Non-adenocarcinoma Non-small Cell Lung Cancer Research Articles

Molecular Signatures of KRAS-Mutated Lung Adenocarcinoma: Analysis of Concomitant EGFR, ALK, STK11, and PD-L1 Status.

Background:KRAS mutations are the most common oncogenic driver mutations of non-small cell lung cancer (NSCLC) in the Western world. Mutations of the KRAS gene are most prevalent in the patient population of current and former cigarette smokers. With the recent pivotal approval of a targeted inhibitor therapy for patients with KRAS p.G12C mutated and pretreated NSCLC, analysis of the heterogeneity of KRAS mutations and concomitant molecular alterations in patients with these tumors at all clinical stages is indicated.Methods:In this retrospective analysis, patient pathology records were reviewed for all cases receiving a pathologic diagnosis of NSCLC within our hospital system. All data were collected with IRB approval. Cases of indeterminate tumor type favoring a non-lung primary, as well as non-adenocarcinoma NSCLC (eg, squamous) were excluded from the cohort. In this hospital system, molecular testing for KRAS mutations is part of a molecular biomarker panel that is reflex ordered at initial diagnosis by the pathologist and may be performed as a single gene test or as a solid organ cancer hotspot panel by next generation sequencing. For each patient, KRAS mutational status and specific KRAS mutations, if present, were collated. Additional information assessed for this study included patient demographics (age, gender, and smoking history), tumor staging if available, PD-L1 expression levels by immunohistochemistry (IHC), and the presence of other genetic alterations (EGFR, ALK, and STK11).Results:Between January 1, 2017 and January 1, 2019, there were 276 patients diagnosed with NSCLC of all stages who had KRAS mutational analysis performed in our hospital system and who met the criteria for inclusion into the study cohort. A KRAS driver mutation was detected in 29% of these patients. The most frequently identified KRAS mutation was p.G12C (38%), followed by p.G12D (21%) and p.G12V (13%). KRAS-mutated lung adenocarcinoma was significantly associated with current or former patient smoking status in this cohort (29/202 (14%) smokers and 1/74 (1%) non-smokers; P = .0006). PD-L1 expression of at least 1% by IHC was present in 43% of KRAS-mutated lung adenocarcinomas and 45% of non-KRAS-mutated adenocarcinomas. In this study, KRAS mutations were not found to co-occur with gene alterations in EGFR, ALK, or STK11. In 48% of cases, at least one genetic alteration (KRAS, ALK, EGFR, or STK11) was identified.Conclusions:In this study cohort, KRAS-mutated lung adenocarcinoma demonstrated significant mutational heterogeneity, which is consistent with previously published studies. KRAS mutational status was also significantly associated with a current or former smoking history. Notably, p.G12C was the most frequently identified KRAS mutation in this cohort, with a frequency of 38%. This finding is particularly relevant given the recent approval of a KRAS p.G12C-specific targeted inhibitor therapy and the continued development of additional KRAS targeted therapies that may prove effective in treating NSCLC. These findings also highlight the necessity of considering molecular testing for KRAS mutations in patients with NSCLC and a smoking history, as this population most frequently harbors KRAS mutations and may benefit from these emerging targeted therapies.

Expression Profiling of Driver Genes in Female Never-smokers With Non-adenocarcinoma Non–small-cell Lung Cancer in China

