EGFR Wild-type Non-small Cell Lung Research Articles

Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein-Overexpressing Advanced Nonsquamous EGFR-Wildtype Non-Small Cell Lung Cancer in the Phase II LUMINOSITY Trial.

Telisotuzumab vedotin (Teliso-V) is a c-Met-directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier: NCT03539536) aimed to identify the optimal c-Met protein-overexpressing non-small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor (EGFR)-wildtype NSCLC. Eligible patients had locally advanced/metastatic c-Met protein-overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous EGFR-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%-<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review. In total, 172 patients with nonsquamous EGFR-wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%). Teliso-V was associated with durable responses in c-Met protein-overexpressing nonsquamous EGFR-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.

Genome-scale CRISPR-Cas9 screen identifies PAICS as a therapeutic target for EGFR wild-type non-small cell lung cancer.

Epidermal growth factor receptor-targeted (EGFR-targeted) therapies show promise for non-small cell lung cancer (NSCLC), but they are ineffective in a third of patients who lack EGFR mutations. This underlines the need for personalized treatments for patients with EGFR wild-type NSCLC. A genome-wide CRISPR/Cas9 screen has identified the enzyme phosphoribosylaminoimidazole carboxylase/phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS), which is vital in de novo purine biosynthesis and tumor development, as a potential drug target for EGFR wild-type NSCLC. We have further confirmed that PAICS expression is significantly increased in NSCLC tissues and correlates with poor patient prognosis. Knockdown of PAICS resulted in a marked reduction in both in vitro and in vivo proliferation of EGFR wild-type NSCLC cells. Additionally, PAICS silencing led to cell-cycle arrest in these cells, with genes involved in the cell cycle pathway being differentially expressed. Consistently, an increase in cell proliferation ability and colony number was observed in cells with upregulated PAICS in EGFR wild-type NSCLC. PAICS silencing also caused DNA damage and cell-cycle arrest by interacting with DNA repair genes. Moreover, decreased IMPDH2 activity and activated PI3K-AKT signaling were observed in NSCLC cells with EGFR mutations, which may compromise the effectiveness of PAICS knockdown. Therefore, PAICS plays an oncogenic role in EGFR wild-type NSCLC and represents a potential therapeutic target for this disease.

Cost of care in EGFR mutant versus wild-type non-small cell lung cancer.

e21084 Background: Lung cancer remains the most commonly diagnosed cancer in the United States, as well as the leading cause of cancer-related mortality. Approximately 84% of all lung cancers are non-small cell lung cancer (NSCLC). Most are diagnosed at an advanced stage when the prognosis is poorest. EGFR is the most common driver mutation in NSCLC with an incidence ranging from 20% in Caucasians, and up to 50% in Asians. Oral tyrosine kinase inhibitors (TKI) are the preferred treatment for EGFR mutant cancers as they provide better outcomes and lower toxicity than chemotherapy (Ch) or immunotherapy (ICI). Therefore, it is imperative to analyze NSCLC patients for these important driver mutations. Cancer care is expensive with the treatments and attendant costs for administration and management. We sought to compare cost of care (COC) in EGFR mutant vs wild-type NSCLC as the treatments and known toxicities differ markedly. Methods: We performed a retrospective COC analysis of NSCLC using claims data from the local BCBS affiliate Highmark (HM) members. Patients were selected based on NSCLC diagnosis codes between October 2016 and September 2018. COC was calculated from claims data to compare treatment of driver mutant NSCLC with targeted therapy versus treatment of wild-type NSCLC with ICI and/or ChT. Data used to compare COC analysis included overall medical costs defined as all medical claims incurred by a patient following start of respective therapy, oncology related medical claims, therapy costs, costs related to emergency room visits and tissue biopsies. Overall medical costs, oncology related costs and therapy costs were measured in per member per month (PMPM). We extracted cost related data at 6 months, 12 months, and 18 months into treatment. Results: Patients treated with ICI and/or ChT incurred $1000-2000 more in PMPM total medical costs than patients treated with targeted therapy. Additionally, chemoimmunotherapy patients were found to have a 5% higher emergency room admission rate along with a longer median length of stay of 1/3 day, when compared to targeted therapy patients. ICI and/or ChT patients showed a 20% higher rate of tissue biopsy and a 5-10% higher rate of repeat tissue biopsy which incurred an additional $300-$400 expense for chemoimmunotherapy patients. Conclusions: The use of targeted treatment with TKIs in EGFR mutant NSCLC patients is more cost effective than ICI and/or ChT in wild-type NSCLC. Routine screening of lung cancer patients with molecular profiling is essential, as identification of such critical driver mutations can alter the treatment plan to be more efficient, providing better care at lower cost.

