presence of these mutations. Analytical sensitivity was assessed for 20 mutations using plasma spiked with synthetic targets. Analytical sensitivities ranging from 1 to 4% were obtained for the tested mutations. Inclusivity was demonstrated for 49 mutations in total. The average turnaround time of a run was <2h 40min and the hands-on time for the assay was <2min. ConclusionsThis study shows that the Idylla™ platform enables the development of a prototype ctEGFR assay with high sensitivity and ease of use combined with a fast turnaround time for the testing of 49 relevant EGFR mutations in 2ml of plasma from NSCLC patients. Legal entity responsible for the studyBiocartis. FundingBiocartis. DisclosureM. Reijans: Full / Part-time employment: Biocartis. S.V. Gestel: Full / Part-time employment: Biocartis. E.D. Haes: Full / Part-time employment: Biocartis. C. Vandesteene: Full / Part-time employment: Biocartis. J.M. Castro Gomez: Full / Part-time employment: Biocartis. C. Gouedard: Full / Part-time employment: BioPath Innovations SA. S. Patera: Full / Part-time employment: BioPath Innovations SA. S. Murray: Full / Part-time employment: BioMarker Solutions Ltd. G.G. Maertens: Full / Part-time employment: Biocartis.

P1.09-28 A Significant Discordance Between PANAMutyper™ and Targeted Deep Sequencing for Detecting EGFR Mutation in NSCLC

Activating mutations in the tyrosine kinase domain of EGFR are predictive biomarkers for response to EGFR-tyrosine kinase inhibitor (TKI) therapy in non-small cell lung cancer (NSCLC). This study aimed to screen EGFR mutations by PNA clamping-assisted fluorescence melting curve analysis (PANAMutyper™) and targeted deep sequencing, and to evaluate the feasibility of targeted deep sequencing for detection of the mutations. We examined EGFR mutations in exons 18, 19, 20, and 21 using PANAmutyper™ for consecutive 2170 NSCLC tissues from November 2016 to March 2019. Of these, targeted deep sequencing was performed in 74 patients. EGFR mutations were identified in 46.4% (1007/2170); 479 (47.6%) had mutations at exon 19, 442(43.9%) at exon 21, 156(15.5%) at exon 20 (including 97 cases with T790M), and 46(4.6%) at exon 18. EGFR mutations were significantly more common in women (63.9%) than men (31.4%) (p <0.001), in adenocarcinoma (54.7%) compared to non-adenocarcinoma (15.3%) (p <0.001). 11.3% (11/97) of T790M mutations was identified in TKI-naïve patients. Interestingly, 27.3% (3/11) of the primary T790M existed alone without L858R or exon 19 deletions. We observed a significant discordance (24.3%: 18/74) of the EGFR mutation between PANAMutyper™ and targeted deep sequencing. Moreover, targeted deep sequencing revealed eight nonsynonymous single-nucleotide variations, ten insertion-deletion variations and one amplification in EGFR, which were not detectable by the PANAMutyper™. In 2 out of 18 discordant cases, EGFR mutations were detected only in PANAMutyper™. EGFR mutations were found frequently in non-adenocarcinomatous NSCLCs, emphasizing that testing for EGFR mutations is essential for all NSCLC patients. As T790M was found in TKI-naive patients, we cannot exclude the possibility of this mutation being a rare mutation existing from the beginning. Taken together, our study demonstrates that primary T790M alone exists and there is a significant discordance between PANAMutyper™ and targeted deep sequencing. The significance of these discrepancies should be carefully interpreted for the patient's treatment and clinical outcome.

P2.14-13 Elevated Expression of Eukaryotic Translation Initiation Factor 3 Subunit C Contributes to EGFR-TKI Resistance in Lung Adenocarcinoma

The treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, in patients with EGFR-mutant lung adenocarcinoma causes tumor regression and improved prognosis. However, drug resistance and tumor relapse eventually occur, and the molecular mechanisms remain to be fully revealed. In this study, we elucidated the novel mechanism of EGFR-TKI resistance and clarified the clinical significance using erlotinib-resistant lung adenocarcinoma cell lines and patient specimens. The erlotinib-resistant cell line, PC9/ER was obtained from PC9 cell line by exposing to increasing concentrations of erlotinib for 6 months. The sensitivity of erlotinib was evaluated by the MTT assay. In order to identify erlotinib-resistance related factors, we performed a proteomics analysis, followed by western blotting. To evaluate the roles of the candidate factor, we performed gene knockdown analysis using siRNAs. The autophagy activity was assessed by the amount of LC3B-II protein or visualization of autophagosomes using LC3B-RFP expression vector. Immunohistochemical staining was performed on tumor biopsies obtained from lung adenocarcinoma patients with activating mutation in EGFR, and we examined the correlation between the staining intensity and clinical EGFR-TKI resistance. Initially, we performed the sequencing analysis of EGFR exons 18 to 21, which cover the tyrosine kinase domain, and found that there was no difference between PC9 and PC9/ER cells. The proteomics analysis revealed ribosomal and translation-related proteins were abundantly identified in PC9/ER cells, compared with PC9 cells. Among them, we found that eukaryotic translation initiation factor 3 subunit C (eIF3c) was overexpressed in PC9/ER cells. The knockdown of eIF3c expression with siRNA improved the sensitivity of EGFR-TKI in PC9/ER cells. Additionally, we observed that LC3B-II increased in PC9/ER cells, but decreased by the knockdown of eIF3c. Consistently, the overexpression of eIF3c upregulated the number of autophagosomes. Moreover, the inhibition of autophagy with chloroquine attenuated erlotinib-resistance in PC9/ER cells. Finally, the frequency of eIF3c-positive samples was higher in biopsy specimens from the patients’ refractory to EGFR-TKI therapy than in those from the patients prior to the treatment with EGFR-TKI. Furthermore, patients with eIF3c-positive tumors had shorter progression-free survival in EGFR-TKI treatment than eIF3c-negative patients. The increased eIF3c expression conferred the resistance to EGFR-TKI in lung adenocarcinoma cells via enhancement of autophagy. Moreover, the patients with increased eIF3c expression in biopsy samples showed poor prognosis. The inhibition of eIF3c could be a new therapeutic strategy for overcoming EGFR-TKI resistance in lung adenocarcinoma patients.

EP1.14-46 The KIF5B-RET Fusion as a Novel Mechanism of Acquired EGFR Tyrosine Kinase Inhibitor Resistance in Lung Adenocarcinoma

Lung cancer is a common malignancy and a leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer. And most NSCLC patients with epidermal growth factor receptor (EGFR) mutations respond well to the treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). Unfortunately, almost all patients with effective EGFR-TKIs therapy eventually develop drug resistance in about 1 year. The most common mechanism of acquired resistance to first-generation EGFR-TKI treatment is the development of the T790M mutation in exon 20 of the EGFR, which occurs in almost one half of cases of acquired resistance. In this case report, we present a 72-year-old male non-smoker patient with an EGFR exon 19 deletion diagnosed with lung adenocarcinoma (LADC), who initially responded to first-generation EGFR-TKI treatment, but developed acquired resistance, and was shown to have gene detected by the next generation sequencing. Repeated liquid biopsy showed the KIF5B-RET fusion gene by next generation sequencing. Therefore, cabozantinib was added to the treatment, and stable disease (SD) was achieved. Unfortunately, the patient did not acquire long-term benefits and the progression-free survival (PFS) was only 2 months Our results suggested that the KIF5B-RET fusion gene is a possible novel cause of acquired resistance to first-generation EGFR-TKIs.

EGFR T790M detection rate in lung adenocarcinomas at baseline using droplet digital PCR and validation by ultra-deep next generation sequencing.

Routine testing of baseline EGFR T790M mutation may have important clinical impact but many discordant data have been reported regarding the diagnostic, prognostic and predictive role of this marker. In this study we aimed to assess T790M frequency in 164 untreated EGFR-mutated NSCLCs using methods with different sensitivity as well as to analyze the relationship between baseline T790M mutation status, patient's clinicopathologic features and tyrosine kinase inhibitors (TKI) treatment outcomes. We compared the diagnostic performance, sensitivity and specificity of three methods, namely MALDI-TOF mass spectrometry (MS), Allele-Specific Real Time PCR (AS-PCR), droplet digital PCR (ddPCR). Ultra-deep next generation sequencing (NGS) validation of T790M-mutant NSCLCs was performed using SiRe® panel. Baseline T790M occurred in 17% of the tumors. Intermediately sensitive techniques such as MALDI-TOF MS (detection limit of T790M ≥5%) allow to detect T790M in 2% of cases exhibiting mutant-allele fractions ranging from 11.5% to 17%. Median overall survival (OS) in these patients was poor (7.3 months) and progression free survival (PFS) was of 3.3 months in patients treated with a 1st generation EGFR TKI. The remaining T790M-positive cases showed very low mutant-allele fractions ranging from 0.07% to 0.38% and required highly sensitive methods such as ddPCR and NGS to be identified. All these cases showed a concurrent sensitizing EGFR mutation (mainly exon 19 deletion), and clinicopathological features similar to those observed in EGFR mutant cancers. Median OS of these patients was 27 months while median PFS after TKI treatment was 20 months. Routine test of baseline EGFR T790M may have an important role in the prediction to EGFR TKI therapy response and should be performed using highly sensitive and quantitative methods, such as ddPCR and NGS, in order to reliably distinguish NSCLCs with high or very low T790M mutant-allele fraction.

