Post Hoc Analysis of Lorlatinib Intracranial Efficacy and Safety in Patients With ALK-Positive Advanced Non-Small-Cell Lung Cancer From the Phase III CROWN Study.

PURPOSE: Lorlatinib significantly improved progression-free survival (PFS) versus crizotinib and showed robust intracranial activity in patients with previously untreated advanced ALK-positive non-small-cell lung cancer (NSCLC) in the phase III CROWN trial. Here, we report post hoc efficacy outcomes in patients with and without brain metastases at baseline, and present data on the incidence and management of CNS adverse events (AEs) in CROWN. METHODS: Eligible patients were randomly assigned 1:1 to first-line lorlatinib (100 mg once daily) or crizotinib (250 mg twice a day); no crossover between treatment arms was permitted. Tumor assessments, including CNS magnetic resonance imaging, were performed at screening and then at 8-week intervals. Regular assessments of patient-reported outcomes were conducted. RESULTS: PFS by blinded independent central review was improved with lorlatinib versus crizotinib in patients with and without brain metastases at baseline (12-month PFS rates: 78% v 22% and 78% v 45%, respectively). Lorlatinib was associated with lower 12-month cumulative incidence of CNS progression versus crizotinib in patients with (7% v 72%) and without (1% v 18%) brain metastases at baseline. In total, 35% of patients had CNS AEs with lorlatinib, most of grade 1 severity. Occurrence of CNS AEs did not result in a clinically meaningful difference in patient-reported quality of life. At analysis, 56% of CNS AEs had resolved (33% without intervention; 17% with lorlatinib dose modification), and 38% were unresolved; most required no intervention. Lorlatinib dose modification did not notably influence PFS. CONCLUSION: First-line lorlatinib improved PFS outcomes and reduced CNS progression versus crizotinib in patients with advanced ALK-positive non-small-cell lung cancer with or without brain metastases at baseline. Half of all CNS AEs resolved without intervention or with lorlatinib dose modification.

Treatment of Choroidal Metastasis from Epidermal Growth Factor Mutant Non-Small Cell Lung Cancer with First-line Osimertinib Therapy.

PURPOSE: To illustrate the regression of a metastatic lesion through ophthalmic imaging and correlating findings with standard chest imaging and treatment with osimertinib, an oral chemotherapy agent specific to Epidermal Growth Factor Receptor + Non-small Cell Lung Cancer (EGFR+ NSCLC). CASE REPORT: A 63-year-old Asian male presented to ophthalmology with a complaint of left blurry vision. Initial ophthalmic exam revealed a choroidal lesion and imaging results highlighted a spiculated lung mass with brain and bony metastases. Osimertinib was chosen for its specificity and ability to cross the blood-brain barrier. Follow-up ophthalmic and radiographic imaging were repeated over the course of treatment. CONCLUSION: After the initiation of osimertinib, ophthalmic and computed tomography imaging highlighted the regression of the ocular metastatic disease and primary malignancy, respectively.Osimertinib is an effective first-line treatment of EGFR+ NSCLC and corresponding metastatic sites. Additionally, ophthalmic imaging can be used to monitor general response to chemotherapy agents when ocular metastasis is identified.

Crizotinib in Patients With MET-Amplified NSCLC.

INTRODUCTION: MET amplification is a rare, potentially actionable, primary oncogenic driver in patients with NSCLC. METHODS: The influence of MET amplification on the clinical activity of the ALK, ROS1, and MET inhibitor, crizotinib (250 mg twice daily), was examined in patients with NSCLC (NCT00585195) who were enrolled into high (≥4 MET-to-CEP7 ratio), medium (>2.2 to <4 MET-to-CEP7 ratio), or low (≥1.8 to ≤2.2 MET-to-CEP7 ratio) amplification categories. Retrospective next-generation sequencing profiling was performed on archival tumor tissue. End points included objective response rate (ORR), duration of response, and progression-free survival. RESULTS: A total of 38 patients with a MET-to-CEP7 ratio greater than or equal to 1.8 by local fluorescence in situ hybridization testing received crizotinib. All patients were response-assessable, among whom 21, 14, and 3 had high, medium, and low MET amplification, respectively. ORRs of 8 of 21 (38.1%), 2 of 14 (14.3%), and 1 of 3 (33.3%), median duration of response of 5.2, 3.8, and 12.2 months, and median progression-free survival values of 6.7, 1.9, and 1.8 months were observed for those with high, medium, and low MET amplification, respectively. MET amplification gene copy number greater than or equal to 6 was detected by next-generation sequencing in 15 of 19 (78.9%) analyzable patients. Of these 15 patients, objective responses were observed in six (40%), two of whom had concurrent MET exon 14 alterations. No responses were observed among five patients with concurrent KRAS, BRAF, or EGFR mutations. CONCLUSIONS: Patients with high-level, MET-amplified NSCLC responded to crizotinib with the highest ORR. Use of combined diagnostics for MET and other oncogenes may potentially identify patients most likely to respond to crizotinib.

Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations.

INTRODUCTION: Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents. METHODS: We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categorized by clonality and class (1 and 2: RAS-independent; 3: RAS-dependent). Cell viability assays were performed in Ba/F3 models. Drug screens were performed in NSCLC cell lines. RESULTS: A total of 305 unique BRAF mutations were identified. Missense mutations were most common (276, 90%), and 45% were variants of unknown significance. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class (p < 0.01). Three patients were treated with MEK with or without BRAF inhibitors. Patients harboring G469V and D594G mutations did not respond, whereas a patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and lifirafenib had more potent inhibition of BRAF non-V600-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line. CONCLUSIONS: In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. Our data indicate that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC.

Outcomes According to ALK Status Determined by Central IHC or FISH in Patients with ALK-Positive NSCLC Enrolled in the Phase III ALEX Study.

INTRODUCTION: We retrospectively examined progression-free survival (PFS) and response by ALK fluorescence in-situ hybridization (FISH) status in patients with advanced ALK immunohistochemistry (IHC)-positive non-small-cell lung cancer (NSCLC) in the ALEX study. METHODS: 303 treatment-naïve patients were randomized to receive twice-daily alectinib 600 mg or crizotinib 250 mg. ALK status was assessed centrally using Ventana ALK (D5F3) CDx IHC and Vysis ALK Break Apart FISH Probe Kit. Primary endpoint: investigator-assessed PFS. Secondary endpoints of interest: objective response rate (ORR) and duration. RESULTS: Investigator-assessed PFS was significantly prolonged with alectinib versus crizotinib in ALK IHC-positive/FISH-positive tumors (n = 203, 67%) (HR 0.37, 95% CI: 0.25-0.56) and ALK IHC-positive/FISH-uninformative tumors (n = 61, 20%) (HR 0.39, 95% CI: 0.20-0.78), but not ALK IHC-positive/FISH-negative tumors (n = 39, 13%) (HR 1.33, 95% CI: 0.6-3.2). ORRs were higher with alectinib versus crizotinib in ALK IHC-positive/FISH-positive tumors 90.6% versus 81.4%; stratified odds ratio [OR] 2.22, 95% CI: 0.97-5.07) and ALK IHC-positive/FISH-uninformative tumors (96.0% versus 75.0%; OR 9.29, 95% CI: 1.05-81.88), but not ALK IHC-positive/FISH-negative tumors (28.6% versus 44.4%; OR 0.45, 95% CI: 0.12-1.74). Next-generation sequencing (NGS) was performed in 35/39 patients with ALK IHC-positive/FISH-negative tumors; no ALK fusion was identified in 20/35 (57.1%) patients by NGS, but 10/20 (50.0%) had partial response/stable disease. CONCLUSION: Outcomes of patients with ALK IHC-positive/FISH-positive and ALK IHC-positive/FISH-uninformative NSCLC were similar to the overall ALEX population. These results suggest that Ventana ALK IHC is a standard testing method for selecting patients for treatment with alectinib.

Scientific Advances in Lung Cancer 2015.

Lung cancer continues to be a major global health problem; the disease is diagnosed in more than 1.6 million new patients each year. However, significant progress is underway in both the prevention and treatment of lung cancer. Lung cancer therapy has now emerged as a "role model" for precision cancer medicine, with several important therapeutic breakthroughs occurring during 2015. These advances have occurred primarily in the immunotherapy field and in treatments directed against tumors harboring specific oncogenic drivers. Our knowledge about molecular mechanisms for oncogene-driven tumors and about resistance to targeted therapies has increased quickly over the past year. As a result, several regulatory approvals of new agents that significantly improve survival and quality of life for patients with lung cancer who have advanced disease have occurred. The International Association for the Study of Lung Cancer has gathered experts in different areas of lung cancer research and management to summarize the most significant scientific advancements related to prevention and therapy of lung cancer during the past year.

Next-generation sequencing reveals a Novel NSCLC ALK F1174V mutation and confirms ALK G1202R mutation confers high-level resistance to alectinib (CH5424802/RO5424802) in ALK-rearranged NSCLC patients who progressed on crizotinib.