Hedgehog Suppresses Paclitaxel Sensitivity by Regulating Akt-Mediated Phosphorylation of Bax in EGFR Wild-Type Non-Small Cell Lung Cancer Cells.

Non-small cell lung cancer (NSCLC) is one of the most common and deadly cancers worldwide. Among NSCLC patients, almost half have wild-type epidermal growth factor receptor (EGFR WT). The primary therapeutic option for these EGFR WT NSCLC patients is chemotherapy, while NSCLC patients with EGFR mutations have more diverse therapeutic options, including EGFR tyrosine kinase inhibitors. Moreover, NSCLC patients with EGFR WT have worse chemotherapy response than EGFR mutant NSCLC patients. Thus, an urgent need exists for novel therapeutic strategies to improve chemotherapy response in EGFR WT NSCLC patients. Hedgehog signaling is known to be highly active in NSCLC; however, its potential role in chemoresistance is not fully understood. In the present study, we found that paclitaxel (PTX) treatment induces hedgehog signaling in EGFR WT NSCLC cells, and inhibition of hedgehog signaling with GDC-0449 (Vismodegib) increases sensitivity to PTX-stimulated apoptosis. Furthermore, GDC-0449 potentiates PTX-induced reactive oxygen species and mitochondrial dysfunction. In contrast, a hedgehog agonist, Hh-Ag1.5, attenuates PTX-induced apoptosis. Mechanistic experiments revealed that hedgehog induces phosphorylation of Akt at Ser473. Akt then phosphorylates Bax at Ser184, which can switch its activity from pro-apoptosis to anti-apoptosis. Taken together, our findings suggest that inhibition of hedgehog signaling might be a promising therapeutic strategy to improve PTX response in EGFR WT NSCLC.

Classification of Non-Small Cell Lung Cancer’s Tumor Immune Micro-Environment and Strategies to Augment Its Response to Immune Checkpoint Blockade

Simple SummaryImmune checkpoint blockade (ICB) has become a major treatment for lung cancer. Better understanding of the tumor immune micro-environment (TIME) in non-small cell lung cancer (NSCLC) is urgently needed to better treat it with this type of therapy. In this review, we describe and explore how NSCLC’s TIME relates to response to ICB, as well as how to treat those with unresponsive types of TIME, which will significantly impact future research in lung cancer immunotherapy.Immune checkpoint blockade (ICB) with checkpoint inhibitors has led to significant and durable response in a subset of patients with advanced stage EGFR and ALK wild-type non-small cell lung cancer (NSCLC). This has been consistently shown to be correlated with the unique characteristics of each patient’s tumor immune micro-environment (TIME), including the composition and distribution of the tumor immune cell infiltrate; the expression of various checkpoints by tumor and immune cells, such as PD-L1; and the presence of various cytokines and chemokines. In this review, the classification of various types of TIME that are present in NSCLC and their correlation with response to ICB in NSCLC are discussed. This is conducted with a focus on the characteristics and identifiable biomarkers of different TIME subtypes that may also be used to predict NSCLC’s clinical response to ICB. Finally, treatment strategies to augment response to ICB in NSCLC with unresponsive types of TIME are explored.