EGFR tyrosine kinase inhibitor therapy for lung cancer treatments and their clinical outcomes: A cohort study in Taiwan.

Malignant cancer is the top cause of mortality in Taiwan. In particular, the mortality rate of with lung cancer reached 39.2/100,000 in 2017. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are being increasingly used to treat lung cancer.; however, due to small sample sizes and a limited number of adequately controlled studies, it is difficult to compare survival rates of traditional chemotherapy with EGFR-TKI therapy when used as a first- or second-line treatment for patients with lung cancer, and therefore data on its efficacy are inconclusive. Therefore, Taiwan's entire 2010–2015 National Health Insurance Database (NHID) was used to perform a retrospective study. The top two anti-neoplastic first-line therapies used for lung cancer were traditional platinum-based doublet chemotherapy and EGFR-TKI therapy. Patients with stage III and IV lung cancer undergoing first-line EGFR-TKI therapy exhibited improved overall survival rates. However, patients with stage I and II lung cancer demonstrated limited benefits. Patients with stage IIIB and IV EGFR mutation (−) patients did not benefit from treatment with EGFR-TKI therapy. The EGFR-TKI gefitinib may be more effective in patients with lung cancer than erlotinib, irrespective of whether patients had been previously treated or not. Patients treated with Gefitinib also exhibited improved survival rates compared with other frequently used chemotherapeutic drugs.

Exon 16-Skipping HER2 as a Novel Mechanism of Osimertinib Resistance in EGFR L858R/T790M-Positive Non-Small Cell Lung Cancer.

Osimertinib is the current recommended treatment for EGFR T790M-positive NSCLC after EGFR tyrosine kinase inhibitor therapy. However, resistance to osimertinib therapy is inevitably acquired after a period of effective treatment. We had a patient with EGFR L858R/T790M-positive NSCLC who initially responded to osimertinib therapy but eventually experienced development of resistance. Plasma cell-free DNA analysis revealed the occurrence of exon 16-skipping HER2, which may have resulted in the erb-b2 receptor tyrosine kinase 2 gene (HER2) splice variant HER2D16. HER2D16 has never been reported in lung cancer, and HER2D16-driven signaling is known to be regulated by Src kinase in breast cancer. We investigated the role of HER2D16 as an osimertinib-resistant mechanism. We constructed and established H1975 cells stably expressing HER2D16. The dimeric formation of HER2D16 was tested by using nonreducing polyacrylamide gel electrophoresis. The effects of the study drugs on signaling transduction were examined by using Western blot. Synergistic effect was assessed by using the Chou-Talalay method. We found that HER2D16 can form a homodimer in NSCLC cells. HER2D16-expressing H1975 cells were resistant to osimertinib treatment. We also found that mutant EGFR and HER2D16 cooperated to activate downstream signaling for osimertinib resistance. In addition, cotreatment with osimertinib and an Src kinase inhibitor failed toreverse resistance, indicating that HER2D16-driven signaling in NSCLC did not occur through a canonical pathway. Finally, we revealed that the combination of osimertinib with the pan-HER small-molecule inhibitor afatinib could synergistically repress cell growth and signaling in H1975-HER2D16 cells. HER2D16 can contribute to osimertinib resistance through an Src-independent pathway. HER2D16 should be included in the molecular diagnosis panel for lung cancer.