BackgroundAlthough smoking is a primary cause of lung cancer, females are overrepresented among never-smokers with the disease. The mutational landscape of adenocarcinoma in never-smoking females has been extensively profiled; however, there is little knowledge about genomic alterations in non-adenocarcinoma non–small-cell lung cancer (NA-NSCLC). In the study, we reviewed the status of oncogenic drivers of NA-NSCLC in these populations. Materials and MethodsComprehensive genomic profiling was performed on DNA extracted from formalin-fixed, paraffin-embedded sections of 52 NA-NSCLC tissues, including 35 squamous cell carcinomas (SQCCs), 11 adenosquamous carcinomas, 5 pulmonary sarcomatoid carcinoma, and 1 large cell carcinoma by next-generation sequencing within a panel of 68 cancer-related genes. ResultsMutations of the common oncogenic drivers (EGFR, KRAS, ALK, ROS1, MET, RET, and ERBB2) occurred in 61.5% of cases. The frequency of well-established targets (EGFR and ALK), new targets without widely available therapies (MET and ERBB2), and potentially actionable targets (RET and DDR2) in SQCCs of female never-smokers was significantly higher than that in The Cancer Genome Atlas dataset. There were 31%, 82%, and 80% of cases with SQCC, adenosquamous carcinoma, and pulmonary sarcomatoid carcinoma, respectively, harboring at least one of the following targets: EGFR, ALK, ERBB2, and MET. Approximately 78% (7/9) of the patients responded to various targeted treatments. ConclusionFemale never-smokers with NA-NSCLC in this study had a high frequency of currently known or potentially actionable oncogenic alterations and could benefit from targeted therapy. Our study also provides evidence for the recommendation of molecular analysis in never-smoking female SQCC.

Characteristics and Response to Crizotinib in ALK-Rearranged, Advanced Non-Adenocarcinoma, Non-Small Cell Lung Cancer (NA-NSCLC) Patients: a Retrospective Study and Literature Review.

Oncogenic fusion genes consisting of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) can be detected in 5-7% of lung adenocarcinoma cases. The prevalence of ALK rearrangement in non-adenocarcinoma, non-small cell lung cancers (NA-NSCLC) is currently unknown. In addition, the efficacy of crizotinib in these patients has not been well established. The aim of this study was to investigate the prevalence of ALK rearrangement in NA-NSCLC patients and the therapeutic efficacy of crizotinib in these patients. We included NA-NSCLC patients who were tested for the presence of ALK rearrangement in our institution from January 2013 to May 2018. The effectiveness of crizotinib in ALK-positive patients was retrospectively analyzed. A literature review was performed and eligible previously published cases were analyzed in combination with our data. A total of 4662 patients were screened and 1696 NA-NSCLC patients were tested for the presence of ALK rearrangement during the study period. Thirty-two positive patients were identified (1.9%, 95% CI, 1.2-2.5%). A statistically higher percentage of younger (58.0 vs. 63.0, p = 0.01), female patients (53.1% vs. 10.8%, p < 0.01) who were non-smokers (71.9% vs. 40.6%, p < 0.01) and whose tumors contained adenocarcinoma components (34.4% vs. 6.1%, p < 0.01) were observed in the ALK-positive group. Eighteen patients were excluded from the study and 14 eligible patients were included for survival analysis. The median duration of crizotinib treatment (MDT) as a proxy for progression-free survival of the 14 eligible patients in our institution was 6.0months (95% CI, 1.2-10.8months). We combined our data with sporadic cases from 16 previous publications (total n = 37) and found that the MDT was 7.0months (95% CI, 6.0-8.0months). Our study suggests the opportunity to test ALK rearrangement in NA-NSCLC patients, especially in younger, female, non-smoking patients containing adenocarcinoma components. Crizotinib provides an option for the treatment of NA-NSCLC patients who have an ALK rearrangement.

Clinical efficacy evaluation of tyrosine kinase inhibitors for non-adenocarcinoma lung cancer patients harboring EGFR-sensitizing mutations.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) as a standard therapy have been used in EGFR-mutated adenocarcinoma of non-small-cell lung cancer (NSCLC) patients in recent years. But in current randomized prospective clinical trials, due to few cases of non-adenocarcinoma patients having been found, the efficacy of TKIs for EGFR-mutated non-adenocarcinoma and the relationship with clinicopathological characteristics remained debatable. The results of retrospective studies showed that the frequency of EGFR mutation was significantly associated with nationality, gender, smoking history, and histology type. Being female, never-smoker and adenocarcinoma had a higher mutation rate. Furthermore, the EGFR mutation rate and efficacies of TKIs in adenocarcinoma were higher than those in non-adenocarcinoma. And in non-adenocarcinoma, the EGFR mutation rate and efficacies of TKIs in adenosquamous cell carcinoma were higher than those in squamous cell carcinoma or in large-cell lung carcinoma. In conclusion, it may be necessary to conduct a large sample prospective study to understand the clinicopathological characteristics of non-adenocarcinomas and to evaluate the efficacy of EGFR TKI and/or chemotherapy for EGFR-mutated non-adenocarcinoma NSCLC. So we searched relevant articles between the year 2010 and 2016 through the major indexed literature database PubMed by searching the keywords such as EGFR mutation, Tyrosine kinase inhibitors, and Non-adenocarcinoma.