Imaging Pattern of Diffuse Intrapulmonary Metastases in Lung Cancer Was Associated with Poor Prognosis to Epidermal Growth Factor Receptor Inhibitors.

BackgroundEpidermal growth factor receptor (EGFR) mutations are more frequently seen in miliary intrapulmonary metastases than EGFR wild-type non-small cell lung cancer (NSCLC). Also, small-scale retrospective studies showed that patients harboring EGFR mutation with miliary pulmonary metastases had a worse prognosis. This study aimed to explore the impact of imaging patterns on the outcomes of EGFR tyrosine kinase inhibitor (TKI) treatment.MethodsA cohort of treatment-naive NSCLC patients harboring EGFR mutation with intrapulmonary metastases who were prescribed with TKI were enrolled. The demographic feature, clinical outcome, and CT imaging of each patient were reviewed and analyzed.ResultsA cohort of 174 patients were enrolled. Five intrapulmonary patterns of imaging were recognized: solid nodular, ground-glass nodular, miliary, multiple uniform nodular, and not otherwise specified. Among them, miliary and multiple uniform nodular patterns had similar poor prognosis, and, therefore, were combined as diffuse group. A worse PFS (9.0 mon, 95% CI: 8.0–10.0 mon) was observed compared with the rest (non-diffuse group, 13.3 mon, 95% CI: 10.2–16.4 mon, p<0.001, HR=0.49). The objective response rates (ORR) between the two groups were 76.8% and 84.1%, respectively, with no significant difference (p = 0.474). The OS of the diffuse and the non-diffuse group were 25.6 mon (95% CI 21.9–29.3 mon) and 35.0 mon (95% CI: 27.5–42.5, p = 0.01, HR= 0.59). Organs like bone (p=0.167), liver (p=0.513), and adrenal gland (p=0.375) were involved in similar frequencies in both groups. However, brain (p=0.070) and leptomeningeal (p=0.078) metastases were less common in the non-diffuse group with marginally statistical significance. The 2 groups contained similar missense mutations, and gene amplification was more common in the non-diffuse group.ConclusionPatients with diffuse intrapulmonary metastases had inferior outcomes after TKI treatment. More aggressive treatments might be warranted for these patients.

317O - Association of survival and blood-based genomic signature with atezolizumab for patients with second-line and third-line EGFR wild-type non-small cell lung cancer: Pooled analysis of individual patient data from the POPLAR and OAK trials

BackgroundIndividual patient data from two multicentre, randomised trials comparing atezolizumab with docetaxel in previously treated advanced non-small-cell lung cancer (NSCLC) were analyzed to identify any preferable therapeutic approaches for patient subsets stratified by EGFR mutation status. MethodsWe pooled 1,137 patients from the phase II POPLAR trial (NCT01903993) and the phase III OAK trial (NCT02008227). Patients were randomly assigned to receive either atezolizumab or docetaxel and were analyzed based on stratification of EGFR mutation status. We built a novel algorithm integrating the blood-based tumor mutation burden and the ctDNA maximum somatic allele frequency (bTMB-MSAF score) and developed a novel clinicopathologic-genomic nomogram to predict individual survival. ResultsIn the whole intention-to-treat population, OS was significantly longer with atezolizumab than with docetaxel (hazard ratio [HR] 0.72, P < 0.001). Among patients without EGFR or ALK mutations, overall survival (OS) was significantly longer with atezolizumab than with docetaxel (HR 0.67; P < 0.001); patients with a bTMB-MSAF score<20 showed improvement in OS (HR 0.56; P < 0.001) and progression-free survival (PFS) (HR 0.74; P = 0.0023), and these patients who concurrently had programmed death ligand 1 (PD-L1) expressing on over 50% tumor cells or over 10% of tumor-infiltrating immune cells (TC3 or IC3) had the greatest OS improvements (HR 0.44; P = 0.007) and promising PFS benefits (HR 0.54; P = 0.019). EGFR mutant patients could not gain significant OS or PFS benefits from atezolizumab over docetaxel, irrespective of PD-L1 expression and bTMB-MSAF score. Patients with low-risk scores had longer OS (HR 0.17; P < 0.001; AUC=0.912 for 3-year OS) than patients with high-risk scores classified by the nomogram. ConclusionsAtezolizumab showed better OS and PFS than docetaxel in previously treated EGFR wild-type NSCLC patients with a bTMB-MSAF score < 20, especially in those with PD-L1 expression of TC3 or IC3. Our clinicopathologic-genomic nomogram is effective in predicting survival of NSCLC patients undergoing atezolizumab. Clinical trial identificationNCT01903993 and NCT02008227. Legal entity responsible for the studyHerui Yao. FundingHerui Yao is funded by the National Science and Technology Major Project under Grant [2020ZX09201021]; National Natural Science Foundation of China under Grant [81372819, 81572596, U1601223]; Natural Science Foundation of Guangdong Province under Grant [2017A030313828]; and Guangzhou Science and Technology Program under Grant [201704020131]. DisclosureAll authors have declared no conflicts of interest.

