Luis Corrales

Pemetrexed/Carboplatin/Bevacizumab followed by Maintenance Pemetrexed/Bevacizumab in Hispanic Patients with Non-Squamous Non-Small Cell Lung Cancer: Outcomes according to Thymidylate Synthase Expression

Objective To evaluate the efficacy and safety of pemetrexed, carboplatin and bevacizumab (PCB) followed by maintenance therapy with pemetrexed and bevacizumab (PB) in chemotherapy-naïve patients with stage IV non-squamous non-small cell lung cancer (NSCLC) through the influence of thymidylate synthase (TS) protein and mRNA expression on several outcomes. The primary endpoints were the overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). Methods A cohort of 144 patients were administered pemetrexed (500 mg/m2), carboplatin (AUC, 5.0 mg/ml/min) and bevacizumab (7.5 mg/kg) intravenously every three weeks for up to four cycles. Maintenance PB was administered until disease progression or unacceptable toxicity. Results One hundred forty-four Colombian patients with a median follow-up of 13.8 months and a median number of 6 maintenance cycles (range, 1–32) were assessed. The ORR among the patients was 66% (95% CI, 47% to 79%). The median PFS and (OS) rates were 7.9 months (95% CI, 5.9–10.0 months) and 21.4 months (95% CI, 18.3 to 24.4 months), respectively. We documented grade 3/4 hematologic toxicities, including anemia (14%), neutropenia (8%), and thrombocytopenia (16%). The identified grade 3/4 non-hematologic toxicities were proteinuria (2%), venous thrombosis (4%), fatigue (11%), infection (6%), nephrotoxicity (2%), and sensory neuropathy (4%). No grade >3 hemorrhagic events or hypertension cases were reported. OS was significantly higher in patients with the lowest TS mRNA levels [median, 29.6 months (95% CI, 26.2–32.9)] compared with those in patients with higher levels [median, 9.3 months (95% CI, 6.6–12.0); p = 0.0001]. TS expression (mRNA levels or protein expression) did not influence the treatment response. Conclusion Overall, PCB followed by maintenance pemetrexed and bevacizumab was effective and tolerable in Hispanic patients with non-squamous NSCLC. This regimen was associated with acceptable toxicity and prolonged OS, particularly in patients with low TS expression. We found a role for Ki67 and TS expression as prognostic factors.

Summary of presentations from the 46th Annual Meeting of the American Society of Clinical Oncology (2010) focus on tumor biology and biomarkers related to lung cancer.

Globally, lung cancer remains the most common cause of cancer-related death. In recent years, it has become clear that development of rational molecular targeted therapies is critical to improve the outcomes of patients with lung cancer. A better understanding of the tumor biology is crucial to achieve this goal. Several new findings in the field of tumor biology were presented at the 46th Annual Meeting of the American Society of Clinical Oncology. Novel genetic mutations were identified in pleural mesothelioma using array-based technologies. Several studies on the development and testing of new molecular diagnostic tests to detect epidermal growth factor receptor tyrosine kinase mutations and EML4-ALK (Echinoderm Microtubule-associated Protein like 4 Anaplastic Lymphoma Receptor Tyrosine Kinase) fusion gene were presented as well.

Characteristics of progression to tyrosine kinase inhibitors predict overall survival in patients with advanced non-small cell lung cancer harboring an EGFR mutation

Background Non-small cell lung cancer (NSCLC) harboring EGFR-sensitizing mutations has a distinct biology and heterogeneous clinical behavior. We evaluated the characteristics to progression such as clinical patterns of progression (dramatic, gradual, and local) with the prognosis of NSCLC patients treated with tyrosine kinase inhibitors (TKIs). Methods We reviewed 123 advanced-NSCLC patients with an EGFR-sensitizing mutation treated with TKIs (gefitinib, erlotinib and afatinib). We assessed patients according to clinical factors and progression pattern to TKIs at three centers. Results For all patients, 58.5%, 31.7% and 9.8% harbored exon19 deletion, exon21 L858R mutation and other-sensitivity mutations, respectively. Median progression-free survival (PFS) was 8.8 months (95% CI: 7.9-9.7). Sixty percent of patients were asymptomatic. Dramatic-progression was the most frequent pattern (50.4%), followed by gradual-progression (32.5%), and local-progression (17.1%). Median overall survival (OS) was 23.1 months (95% CI: 17.4-28.9). In the univariate analysis, factors associated to a longer OS included pattern [gradual-progression (32.1), dramatic (19.5) and local (18.8 months), P=0.008], and the time to progression to TKI [>12 months (38.5), 6-12 months (19.1), <6 months (9.6), P<0.001]. Multivariate analysis showed that only time to progression to TKI was independently associated to OS and PFS. Conclusions Factors at TKI progression associated to a longer OS can define a subset of patients who may benefit from continued TKI therapy, as well as from local-ablative therapy in progression sites, especially in patients without T790M or who lack access to third-generation TKI.