A Review of EGFR-TKIs Therapy of Non-small Cell Lung Cancer with Uncommon EGFR Mutations

肺癌是目前最常见的癌症，也是导致癌症死亡的首要原因。非小细胞肺癌（non-small cell lung cancer, NSCLC）占85%以上，且高达50%的亚洲NSCLC患者携带表皮生长因子受体（epidermal growth factor receptor, EGFR）基因突变。研究证明，伴有EGFR突变的NSCLC患者接受表皮生长因子受体-酪氨酸激酶抑制剂（epidermal growth factor receptor-tyrosine kinase inhibitors, EGFR-TKIs）治疗能获得更好的生存结果。然而，因为EGFR罕见突变相对治疗效果较差，会对研究结果带来负面影响，所以大部分研究EGFR-TKIs疗效的临床试验都不包含罕见突变患者，另外EGFR罕见突变本身就少见，就导致临床试验中这部分患者数量较少。由于EGFR罕见突变样本量少且具有高度异质性，EGFR-TKIs对EGFR罕见突变患者的疗效仍然不清楚。本文就EGFR罕见突变与EGFR-TKIs的疗效关系进行综述，为携带EGFR罕见突变的NSCLC患者合理选择治疗方式提供指导和建议。

Intracavitary chemotherapy with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is not superior to TKI monotherapy in controlling malignant pleural effusion recurrence in EGFR-mutated lung cancer patients.

Epidermal growth factor receptor (EGFR) mutated non-small cell lung cancer (NSCLC) patients benefit from EGFR-tyrosine kinase inhibitors (TKIs) therapy. There are few studies comparing the efficacy between intrapleural chemotherapy combination with TKIs and TKIs alone in controlling re-accumulation of malignant pleural effusions (MPEs). The purpose of the study was to determine if patients with EGFR-mutated NSCLC and MPEs would benefit from intrapleural chemotherapeutics with an oral EGFR-TKI than EGFR-TKI alone. We evaluated EGFR-mutated lung cancer patients with MPEs in Zhejiang Cancer Hospital. We evaluated the efficacy. Progression-free survival (PFS) and overall survival (OS) was evaluated by Kaplan-Meier method. One hundred one NSCLC patients with MPEs at the time of diagnosis were included. We divided the patients into two groups. The overall response rate (ORR) with respect to MPE recurrence between the TKI alone and combination therapy groups was 65.5% (38/58) and 58.1% (25/43) (P=0.449). The disease control rate was 89.7% (52/58) and 86.0% (37/43) (P=0.579), respectively. The PFS in the TKI alone and TKI plus intrapleural drugs was 10.3 and 9.9 months, respectively (P=0.746). The intrapleural PFS was 11.4 and 11.0 months for the TKI alone and combination groups, respectively (P=0.188). The OS was 24.9 and 22.6 months (P=0.543), respectively. Hematologic toxicity and chest pain were more frequent in the combination therapy than TKI alone groups. Intrapleural chemotherapy with TKI did not improve the efficacy of controlling MPEs in patients with EGFR-mutated NSCLC, but may increase adverse events, which are typical side effects of chemotherapy. We could treat these patients with TKI drugs alone combined with pleural effusion drainage.

Additional local consolidative therapy has survival benefit over EGFR tyrosine kinase inhibitors alone in bone oligometastatic lung adenocarcinoma patients

ObjectivesWhether epidermal growth factor receptor tyrosine-kinase inhibitors (EGFR-TKIs) plus local consolidative therapy (LCT) has survival benefit over EGFR-TKIs alone in lung adenocarcinoma patients with EGFR mutation and bone oligometastases remains controversial. Materials and methodsWe conducted a retrospective study to assess the effects of LCT in lung adenocarcinoma patients with bone oligometastases and EGFR mutation. The primary endpoint was overall survival (OS); the secondary endpoints was progression-free survival (PFS). ResultsA total of 127 lung adenocarcinoma patients with EGFR mutation and bone oligometastases were assessed, including 65 patients received EGFR-TKIs alone (monotherapy group) and 62 patients received EGFR-TKIs plus local consolidative therapy (LCT) (combination group). Addition of LCT was associated with significantly longer OS (36.3 vs. 21.0 months, P = 0.01; hazard ratio [HR] = 0.537, 95% confidence interval [CI]: 0.360-0.801, p = 0.01) and PFS (14.0 vs. 8.1 months, P = 0.01; HR = 0.613, 95%CI: 0.427-0.879, p = 0.01) in the whole cohort. ConclusionIn lung adenocarcinoma patients with EGFR-mutation and bone oligometastases, LCT plus EGFR-TKIs therapy is associated with significantly longer OS and PFS compared with EGFR-TKIs therapy alone, indicating that LCT plus EGFR-TKIs therapy might be a better therapeutic option for this patient population.