P1.02-013 Clinicopathological Characteristics and Survival of ALK, ROS1 and RET Arrangements in Non-Adenocarcinoma Non-Small Cell Lung Cancer Patients

ALK, ROS1 and RET rearrangements represent three most frequency of fusion genes in non-small cell lung cancer (NSCLC). Rearrangements of the three genes are predominantly found in lung adenocarcinoma，while,rare in non-adenocarcinoma. The aim of this study was to investigate the frequency, clinicopathological characteristics and survival of ALK, ROS1 and RET arrangements in non-adenocarcinoma NSCLC patients. We screened ALK, ROS1, and RET arrangements in patients with completely resected non-adenocarcinoma NSCLC using reverse transcriptase polymerase chain reaction (PCR). All positive samples were confirmed with fluorescence in situ hybridization (FISH). Survival analysis was performed with Kaplan-Meier method and log-rank for comparison. Totally, 385 patients, who underwent complete resection, including 245 with squamous cell carcinoma, 85 with adenosquamous carcinoma and 55 with large cell carcinoma were enrolled. Twelve patients were identified as harboring fusion genes, including seven with ALK, three with ROS1 and two with RET rearrangements. The frequencies of fusions in adenosquamous carcinoma, squamous cell carcinoma, and large cell carcinoma were 8.2%, 1.6% and 1.8%, respectively. The median age of 12 patients was 49.5 years and three patients had smoking history. No survival difference existed between fusion genes positive and negative patients (36.7 vs.50.2 months, P=0.21). The frequencies of ALK, ROS1 and RET rearrangements are low in non-adenocarcinoma NSCLC patients, and the clinical characteristics are similar with those in lung adenocarcinoma. Fusions of the three genes are not prognostic marker for non-adnocarcinoma NSCLC patients.

P2.02-046 Prognostic Value of Early Tumor Regression during Chemo-Radiotherapy in Locally Advanced Non-Small Cell Lung Cancer

Volumetric changes are observed on serial cone-beam computed tomography (CBCT) images obtained for image-guidance throughout the course of radical radiotherapy for non-small cell lung cancer (NSCLC). This study aims to a) examine whether the magnitude of tumor regression is correlated with disease control and survival; b) explore the potential difference between adenocarcinoma and non-adenocarcinoma NSCLC subtypes. In a previous study from our institution, primary tumor volumes were assessed on weekly CBCT images of 60 NSCLC patients treated with radical radiotherapy from January 2006 to June 2007. We performed a retrospective review of these patients, documenting patient-, tumor-, and treatment-related details. Outcome measures included loco-regional failure free survival (LRFFS), distant failure free survival (DFFS), disease free survival (DFS) and overall survival (OS), which were calculated using Kaplan-Meier method. Uni-variable analysis (UVA) and multivariable analysis (MVA) were performed using Cox regression model. Further analysis was performed for the adenocarcinoma and non-adenocarcinoma subgroups. Forty-five patients with locally advanced NSCLC were included in this study. Median follow-up was 22.1 months for all patients, and 90 months for alive patients (range: 0.9-108). The distribution of 7th ed. AJCC stage was as follows: stage II 8.9%; IIIA 66.7%; IIIB 24.4%. Twenty patients (44.4%) had adenocarcinoma, while 25 patients (55.6%) had non-adenocarcinoma. Twenty-eight patients (62.3%) received total radiation dose ≥ 60Gy, 15 patients (33.3%) received 45Gy as neoadjuvant therapy, and 2 patients (4.4%) received 58-59Gy due to missed fractions. 23 patients (51.1%) had more than 30% regression by fraction 15 and 32 patients (71.1%) by treatment completion. In UVA, adenocarcinoma (p=0.03) was associated with better LRFFS; young age was associated with better LRFFS (p=0.02), DFFS (p=0.048) and OS (p=0.04). In MVA, large regression by fraction 15 was associated with better DFS (p=0.047). For patients with adenocarcinoma, MVA showed that large regression by fraction 15 was associated with better DFFS (p=0.01), DFS (p=0.01) and OS (p=0.02). For patients with non-adenocarcinoma, larger regression by treatment completion and trimodality therapy (radiation dose of 45Gy) were associated with better LRFFS (p=0.02, 0.04). Evaluation of tumor regression on CBCT images during radiotherapy may be predictive of treatment response. Early tumor regression, as indicated by regression ≥ 30% by fraction 15, was associated with better DFS for all patients; and this was associated with better DFFS, DFS and OS for the adenocarcinoma cohort. This observation may provide insight into when and how to best utilize adaptive radiotherapy.