EGFR Amplification and Sensitizing Mutations Correlate with Survival in Lung Adenocarcinoma Patients Treated with Erlotinib (MutP-CLICaP)

BackgroundNon-small cell lung cancer (NSCLC) has a 5-year survival of 5–16%. Epidermal growth factor receptor (EGFR) mutations, in most cases, confer sensitivity to EGFR tyrosine kinase inhibitor (TKI) therapy. Nonetheless, it is still unclear why clinical outcomes vary among patients with identical EGFR mutations. The amplification of the EGFR gene (EGFRamp) may play a significant role.ObjectiveCompare the complete (CR) and partial response (PR) rates, overall survival (OS), and progression-free survival (PFS) in Hispanic patients with lung adenocarcinoma treated with erlotinib with EGFR mutations (L858R or exon 19 deletion [Del19]) with and without concomitant EGFRamp.Patients and MethodsSeventy-two EGFR-positive lung adenocarcinoma patients of Hispanic origin, who underwent first-line treatment with erlotinib, were evaluated for EGFRamp by fluorescence in situ hybridization (FISH). The clinical outcomes were analyzed according to EGFR mutations and EGFRamp status.Results30.6% of samples showed EGFRamp, more frequently present in patients with Del19 (p = 0.05). Patients with EGFRamp had a longer PFS (in months) [(28.5, 95% CI 22.3–34.6) vs. (11.0, 95% CI 8.2–16.7); p = 0.002] and OS [(37.8, 95% CI 30.9–44.7) vs. (27.1, 95% CI 12.8–41.3); p = 0.009] than those without. EGFRamp significantly influenced the response to erlotinib (p = 0.0001). EGFRamp+/Del19 had a longer OS, 37.8 (95% CI 31.0–44.6), compared to EGFRamp+/L8585R, 27.5 (95% CI 12.4–42.5) (p < 0.001) and longer PFS (p = 0.043).ConclusionAmong Hispanic patients, EGFRamp was present in 30% of patients with EGFR mutations. EGFR mutations and EGFRamp are associated with better OS, PFS, CR, and PR to erlotinib and, hence, could aid in the correct selection of patients that benefit from EGFR TKI treatment.

Real-World Treatment Patterns, Survival, and Prediction of CNS Progression in ALK-Positive Non-Small-Cell Lung Cancer Patients Treated with First-Line Crizotinib in Latin America Oncology Practices

Objective: This study describes the real-world characteristics, treatment sequencing, and outcomes among Hispanic patients with locally advanced/metastatic ALK-positive non-small-cell lung cancer (NSCLC) treated with crizotinib. Methods: A retrospective patient review was conducted for several centers in Latin America. Clinicians identified ALK-positive NSCLC patients who received crizotinib and reported their clinical characteristics, treatments, and survival. Overall survival and progression-free survival (PFS) were described. A Random Forest Tree (RFT) model was constructed to predict brain progression. Results: A total of 73 patients were included; median age at diagnosis was 58 years, 60.3% were female, and 93.2% had adenocarcinoma. Eighty-nine percent of patients were never smokers/former smokers, 71.1% had ≥2 sites of metastasis, and 20.5% had brain metastases at diagnosis. The median PFS on first-line crizotinib was 7.07 months (95% CI 3.77–12.37) and the overall response rate was 52%. Of those who discontinued crizotinib, 55.9% progressed in the central nervous system (CNS). The RFT model reached a sensitivity of 100% and a specificity of 88% for prediction of CNS progression. Conclusions: The overall response rate and the PFS observed in Hispanic patients with ALK-positive NSCLC treated with first-line crizotinib were similar to those in previous reports. An RFT model is helpful in predicting CNS progression and can help clinicians tailor treatments in a resource-limited practice.