P2.01-20 Anlotinib vs. Docetaxel in Advanced Non-Squamous NSCLC (EGFR Wild-Type) After Progression on Platinum-Based Chemotherapy: A Trial Protocol

Anlotinib, an oral VEGFR, FGFR, PDGFR and c-Kit tyrosine kinase inhibitor, showed significantly longer overall survival in a phase 3 trial. In the multi-center, open-label, randomized controlled ALTER-L023 trial, we compared anlotinib with docetaxel as second-line treatment in patients with advanced non-squamous EGFR wild-type non-small cell lung cancer (NSCLC) previously given platinum-based doublet chemotherapy. This multi-center, open-label, randomized controlled ALTER-L023 trial was conducted at 10 hospitals in China. Eligible patients with previously treated non-squamous EGFR wild-type NSCLC were randomly assigned (1:1) to receive anlotinib (12 mg QD from day 1 to 14 of a 21-day cycle) or docetaxel (75mg/m2, on day 1 of a 21-day cycle) till progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS), that was defined as the time from randomization to disease progression or death. The secondary endpoints included objective response rate, disease control rate, duration of response and safety. Based on a two-sided log-rank test at 5% significance level, a power of 80% and a median PFS of 6 months for anlotinib versus 3 months for docetaxel, the simple size was estimated at 77 patients. Allowing for 15% dropouts, the sample size was set at 88 patients (44 patients in both groups). Clinical trial information: NCT03703596 Section not applicable Section not applicable

Radiosensitivity Differences between EGFR Mutant and Wild-Type Lung Cancer Cells are Larger at Lower Doses.

In the era of precision medicine, radiotherapy strategies should be determined based on genetic profiles that predict tumor radiosensitivity. Accordingly, pre-clinical research aimed at discovering clinically applicable genetic profiles is needed. However, how a given genetic profile affects cancer cell radiosensitivity is unclear. To address this issue, we performed a pilot in vitro study by utilizing EGFR mutational status as a model for genetic profile. Clonogenic assays of EGFR mutant (n = 6) and wild-type (n = 9) non-small cell lung carcinoma (NSCLC) cell lines were performed independently by two oncologists. Clonogenic survival parameters SF2, SF4, SF6, SF8, mean inactivation dose (MID), D10, D50, α, and β were obtained using the linear quadratic model. The differences in the clonogenic survival parameters between the EGFR mutant and wild-type cell lines were assessed using the Mann–Whitney U test. As a result, for both datasets, the p values for SF2, SF4, D50, α, and α/β were below 0.05, and those for SF2 were lowest. These data indicate that a genetic profile of NSCLC cell lines might be predictive for their radiation response; i.e., EGFR mutant cell lines might be more sensitive to low dose- and low fraction sized-irradiation.