High NF-E2-related factor 2 expression predicts poor prognosis in patients with lung cancer: a meta-analysis of cohort studies

NF-E2-related factor 2 (Nrf2) plays an important role in tumour proliferation and chemoresistance. Nrf2 expression levels may be associated with prognosis of lung cancer, but previous results have been inconsistent. Pooled hazard ratios (HRs) and odds ratios were calculated to assess the prognostic value of the Nrf2 expression in this meta-analysis. Nine studies with 940 patients were included. A high Nrf2 expression level was significantly related to decreased overall survival (OS) (HR = 1.948, 95% CI = 1.564–2.427), lower response rate (HR = 2.675, 95% CI = 1.553–4.610), and poor progression-free survival (HR = 3.078, 95% CI = 1.791–5.293). Subgroup analysis demonstrated that high-Nrf2-expression was significantly correlated with worse OS of patients possessing epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) or undergoing chemotherapeutic treatments (HR = 2.500, 95% CI = 1.556–4.018). Conversely, this high expression was not significantly related to the OS of patients with surgical resection (HR = 1.750, 95% CI = 0.995–3.080, and p=.052). High Nrf2 expression was significantly correlated with worse OS of patients in advanced stage (HR = 2.500, 95% CI = 1.556–4.018), compared with early cancer stage (HR = 1.609, 95% CI = 0.675–3.835, and p=.283). This meta-analysis suggests that high Nrf2 expression may be a predictive factor of poor outcomes in lung cancer. Therefore, Nrf2 likely plays an important role in prognostic evaluation and may be a therapeutic target for EGFR-TKIs therapy and chemotherapy.

Safety, tolerability, and anti-tumor activity of olmutinib in non-small cell lung cancer with T790M mutation: A single arm, open label, phase 1/2 trial

ObjectivesThe aim of this phase 1/2 study was to evaluate the safety, tolerability, pharmacokinetics and antitumor activity of olmutinib in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who had failed ≥ 1 previous line of EGFR-tyrosine kinase inhibitor (TKI) therapy. Materials and methodsPhase 1 consisted of dose-escalation and four dose-expansion parts (1: olmutinib 300 mg once daily; 2A: 800 mg once daily [EGFR T790 M mutation-positive patients]; 2B: 500 mg twice daily [EGFR T790 M mutation-positive]; 3: 800 mg once daily [EGFR T790 M mutation-negative]). In phase 2, EGFR T790 M mutation-positive patients received olmutinib 800 mg once daily. Data from expansion part 2A and phase 2 were integrated (`pooled phase 2′). Each olmutinib cycle was 21 days. Outcomes included: tumor response, treatment-emergent adverse events (TEAEs), pharmacokinetic parameters. ResultsOverall, 272 patients received at least one olmutinib dose: dose-escalation (n = 66), expansion parts (n = 165), phase 2 (n = 41). In pooled phase 2, the overall objective response rate, confirmed by independent review, was 55.1% (38/69 evaluable patients; 95% CI, 42.6–67.1). All responses were partial responses; 23 patients had stable disease. Estimated median progression-free survival was 6.9 (95% CI, 5.6–9.7) months; estimated median overall survival was not reached. The most frequent treatment-related AEs were diarrhea (59.2% of patients), pruritus (42.1%), rash (40.8%), and nausea (39.5%). ConclusionOlmutinib showed effective clinical activity with a manageable safety profile, indicating therapeutic potential for T790M-positive NSCLC patients who have failed ≥ 1 previous line of EGFR-TKI therapy.