Clinicopathological characteristics and survival of ALK, ROS1 and RET rearrangements in non-adenocarcinoma non-small cell lung cancer patients

ABSTRACTBackground: ALK, ROS1 and RET rearrangements represent 3 most frequent fusion genes in non-small cell lung cancer (NSCLC). Rearrangements of these 3 genes exist predominantly in lung adenocarcinoma while rarely in non-adenocarcinoma. Our objective was to explore the frequency, clinicopathological characteristics and survival of ALK, ROS1 and RET rearrangements in non-adenocarcinoma NSCLC patients.Methods: ALK, ROS1 and RET rearrangements were screened by reverse transcriptase polymerase chain reaction (RT-PCR) in patients with completely resected non-adenocarcinoma NSCLC. All positive samples were confirmed with fluorescence in situ hybridization (FISH). Survival analysis was performed with Kaplan-Meier method and log-rank for comparison.Results: A total of 385 patients underwent complete resection, including squamous cell carcinoma (n = 245), adenosquamous carcinoma (n = 85) and large cell carcinoma (n = 55). Twelve of them were identified as harboring fusion genes, including ALK (n = 7), ROS1 (n = 3) and RET (n = 2) rearrangements. The fusion frequencies of adenosquamous, squamous cell and large cell carcinomas were 8.2%, 1.6% and 1.8% respectively. Their median age was 49.5 y and 3 of them had a smoking history. No survival difference existed between fusion gene positive and negative patients (36.7 vs.50.2 months, P = 0.21).Conclusion: The frequencies of ALK, ROS1 and RET rearrangements are low in non-adenocarcinoma NSCLC patients. And their clinical characteristics are similar to those in lung adenocarcinoma. Fusions of the above 3 genes are not prognostic factor for non-adnocarcinoma NSCLC patients.

Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma lung cancer patients harboring EGFR-sensitizing mutations in China.

EGFR tyrosine kinase inhibitors (TKIs) have been established as standard therapy for EGFR-mutated adenocarcinomas; for non-adenocarcinoma non-small cell lung cancer (NSCLC) patients, this therapy remains debatable. Stage IIIB/IV patients with non-adenocarcinoma NSCLC who underwent EGFR testing were identified at the Shanghai Chest Hospital from January 2009 to September 2014. A total of 51 patients with EGFR-sensitizing mutations [26 patients with squamous cell carcinoma (SCC), 15 patients with adenosquamous cell carcinoma (ASC), and 10 patients with large cell lung carcinoma (LCLC)] were available for analysis of EGFR TKI treatment efficacy. The progression-free survival (PFS) for the 51 patients harboring EGFR-sensitizing mutations was 4.93months (95% CI 3.93-5.93). The PFS for the SCC, ASC, and LCLC patients was 3.98months (95% CI 3.32-4.63), 8.08months (95% CI 4.17-12.00), and 4.40months (95% CI 1.56-7.24), respectively. Among the 51 non-adenocarcinoma NSCLC patients, the PFS of the non-smokers and smokers was 5.49months (95% CI 3.28-7.70) and 3.78months (95% CI 2.61-4.95), respectively (P=0.036). The PFS for the patients with a deletion in exon 19 and for those with an exon 21 L858R mutation was 5.16months (95% CI 4.21-6.11) and 4.04months (95% CI 2.35-5.73), respectively (P=0.414). EGFR TKIs could be an option for the treatment of EGFR-mutated non-adenocarcinoma NSCLC, especially for patients with adenosquamous histology and non-smokers.