Erlotinib en 2e ou 3e ligne pour les cancers bronchiques non à petites cellules sans mutation de l’EGFR : données en vie réelle

The benefit of tyrosine kinase inhibitors for patients with an EGFR wild-type non-small cell lung cancer (NSCLC) remains controversial. The survival of patients with an EGFR wild-type NSCLC who received second- or third-line erlotinib treatment was assessed using real-life data that had been collected in a prospective, national, multicenter, non-interventional cohort study. Data from 274 patients were analysed, 185 (68%) treated with erlotinib and 89 (32%) treated with supportive care only. The median overall survival was 4.2months (95% CI [3.5; 5.4]) with erlotinib, and 1.3months (95% CI [1.0; 1.8]) with supportive care. Survival rate at 3, 6, and 12months was 62%, 37%, and 17%, respectively, with erlotinib, versus 20%, 8%, et 3%, with exclusive supportive care. Significant predictive factors for longer overall survival were the presence of adenocarcinoma, and use of 1st line chemotherapy including either taxanes, pemetrexed or vinorelbine (P<0.05). Erlotinib remains a valuable therapeutic option to treat inoperable locally advanced or metastatic NSCLC after failure of at least one prior chemotherapy regimen in fragile patients who are not eligible for chemotherapy.

P1.13-36 Randomized Phase 2 Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer

P1.13-36 Randomized Phase 2 Trial of Seribantumab in Combination with Erlotinib in Patients with EGFR Wild-Type Non-Small Cell Lung Cancer

Shikonin enhances sensitization of gefitinib against wild-type EGFR non-small cell lung cancer via inhibition PKM2/stat3/cyclinD1 signal pathway

AimsMutant EGFR Non-small cell lung cancer has benefit from gefitinib, but it has limited effect for wild-type EGFR tumors. Shikonin, a natural naphthoquinone isolated from a traditional Chinese medicine, the plant Lithospermum erythrorhizon (zicao), not only can inhibit the tumor growth, but also overcome cancer drug resistance. Our aim is to investigate whether shikonin can enhance antitumor effect of gefitinib in EGFR wild-type lung cancer cells in vitro and in vivo. Materials and methodsCCK-8 was used to determine the proliferation of EGFR wild-type non-small cell lung cancer. Apoptosis and cell cycle were detected by flow cytometry. PKM2, STAT3, p-STAT3 and cyclinD1 were detected by Western blot. A549 tumor model was established to observe the antitumor effect of shikonin combination with gefitinib in vivo. Key findingsThe results showed that combination of shikonin with gefitinib exhibited synergistic antitumor effect in vitro and in vivo. Its potential molecular mechanisms may be associated with inhibition of PKM2/STAT3/cyclinD1. SignificanceThese results provide a promising therapeutic approach for the treatment of wild-type EGFR non-small cell lung cancer.

A study of EGFR wild-type non-small cell lung cancer ALK genetic mutation

Background: the positive rate and clinicopathological features of EML4-ALK, the relationship between EGFR mutations in non-small cell lung cancer (NSCLC) patients are the state of confusion, automatic immunohistochemistry to detect the expression of ALK protein, to provide reference for clinical diagnosis and treatment.

EGFR tyrosine kinase inhibitors versus chemotherapy in EGFR wild-type pre-treated advanced nonsmall cell lung cancer indaily practice.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are approved for second-line treatment of EGFR wild-type (EGFR-wt) nonsmall cell lung cancer (NSCLC). However, results from randomised trials performed to compare EGFR-TKIs with chemotherapy in this population did not show any survival benefit. In the era of immunotherapy, many drugs are approved for second-line treatment of EGFR-wt NSCLC and there is a need to reassess the role of EGFR-TKIs in this setting.The Biomarkers France study is a large nationwide cohort of NSCLC patients tested for EGFR mutations. We used this database to collect clinical, biological, treatment and outcome data on EGFR-wt patients who received second-line treatment with either EGFR-TKIs or chemotherapy.Among 1278 patients, 868 received chemotherapy and 410 received an EGFR-TKI. Median overall survival and progression-free survival were longer with chemotherapy than with an EGFR-TKI. Overall survival was 8.38 versus 4.99 months, respectively (hazard ratio 0.70, 95% CI 0.59-0.83; p<0.0001) and progression-free survival was 4.30 versus 2.83 months, respectively (hazard ratio 0.66, 95% CI 0.57-0.77; p<0.0001).This study is helpful to guide a multiline treatment strategy for EGFR-wt NSCLC patients. Immunotherapy is approved for second-line treatment. For third-line treatment, chemotherapy results in longer overall survival and progression-free survival, and should be preferred to EGFR-TKIs.