Incidence of hepatitis B reactivation during epidermal growth factor receptor tyrosine kinase inhibitor treatment in non–small-cell lung cancer patients

BackgroundReactivation of hepatitis B virus (HBV) is a documented risk during cytotoxic chemotherapy in patients with lung cancer. Cases of HBV reactivation in non–small-cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment have been reported; however, the incidence of HBV reactivation in patients treated with EGFR TKIs has not yet been reported. Materials and methodsWe enrolled 171 patients who were diagnosed as having NSCLC from 2011 through 2017 and who also had positive hepatitis B surface antigen (HBsAg). All patients had received EGFR TKIs as anticancer treatment for at least 2 weeks during their treatment course. Reactivation of HBV is defined as one of the following: an increase in HBV DNA by at least 10-fold compared to baseline or an absolute increase to >10ˆ5 IU/mL with abnormal liver function. ResultsThe median duration of EGFR TKI treatment was 10.5 months (95% confidence interval: 8.2–12.8). Sixteen (9.36%) patients met the criteria of HBV reactivation during EGFR TKI treatment, with an annual incidence of 7.86%. HBV reactivation occurred during erlotinib treatment in 6 patients, followed by 5 patients with gefitinib treatments, 3 patients with osimertinib treatment and 2 with afatinib treatment. No independent risk factor for HBV reactivation was identified. ConclusionNSCLC patients receiving EGFR TKI treatment may have a clinically meaningful risk of HBV reactivation during the treatment period. Thus, monitoring liver function, HBV viral load and serology of HBV (i.e., HBeAg and anti-HBc) during EGFR TKI therapy is recommended for NSCLC patients with positive HBsAg.

Abstract 4752: Exon-16-skipping HER2 contributes to osimertinib-resistance through Src-independent manner in EGFRL858R/T790M-positive non-small-cell lung cancer

Abstract Osimertinib is current recommended treatment for EGFR T790M-positive NSCLC following progression on prior EGFR tyrosine kinase inhibitor therapy. However, acquired resistance to osimertinib therapy inevitably developed after a period of effective treatment. We had a patient of EGFR L858R/T790M-positive NSCLC who initially responded to osimertinib therapy but eventually developed resistance. Plasma cell-free DNA analysis disclosed exon-16-skipping HER2 (HER2Δ16) in one osimertinib treated patient. HER2Δ16 was regarded as an oncogenic driver in breast cancer and has never been reported in lung cancer before. Therefore, it’s intriguing to investigate the role of HER2Δ16 in osimertinib resistance in NSCLC. The purpose of this study is to explore the mechanism of HER2Δ16-mediated resistance to osimertinib and to explore strategies to overcome the resistance. We constructed and established H1975 cells stably expressing either vehicle, WT-HER2 or HER2Δ16. We observed that without osimertinib treatment, there was no difference in cell growth and the response to EGF-stimulation. However, when treated with osimertinib, H1975-HER2Δ16 cells were more resistant under normal and EGF-stimulating conditions compared to vehicle or WT-HER2 expressing cells. Moreover, osimertinib treatment in H1975-HER2Δ16 cells had less inhibitory effect on phosphor-ERK and phosphor-AKT compared to vehicle or H1975-WT-HER2 cells. Interestingly, co-treatment of osimertinib with Src-kinase inhibitor, dasatinib, failed to reverse the resistance, indicating that HER2Δ16-driven osimertinib-resistance was independent of Src-kinase. Finally, we revealed that combination of osimertinib with the HER2 small molecular inhibitor, afatinib, can suppress cell growth in H1975-WT-HER2 and H1975-HER2Δ16 cells. In summary, we have shown that HER2Δ16, may be a resistance mechanism to osimertinib in EGFR mutated NSCLC and that HER2Δ16-driven resistance was Src-kinase independent. Moreover, we found the HER2Δ16-driven resistance could be rescued by combination of osimertinib with afatinib. Citation Format: Chia-Chi Hsu, Bin-Chi Liao, Wei-Yu Liao, Aleksandra Markovets, Daniel Stetson, Kenneth Thress, Chih-Hsin Yang. Exon-16-skipping HER2 contributes to osimertinib-resistance through Src-independent manner in EGFRL858R/T790M-positive non-small-cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4752.