Epidermal growth factor receptor mutations and brain metastasis in patients with nonadenocarcinoma of the lung.

This study explored the potential association between epidermal growth.factor receptor. (EGFR) mutation status and brain metastasis in patients with nonadenocarcinoma nonsmall cell lung cancer. (NSCLC). We analyzed clinical data from 286 patients with nonadenocarcinoma NSCLC, who were tested for EGFR mutations and underwent brain magnetic resonance imaging at diagnosis. We examined the relationship between EGFR mutation and brain metastasis at initial presentation. Of the 286 patients, 20 patients (7.0%) had EGFR mutations. EGFR mutations were more frequent in younger patients (11.1% in patients =64 years vs. 3.3% in patients >64 years: P = 0.01), females (21.4% vs. 3.5% in males: P <0.001), never-smokers (25.0% vs. 3.4% in smokers: P < 0.001), and tumors with nonsquamous histology (25.0% vs. 4.1% in squamous histology: P < 0.001). At diagnosis, the frequency of EGFR mutations was significantly different in patients with metastasis to different sites (4.0% [no metastases] vs. 10.4% [extracranial metastases] vs. 40.0% [brain metastases], P < 0.001). The strong association between EGFR mutation and brain metastasis remained significant in multivariate analysis (adjusted odds ratio [OR] = 9.68, 95% confidence interval [CI] =2.32-40.45; P = 0.002). Associations were also found for EGFR mutation status with nonsquamous histology (adjusted OR = 4.46, 95% CI = 1.46-13.56; P = 0.008). This study indicates that the likelihood of nonadenocarcinoma patients having EGFR mutant tumors may differ according to brain metastasis and squamous cell histology.

Randomized, phase III trial of figitumumab in combination with erlotinib versus erlotinib alone in patients with nonadenocarcinoma nonsmall-cell lung cancer

Figitumumab (CP-751,871) is a fully human IgG2 monoclonal antibody that inhibits the insulin-like growth factor 1 receptor. This multicenter, randomized, phase III study investigated the efficacy of figitumumab plus erlotinib compared with erlotinib alone in patients with pretreated, nonsmall-cell lung cancer (NSCLC). Patients (stage IIIB/IV or recurrent disease with nonadenocarcinoma histology) who had previously received at least one platinum-based regimen were randomized to receive open-label figitumumab (20 mg/kg) plus erlotinib 150 mg/day or erlotinib alone every 3 weeks. The primary end point was overall survival (OS). Of 583 patients randomized, 579 received treatment. The study was closed early by an independent data safety monitoring committee due to results crossing the prespecified futility boundary. At the final analysis, median OS was 5.7 months for figitumumab plus erlotinib and 6.2 months for erlotinib alone [hazard ratio (HR) 1.09; 95% confidence interval (CI) 0.91-1.31; P = 0.35]. Median progression-free survival was 2.1 months for figitumumab plus erlotinib and 2.6 months for erlotinib alone (HR 1.08; 95% CI 0.90-1.29; P = 0.43). Treatment-related nonfatal serious adverse events occurred in 18% and 5% of patients in the figitumumab arm or erlotinib alone arm, respectively. There were nine treatment-related deaths (three related to both drugs, four related to erlotinib alone and two related to figitumumab). The addition of figitumumab to erlotinib did not improve OS in patients with advanced, pretreated, nonadenocarcinoma NSCLC. Clinical development of figitumumab has been discontinued. NCT00673049.