Acquired secondary mutations in the anaplastic lymphoma kinase (ALK) gene have been identified in ALK-rearranged (ALK+) non-small-cell lung cancer (NSCLC) patients who developed disease progression while on crizotinib treatment. Here, we identified a novel secondary acquired NSCLC ALK F1174V mutation by comprehensive next-generation sequencing in one ALK+ NSCLC patient who progressed on crizotinib after a prolonged partial response to crizotinib. In a second case, we identified a secondary acquired ALK G1202R, which also confers resistance to alectinib (CH5424802/RO5424802), a second-generation ALK inhibitor that can inhibit ALK gatekeeper L1196M mutation in vitro. ALK G1202R is located at the solvent front of the ALK kinase domain and exhibits a high level of resistance to all other ALK inhibitors currently in clinical development in vitro. Comprehensive genomic profiling of resistant tumor is increasingly important in tailoring treatment decisions after disease progression on crizotinib in ALK+ NSCLC given the promise of second-generation ALK inhibitors and other therapeutic strategies.

MET overexpression assessed by new interpretation method predicts gene amplification and poor survival in advanced gastric carcinomas.

The establishment of better selection criteria for identifying sub-populations that may benefit from treatment is a key aspect of the development and success of targeted therapy. To investigate methods for assessing MET overexpression in gastric cancer, we conducted immunohistochemistry using a new anti-Total MET monoclonal antibody in a single-institution cohort of 495 patients. As antibody is directed against a membranous and/or cytoplasmic epitope, two interpretation methods were used: (1) membranous and cytoplasmic and (2) membranous alone. In selected 120 cases, copy number gain and mRNA expression levels were measured using quantitative real-time PCR. Further in situ hybridization confirmed the presence of MET gene amplification. Among the 495 gastric cancers, simultaneous membranous and cytoplasmic overexpression of MET was found in 108 cases (21.8%) and membranous alone overexpression was observed in 40 cases (8.1%). The highest correlation was observed in membranous and cytoplasmic staining of MET: MET expression scores correlated significantly with high MET mRNA levels (r=0.465, P<0.0001), increased copy number gain (r=0.393, P=0.000002) and amplification of MET gene. Moreover, patients with MET overexpression showed shorter overall survival (HR, 1.781; 95% CI, 1.324-2.395; P<0.001) and disease-free survival (HR, 1.765; 95% CI, 1.227-2.541; P=0.002) compared with patients without MET overexpression. However, membranous overexpression of MET did not highly correlate with mRNA level (r=0.274, P=0.002), copy number gain or survival (P>0.05). We developed highly correlating interpretation methods of MET immunohistochemistry in gastric carcinomas. MET overexpression is an independent prognostic factor and could be a potential target and predictor of benefit for targeted therapy with MET inhibitors.

Long exposure of environmental tobacco smoke associated with activating EGFR mutations in never-smokers with non-small cell lung cancer.

PURPOSE: To examine an association between environmental tobacco smoke (ETS) and activating epidermal growth factor receptor (EGFR) mutations in never-smokers with non-small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: A total of 126 never-smokers with NSCLC were prospectively included in this study. Detailed ETS information was obtained through a standardized questionnaire including exposure period, place, and duration. Cumulative dose of ETS (CETS) was evaluated as a sum of the number of the exposure years at home and/or workplace. EGFR and K-ras mutations were determined using real-time PCR amplification. RESULTS: A total of 124 patients (98.4%) had ETS exposure with median CETS of 50 years (range: 0-118). Activating EGFR mutations were detected in 62.7% of the 126 patients and K-ras in 2 of 114 patients. The incidence of activating EGFR mutations was significantly higher in females than in males (67.6% vs. 26.7%; P = 0.002), and increased in quintile groups separated on the basis of CETS (shortest group = 44.0%, longest = 84.6%; P = 0.0033). In the multivariate logistic regression model, including gender, CETS, age, and family history of cancer, both gender and CETS were significantly associated with an incidence of activating EGFR mutations; the odds ratio for the EGFR mutations were 5.13 [95% confidence interval, CI = 1.47-18.0; P = 0.0105] for females and 1.02 (95% CI = 1.00-1.04; P = 0.0193) for each 1-year increment in CETS. CONCLUSIONS: Females and increased ETS exposure are closely associated with EGFR mutations in never-smokers with NSCLC.

Japanese ethnicity compared with Caucasian ethnicity and never-smoking status are independent favorable prognostic factors for overall survival in non-small cell lung cancer: a collaborative epidemiologic study of the National Hospital Organization Study Group for Lung Cancer (NHSGLC) in Japan and a Southern California Regional Cancer Registry databases.