464P Apatinib (YN968D1) in performance status 2 or 3 patients with EGFR wild-type metastatic non-small cell lung cancer (NSCLC): A single-arm phase II study

464P Apatinib (YN968D1) in performance status 2 or 3 patients with EGFR wild-type metastatic non-small cell lung cancer (NSCLC): A single-arm phase II study

Pharmacodynamic separation (PDS) of pemetrexed (Pem) and erlotinib (Erl) in patients (pts) with advanced, EGFR wild-type (wt) Non-Small Cell Lung Cancer (NSCLC): A randomized phase II trial.

8044 Background: We previously reported that PDS of Pem and Erl (Pem 500 mg/m2 IV on day 1 and Erl 150 mg po QD on days 2-17 of a 21-day cycle) as 2nd-line therapy has promising clinical activity o...

Cabozantinib (C), erlotinib (E) or the combination (E+C) as second- or third-line therapy in patients with EGFR wild-type (wt) non-small cell lung cancer (NSCLC): A randomized phase 2 trial of the ECOG-ACRIN Cancer Research Group (E1512).

8003 Background: Cabozantinib (C) is a small molecule inhibitor of multiple receptor tyrosine kinases, including MET, VEGFR2 & RET. MET is involved in tumor differentiation & VEGFR2 is a mediator of angiogenesis. Erlotinib (E) is FDA approved for the treatment of NSCLC. Methods: The primary objective of this randomized phase II study was to compare progression-free survival (PFS) of patients (pts) treated with E vs. C, & E vs E+C; each comparison had 91% power to detect a PFS hazard ratio (HR) of 0.5 with a 1-sided 0.10-level test stratified on prior number of therapies & ECOG PS. Secondary objectives included overall survival (OS), RECIST 1.1 response & CTCAE v4 toxicity. Pts were selected with previously treated (1-2 regimens) metastatic non-squamous EGFR wt NSCLC. Submission of archival tissue for central MET IHC testing was required. Oral daily dosing was: E-150 mg; C-60 mg; E+C-150 mg E, 40 mg C. Imaging was performed every 8 weeks. Pts optionally crossed over to E+C following progression on E or C. ...

AKT inhibition synergistically enhances growth-inhibitory effects of gefitinib and increases apoptosis in non-small cell lung cancer cell lines

ObjectivesEGFR inhibitors are ineffective against most EGFR wild-type non-small cell lung cancer, for which novel treatment strategies are needed. AKT signalling is essential for mediating EGFR survival signals in NSCLC. We evaluated the combination of gefitinib and two different AKT inhibitors, the allosteric inhibitor AKTi-1/2 and the ATP-competitive pan-AKT inhibitor AZD5363, in EGFR-mutant (HCC-827 and PC-9) and -wild-type (NCI-H522, NCI-H1651), non-small cell lung cancer cell lines. Materials and methodsDrug interaction was studied in two EGFR mutant and two EGFR wild-type non-small cell lung cancer cell lines by calculating combination index (CI) using median effect analysis. The effects on p-EGFR, p-ERK, p-AKT, p-S6 and apoptosis were studied by Western blot analysis. ResultsThe combination of gefitinib and AKTi-1/2 or AZD5363 showed synergistic growth inhibition in all cell lines. CI values for the combination of gefitinib and AKTi-1/2 were 0.35 (p=0.0048), 0.56 (p=0.036), 0.75 (p=0.13) and 0.64 (p=0.0003) in NCI-H522, NCI-H1651, HCC-827 and PC-9 cell lines, respectively; CI values of 0.45 (p=0.0087) and 0.22 (p<0.0001) were observed in NCI-H522 and PC-9 cells, respectively, when gefitinib was combined with AZD5363. Additive inhibition of signalling output through AKT and key downstream proteins (S6) and increased apoptosis were demonstrated. ConclusionDual inhibition of EGFR and AKT may be a useful up-front strategy for patients with EGFR-mutant and -wild-type non-small cell lung cancer.