P0175 EGFR mutations in non-small-cell lung cancers: A single institute experience

<h3>Background</h3> Mutations in the tyrosine kinase domain of EGFR in non-small-cell lung cancer (NSCLC) are predictive of response to EGFR-targeted therapy in advanced stages of disease. This study aimed to determine the frequency of EGFR mutations in NSCLCs and to correlate their presence with clinical characteristics. <h3>Methods</h3> In this retrospective study, EGFR mutations in exons 18, 19, 20, and 21 in formalin-fixed paraffin-embedded biopsy specimens of consecutive NSCLC patients were assessed by real-time PCR. The study was conducted over a period of 5years from January 2009 to December 2013 in the Department of Medical Oncology in our institute. <h3>Findings</h3> EGFR mutations were detected in NSCLCs from 20 (25%) of 80 patients, being significantly more common in women (37.03%) than in men (18.8%) (odds ratio [OR] 0.39; 95% confidence interval [CI] 0.13–1.11; <i>p</i>=0.075) and in never smokers (42.85%) than in smokers and ex-smokers (11.11%) (OR 0.25, 95% CI 0.081–0.76; <i>p</i>=0.011). Mutations were more common in adenocarcinoma (32.07%) compared to non-adenocarcinoma NSCLCs (11.11%) (OR 3.7778; 95% CI 0.997–14.30; <i>p</i>=0.04). <h3>Interpretation</h3> In our patients with NSCLC, the EGFR mutation rate was similar to that in other Asian populations. EGFR mutations were significantly more common in female patients and in never smokers. Never smoking status of patients and adenocarcinoma histology were significant independent predictors for the presence of EGFR mutations.

Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancers in a Multiethnic Malaysian Patient Population

Mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) in non- small cell lung cancer (NSCLC) are predictive of response to EGFR-targeted therapy in advanced stages of disease. This study aimed to determine the frequency of EGFR mutations in NSCLCs and to correlate their presence with clinical characteristics in multiethnic Malaysian patients. In this prospective study, EGFR mutations in exons 18, 19, 20 and 21 in formalin-fixed paraffin-embedded biopsy specimens of consecutive NSCLC patients were asessed by real-time polymerase chain reaction. EGFR mutations were detected in NSCLCs from 55 (36.4%) of a total of 151 patients, being significantly more common in females (62.5%) than in males (17.2%) [odds ratio (OR), 8.00; 95% confidence interval (CI), 3.77-16.98; p<0.001] and in never smokers (62.5%) than in ever smokers (12.7%) (OR, 11.50; 95%CI, 5.08-26.03; p<0.001). Mutations were more common in adenocarcinoma (39.4%) compared to non-adenocarcinoma NSCLCs (15.8%) (p=0.072). The mutation rates in patients of different ethnicities were not significantly different (p=0.08). Never smoking status was the only clinical feature that independently predicted the presence of EGFR mutations (adjusted OR, 5.94; 95%CI, 1.94- 18.17; p=0.002). In Malaysian patients with NSCLC, the EGFR mutation rate was similar to that in other Asian populations. EGFR mutations were significantly more common in female patients and in never smokers. Never smoking status was the only independent predictor for the presence of EGFR mutations.

Abstract 5464: In-vitro studies of MM-121/SAR 256212, an anti-ErbB-3 antibody, in combination with erlotinib in EGFR-wild-type NSCLC.