Abstract 4748: RICTOR signaling modulates the activity of EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutated non-small cell lung cancer (NSCLC)

Abstract Background: Molecularly-targeted therapy has significantly improved the therapeutic efficiency and clinical outcome in a subgroup of NSCLC patients. However, drug resistance inevitably emerges, such as resistance to EGFR TKIs in EGFR-mutated NSCLC. RICTOR is a key component of the mTORC2 complex and plays important roles in cell survival, proliferation, migration and invasion. RICTOR has also been suggested to play a part in the regulation of drug resistance to HER2-targeted therapy in HER2-amplified breast cancer, a niche close to EGFR-targeted therapy. In our current study, we hypothesize that RICTOR modulates the activity of EGFR TKIs in EGFR-mutated NSCLC. Co-targeting RICTOR and EGFR signaling pathways could be a new therapeutic strategy for patients with EGFR-mutated lung cancer. Results: Genetically modified EGFR-mutated NSCLC cell lines with different RICTOR expression levels have been developed. RICTOR knockdown significantly increases the sensitivity to all three generations of TKI inhibitors (erlotinib, afatinib and osimertinib), whereas overexpression of RICTOR renders the cells more resistant to EGFR TKIs. In addition, RICTOR knockdown restores the sensitivity of erlotinib-resistant HCC827 cells due to AXL overexpression (IC50: 216µM vs. 0.256 µM with RICTOR knockdown, P&amp;lt;0.001). Pharmacological inhibition of the RICTOR signaling pathway with the mTOR1/2 inhibitor (sapanisertib) also improves EGFR TKI sensitivity. Taken together, RICTOR signaling modulates the efficacy of EGFR TKIs in the EGFR-mutated lung cancer models. Conclusion: Our study provides a new insight into the role of RICTOR signaling modulation in increasing efficacy of EGFR TKI therapy in EGFR-mutated NSCLC. The combination of mTOR1/2 inhibitor and EGFR inhibitor could be a potential novel strategy leading to better therapeutic efficacy. Note: This abstract was not presented at the meeting. Citation Format: Ni Fan, Yiyu Zou, Balazs Halmos, Roman Perez-Soler, Haiying Cheng. RICTOR signaling modulates the activity of EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutated non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4748.

Abstract 4930: PAI1, a β catenin transcriptional target, serves as a surrogate biomarker to predict EGFR TKI mediated drug persistence in EGFR mutant NSCLC

Abstract Lung cancer management has been transformed by the discovery and effective targeting of driver mutations such as epidermal growth factor receptor (EGFR). Tyrosine Kinase Inhibitors (TKIs) that block EGFR kinase activity such as erlotinib and osimertinib cause dramatic tumor shrinkage and prolonged responses in patients whose tumors have activating EGFR mutations. However, resistance universally develops. Drug persister cells with properties of cancer stem cell-like cells play a major role in drug resistance. In tumors without pre-existing resistant clones, some tumor clonogens survive, despite expressing the driver mutation, to acquire target reactivation or bypass resistance mechanisms. Identification of biomarkers that are mechanistically linked to EGFR TKI resistant cell populations would have clinical utility in early determination of disease recurrence in EGFR mutant NSCLC patients. Previously, we have reported that EGFR-TKI treatment activates Notch3, and here we have identified that Notch3 activates β-catenin transcriptional target, PAI1, which could play a role in drug persistence and could be used for early identification of disease recurrence. Our in vitro ELISA studies have identified an increase in secreted PAI1 levels after treatment with the EGFR TKIs erlotinib and osimertinib demonstrate that measuring PAI1 levels could serve as an indicator of EGFR TKI persistence. To further validate PAI1 as a surrogate biomarker for EGFR TKI treatment, we performed a retrospective study in NSCLC patients (n = 42) with EGFR mutant tumors. Using ELISA to detect PAI1 protein in pre- and post-treatment serum samples as a mechanism-based indicator for β-catenin activation, we observed a broad range in pre-treatment PAI1 levels, spanning from 0.8 ng/ml to 134 ng/ml, suggesting a variable baseline β-catenin activation. Doing survival analysis after dichotomizing patients into low and high baseline PAI1 level groups, we found patients with low basal PAI1 levels had a significantly shorter PFS with EGFR TKI treatment compared to patients with high basal levels. Comparing patients with a ≥ 2-fold induction to those with less than 2-fold, there was a similar trend for worsened survival in those who showed significant induction of PAI1. Overall, we demonstrate that PAI1 expression is a candidate marker for β-catenin activation and the development of drug persisters; thus, it is a potential surrogate marker for poor outcome in patients receiving EGFR TKI therapy and a potential biomarker for selecting patients for β-catenin-targeted therapy. Citation Format: Rajeswara Rao Arasada, Walter Wang, Shankar Suman, David Paul Carbone. PAI1, a β catenin transcriptional target, serves as a surrogate biomarker to predict EGFR TKI mediated drug persistence in EGFR mutant NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4930.