BACKGROUND: We previously reported that Asian ethnicity was a favorable prognostic factor for overall survival (OS) in non-small cell lung cancer (NSCLC). In this study, we performed a combined data analysis from a Japanese Cancer Registry and a regional California Cancer Registry to further validate this observation. METHODS: Retrospective population-based analysis of Japanese and Caucasian patients with NSCLC with known smoking status from the Japanese National Hospital Organization Study Group for Lung Cancer and a Southern California Regional Cancer Registry between 1991 and 2001. RESULTS: A total of 15,185 Japanese and 13,332 US Caucasian patients were analyzed. Median age of Japanese patients was 68 years compared with 69 years for Caucasian patients (p < 0.0001). A total of 29.3% of Japanese compared with 7.3% Caucasian patients were never-smokers. Never-smoking status conferred significant improved OS for Japanese (p < 0.0001) and a trend for improved OS for Caucasian patients (p = 0.1282). Univariate analysis revealed Japanese patients with stage III (versus Caucasian; hazard ratio [HR] = 0.830, 95% confidence interval [CI]: 0.789-0.873, p < 0.0001) and IV disease (versus Caucasian; HR = 0.955, 95% CI: 0.915-0.997, p = 0.0369) had improved OS compared with Caucasian patients. Multivariate analysis revealed Japanese ethnicity (versus Caucasian; HR = 0.937, 95% CI: 0.898-0.978, p = 0.0028) and never-smoker status (versus ever-smoker; HR = 0.947, 95% CI: 0.909-0.987, p = 0.0104) to be independent favorable factors for OS in addition to younger age, female gender, early stage, and treatment received (surgery, radiation, and chemotherapy). CONCLUSIONS: Japanese ethnicity when compared with Caucasian ethnicity and never-smoker status are independent favorable prognostic factors for OS in NSCLC.

Performance status and smoking status are independent favorable prognostic factors for survival in non-small cell lung cancer: a comprehensive analysis of 26,957 patients with NSCLC.

BACKGROUND: Performance status (PS) is an important factor in determining survival outcome in non-small cell lung cancer (NSCLC) but is generally confounded by stage, age, gender, and smoking status. We investigated the prognostic significance of PS taking into account these important factors. METHODS: Retrospective analysis of registry database of the National Hospital Study Group for Lung Cancer (NHSGLC) between 1990 and 2005. Univariate analysis was performed using Kaplan-Meier method. Multivariate analysis was performed using Cox proportional hazards model to identify independent prognostic factors. RESULTS: A total of 26,957 patients with NSCLC were analyzed of which 12,613 patients (46.8%) had World Health Organization (WHO) PS = 0, 8,137 patients were never smokers (30.2%), and most of them were females (72.7%). The majority of PS = 0 patients presented with stage I disease (56.9%). Patients with PS = 0 constituted the group with the highest proportion of never smokers (36.7%). There was a significant difference in the median overall survival (OS) between patients with PS = 0 and PS = 1 (51.5 months versus 15.4 months, respectively; p < 0.0001) and among patients with various PS within individual American Joint Committee on Cancer stage (all p values <0.0001). Never smokers had significantly improved median OS than ever smokers (30.0 months versus 19.0 months, respectively; p < 0.0001). Multivariate analysis demonstrated good PS, never smoker (versus ever smoker; hazard ratio = 0.935, 95% confidence interval: 0.884-0.990; p = 0.0205), early stage, female gender, squamous cell carcinoma histology, and treatment were all as independent favorable prognostic factors. CONCLUSIONS: PS and smoking status are independent prognostic factors for OS in NSCLC.

The applicability of the proposed IASLC staging revisions to small cell lung cancer (SCLC) with comparison to the current UICC 6th TNM Edition.

BACKGROUND: We examined the impact of the proposed Internal Association for the Study of Lung Cancer (IASLC) tumor, node, metastasis (TNM) and stage grouping revisions on staging and survival outcome of small cell lung cancer (SCLC). METHODS: A total of 10,660 SCLC patients from the California Cancer Registry between 1991 to 2005 with complete TNM staging were identified and reclassified according to the IASLC proposed TNM revisions and new stage groupings. Surveillance Epidemiology and End Results extent of disease codes were used to identify various T4 and M descriptors. Cox proportional hazards regression was used to identify prognostic factors. RESULTS: Survival was correlated with the current UICC6 and IASLC proposed T descriptors. Patients without mediastinal lymph node involvement (N 0-1) had superior survival compared to patients with mediastinal lymph node involvement (N 2-3). The IASLC proposed stage grouping results in better separation of survival curves among early stage SCLC than the current Union Internationale Centre le Cancer (UICC) 6 stage groupings by both univariate and multivariate analyses. Pleural effusion (IASLC M1a) in SCLC had survival similar to other IASLC M1a categories (pericardial effusion, contralateral intrapulmonary metastasis) by pairwise hazard ratio comparisons. CONCLUSIONS: The IASLC proposed TNM staging changes result in better separation of stage-specific SCLC survival curves than the current UICC6 staging system. The new IASLC M1a descriptors (pleural effusion, pericardial effusion, and contralateral/bilateral intrapulmonary metastasis) adequately prognosticate SCLC patients as having metastatic disease.