Abstract MM-121/SAR 256212 is a fully human anti ErbB3/HER3 antibody that blocks ligand-induced receptor activation. Formation of EGFR/ErbB3 (ErbB1-3) heterodimers has been implicated as a major driver of tumor growth and survival in non-small cell lung cancer (NSCLC). Although erlotinib remains the standard-of-care treatment for patients with EGFR-wild-type NSCLC who have failed platinum combination chemotherapy, clinical benefit is typically modest. To address this unmet medical need, we investigated the combination of erlotinib with MM-121 in pre-clinical models of NSCLC. We initially assembled a panel of 25 EGFR-WT NSCLC cell lines spanning the most common histological subtypes (adenocarcinoma, squamous and large-cell carcinoma). Clinical studies show that tumors harboring activating Ras mutations less commonly respond to ErbB-directed therapies. To explore the effect of Ras mutations on responsiveness to MM-121, we also selected our cell lines to include a variety of H-/K-/N-Ras genotypes. Using a carefully optimized in-vitro 3D culture system, we then measured cell viability in response to MM-121, erlotinib or a combination of the drugs in the presence or absence of exogenously added epidermal growth factor (EGF) and/or heregulin-β1 (HRG). Our results indicate that MM-121 inhibits HRG-driven cell proliferation in the studied cell lines. In the five cell lines exhibiting dual-EGF-HRG-driven cell proliferation, the combination of MM-121 with erlotinib demonstrated superior inhibition of cell viability over erlotinib alone.To assess the ability of MM-121 to inhibit tumor cell growth independent of exogenously supplied HRG, we established mouse xenografts from three of the cell lines and treated mice with erlotinib, MM-121, or a combination of the two. All three in-vivo models showed greatly enhanced inhibition of tumor cell growth compared to erlotinib alone in a manner consistent with our in-vitro results. Analyzing our in vitro data we found that mutations in Ras genes (HRAS, KRAS, NRAS) do not preclude response to MM-121 or incremental benefit from the combination of MM-121 with erlotinib over erlotinib alone. Non-adenocarcinoma origin likewise did not preclude response to MM-121, although a weak trend towards diminished activity in the ten non-adenocarcinoma NSCLC cell lines was apparent. Merrimack Pharmaceuticals and Sanofi are co-developing MM-121 and a Phase 1-2 study of MM-121 in combination with erlotinib is currently enrolling patients with EGFR-wild-type NSCLC. Citation Format: Marisa J. Wainszelbaum, Mark S. Sevecka, Olga Burenkova, Gabriela Garcia, William Kubasek, Gavin MacBeath. In-vitro studies of MM-121/SAR 256212, an anti-ErbB-3 antibody, in combination with erlotinib in EGFR-wild-type NSCLC. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5464. doi:10.1158/1538-7445.AM2013-5464

Efficacy of EGFR tyrosine kinase inhibitors for non-adenocarcinoma NSCLC patients with EGFR mutation

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) gefitinib and erlotinib have shown dramatic response rate (RR) and significant prolongation of progression-free survival (PFS) in non-small-cell lung cancer (NSCLC) patients with EGFR mutation. Since only a few patients with non-adenocarcinoma histology have been enrolled in clinical trials, the efficacy of EGFR TKIs in non-adenocarcinoma NSCLC patients with EGFR mutation has not yet been fully determined. We retrospectively analyzed clinical outcomes, including RR, PFS, and OS, in patients who were treated with the EGFR TKIs gefitinib or erlotinib and compared the results with those of adenocarcinoma patients with EGFR mutation and non-adenocarcinoma patients with wild-type EGFR. Among 250 patients with non-adenocarcinoma of the lung who underwent EGFR mutation genotyping, 21 were found to have an EGFR mutation (8.4%). Twelve of the 21 patients were treated with the EGFR TKIs gefitinib (n=6) or erlotinib (n=6). The most common mutation was exon 19 deletion (n=7). The RR and disease control rate for 12 patients receiving EGFR TKIs were 50 and 75%, respectively. The median PFS was 3.67months (95% CI: 1.34-5.99), which was significantly lower than that of 269 adenocarcinoma patients with EGFR mutation (13.53months) but better than that of 32 non-adenocarcinoma patients with wild-type EGFR (1.83months) who were treated with EGFR TKIs. The results of this study show that the EGFR mutation rate in Korean patients with non-adenocarcinoma of the lung is relatively high and that the clinical outcomes of EGFR TKIs are modest.