Second- and third-line treatment of EGFR wild-type non-small cell lung cancer (NSCLC): A retrospective real-world practice review of the use of tyrosine kinase inhibitors at a single tertiary care center.

e19147 Background: Wild-type NSCLC constitutes the large majority of lung cancers, but treatment is limited. Current standard for second-line treatment are pemetrexed, docetaxel or erlotinib. Few t...

Abstract A66: Ablative radiotherapy increases invasion potential in EGFR-wildtype non-small cell lung cancer cells compared to fractionated radiotherapy.

Abstract Introduction: Non-small cell lung cancer (NSCLC) accounts for over 80% of all lung cancer cases. Nearly 70% of lung cancer patients will undergo radiotherapy (RT). Recent trends in RT have shown an increase in the use of ablative radiotherapy (ART) in inoperable small tumors with response rates of 80-90% in NSCLC patients. However, despite the high rate of local control, early clinical data shows no advantage in survival due to distant metastasis after ART compared to conventional fractionated radiotherapy (FRT). In addition, patient selection for ART is independent of the status of the epidermal growth factor receptor (EGFR) which has been shown to play a role in radiation response. We investigated the effect of ART compared to FRT on cell invasion, proliferation, senescence and clonogenic survival of NSCLC cell lines harboring wild type and mutated EGFR. Methods: The cell lines used were A549, H1975 and HCC827. Cell irradiation was performed using a Faxitron X-Ray machine. Radiation doses of 8Gy and12Gy were delivered in fractionated or single sessions. The effect of radiation on cells was investigated using the clonogenic assay, MTT proliferation assay, matrigel invasion assay and senescence-associated beta-galactosidase. Results: ART significantly suppressed the proliferative and clonogenic potential of wild-type EGFR A549 cells compared to FRT. In addition, a significant increase in the number of senescent as well as large, polynucleated cells was observed in the ART-treated group compared to the FRT-treated group. Analysis of the invasive potential of the cells revealed a 2-fold increase in invasion 5 days after exposure to ART of 12Gy compared to control. The FRT group showed a 1.4-fold increase in invasion compared to control. Contrary to A549 cells, EGFR-mutated NSCLC HCC827 and H1975 cells, showed no significant difference after exposure to ART compared to FRT. In addition, both ART and FRT-treated groups showed a similar increase in the number of senescent, large and polynucleated cells. A significant reduction in the number of invading cells after exposure to either FRT or ART was observed compared to the control. Conclusion: ART significantly reduces cell proliferation and clonogenic survival compared to FRT in wild-type EGFR A549 cells. This differential response between the type of treatment (ART vs FRT) was not seen in NSCLC cell lines harboring EGFR mutations. In contrast to reduced cell proliferation, there was a significant increase in the invasive capacity of cells after ART compared to FRT in A549 cells only. These results can have significant consequences in the selection and treatment of NSCLC patients for ART. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A66. Citation Format: Ayman J. Oweida, Jack Xu, Siham Sabri, Bassam Abdulkarim. Ablative radiotherapy increases invasion potential in EGFR-wildtype non-small cell lung cancer cells compared to fractionated radiotherapy. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A66.