Efficacy of gefitinib for non‐adenocarcinoma non‐small‐cell lung cancer patients harboring epidermal growth factor receptor mutations: A pooled analysis of published reports

The efficacy of gefitinib for patients with non-adenocarcinoma non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations is unclear, because only a small percentage of patients enrolled in the clinical trials to evaluate the efficacy of gefitinib for tumors harboring EGFR mutation were non-adenocarcinoma NSCLC. A pooled analysis was conducted to clarify the efficacy of gefitinib for non-adenocarcinoma NSCLC patients harboring EGFR mutations. A systematic search of the PUBMED databases was conducted to identify all clinical reports that contained advanced non-adenocarcinoma NSCLC patients harboring EGFR mutations and treated with gefitinib. The selected patients were advanced non-adenocarcinoma NSCLC patients harboring EGFR mutations who were treated with gefitinib and described in reports containing the data of the histology, status of EGFR mutations and response to gefitinib. This study selected 33 patients from 15 reports. Twenty-seven and three of the 33 patients were squamous cell carcinoma and adenosquamous cell carcinoma, respectively. One patient each had large-cell carcinoma, pleomorphic carcinoma and spindle cell carcinoma. Twenty-one patients (64%) had sensitive EGFR mutations. The response rate (RR), disease control rate (DCR) and median progression-free survival (mPFS) was 27%, 67-70% and 3.0 months, respectively. These factors were statistically significantly inferior in the non-adenocarcinoma NSCLC patients harboring EGFR mutations to adenocarcinoma patients harboring EGFR mutations selected from the same published reports (RR: 27%vs 66%, P = 0.000028; DCR: 67-70%vs 92-93%, P = 0.000014; mPFS: 3.0 vs 9.4 months, P = 0.0001, respectively). Gefitinib is less effective in non-adenocarcinoma NSCLC harboring EGFR mutations than adenocarcinoma harboring EGFR mutations.

Abstract 4299: Poor prognosis in smokers with non-small cell lung cancer correlates with the presence of a reparative progenitor cell population

Abstract Cigarette smoking is the most significant risk factor for the initiation and development of lung cancer. Tobacco exposure often results in chronic inflammation, tissue injury, and airway repair. A recent hypothesis demonstrates the presence of a stem/progenitor cell population that involved in airway epithelial repair. These cells may be tumor-initiating cells in lung cancer, and subsequently may be involved in tumor recurrence and metastasis. In the airway epithelium, cells that express keratin (K) 5 and its intermediate filament binding partner K14 are considered to be progenitor cells in the adult large airways at steady state and during airway epithelial repair. In order to identify subpopulations of airway epithelial stem/progenitor cells under steady state conditions, normal repair, aberrant repair with premalignant lesions, and lung cancer, and their respective correlation with injury and prognosis, we used immunostaining on mouse and human lung tissues, along with a human lung cancer tissue microarray. We found K5 and K14 expression in the steady state submucosal glands and gland ducts. In the basal layer of normal airway pseudostratified columnar epithelium, only K5 expression was prominent while K14 expression was absent. In a heterotopic, syngeneic, murine tracheal transplant model of repairing airway epithelium, we identified a population of K14+ progenitor epithelial cells that was temporally involved in normal repair after injury. Dysregulated repair resulted in persistence of K14+ cells in the airway epithelium of premalignant lesions. In human patients (n = 399), the presence of K14+ cells in non-small cell lung cancer (NSCLC) predicted poorer outcomes (P = 0.004) especially in patients who are smokers (P = 0.001). The predictive value was more pronounced in current smokers (P = 0.01) compared to former smokers (P = 0.04). In never smokers, the presence of K14+ cells had no predictive value for outcome. We found that the presence of K14+ cells in the primary tumors of current smokers was associated with metastatic disease (P = 0.02). We further found that non-adenocarcinoma NSCLCs from current smokers with metastases had a higher percentage of K14+ cells in the primary tumor sites. (P = 0.004). Examination of K14 expression in distant metastatic sites revealed a significant increase in the number of K14-expressing cells in metastases compared to the primary sites in squamous lung cancer, but not in other histologic subtypes. Our data propose that dysregulated repair after injury leads to a self-renewing K14+ progenitor cell population in premalignant lesions. The presence of K14+ progenitor airway epithelial cells in NSCLC predicted a poor prognosis with the strongest predictive value in smokers, where it correlated with metastasis. This suggests that reparative K14+ progenitor cells are the putative tumor-initiating cells in this subgroup of smokers with NSCLC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4299.