EGFR exon 20 insertion in lung adenocarcinomas among Hispanics (geno1.2-CLICaP)

OBJECTIVES Contrasting other EGFR mutations (EGFRm) in lung adenocarcinomas, insertions in exon 20 (exon20ins) are generally associated with resistance to targeted therapy, limiting therapeutic options and impoverishing the prognosis compared to other EGFRm. We sought to extensively characterize exon20ins from a large cohort of lung adenocarcinomas in Hispanic patients. MATERIALS AND METHODS This was a region-wide, observational longitudinal cohort study to evaluate characteristics and outcomes of patients with exon20ins in lung adenocarcinoma, based on a secondary analysis of electronic records from the Geno1.2-CLICaP Platform and extended genotype testing. Patients from six Latin-American countries were included (Argentina, Colombia, Costa Rica, Ecuador, Panama, and Mexico). Data obtained included the molecular spectrum (extended genotyping for mutations in BRAF, NRAS, PIK3CA, Her2 and MEK1, as well as for EGFR amplification, ALK and PD-L1 protein expression), clinic-pathologic characteristics, prevalence and outcomes to therapeutic approach. RESULTS AND CONCLUSIONS 4.005 patients diagnosed with stage III/IV lung adenocarcinoma from 2011 to 2016 were initially screened. Among these, 88 patients had a confirmed exon20 in. and were included; median age was 66-years, 62.5% were females, 64% were never smokers and 39% presented with brain metastases. The H773insH variant was the most frequent, making up 21.6% of cases. A common EGFRm was concomitantly found in 36.4% (del19/L858R), and 8% (G719X/L861Q/S768I) of cases. Five cases had additional mutations in PI3K, KRAS and MEK1, 26% had EGFR amplification and 81.7% had PD-L1 expression 1-50%. Overall response rate to first-line therapy was 28% and overall survival was 16.4 months. Prognosis was positively influenced by the concomitant presence of common EGFRm and response to first-line. Our results suggest that patients with EGFR exon20ins have similar clinical characteristics to those with common EGFRm but a poorer prognosis. Last, the mean PD-L1 expression in this population seems higher than for patients with common EGFRm.

Probable hereditary familial overlap syndrome with multiple synchronous lung tumors

Here we report a case of a young, never-smoker Hispanic woman with a hereditary familial overlap syndrome (Li-Fraumeni plus CDH1). The patient developed multiple synchronous primary lung adenocarcinomas related to Intra-Alveolar Tumor Spread (STAS) several years after the diagnosis of a locally advanced lower limb osteosarcoma. Comprehensive genomic profiling by next generation sequencing (NGS) was performed on 90 cancer-related genes over each lung lesion (including two nodules of acinar adenocarcinoma, one lepidic spread tumor and in the STAS area). Likewise, the broad genomic analysis was performed on archival tissue from the previous bone tumor. Lung tumors were found to harbor PIK3CA (invasive lesions) and a rare in-frame insertion of nucleotides in exon 19 of EGFR (lepidic tumor). STAS area showed KRAS and BRAF mutations in two different segments, and osteosarcoma tested positive for well known PIK3CA, KRAS and CDH1 alterations. This unique case raises practical questions as to the challenges of molecular testing and highlights the potential association of germline TP53 and CDH1 mutations with concurrent somatic alterations that elucidate the basis of tumor heterogeneity.

P3.01-11 Depression and Inflammation in Patients with EGFR-Mutated Non-Small Cell Lung Cancer

Background: Lung cancer is a commonly diagnosed cancer, and the leading cause of cancer death around the world. Over 80% of lung cancer patients in México are diagnosed in advanced stage. Common symptoms include cough, dyspnea, weight loss, and chest pain. Dyspnea is one of the most common symptoms in patients with lung cancer at initial presentation with a prevalence of 55e90%. The intensity of dyspnea is an important and validated factor for assessment of quality of life (QOL) in cancer patients. In addition, improvement of healthrelated QOL and symptoms, such as dyspnea, are related with the efficacy of chemotherapeutic regimens and favorable outcome in lung cancer. In this study, we investigated the association between the degree of dyspnea and clinical outcomes to identify the prognostic role of dyspnea in hispanic patients with non-small cell lung cancer (NSCLC). Method: We retrospectively reviewed lung cancer database of Centro Oncologico Estatal ISSEMYM. From 2013 to 2016 we enrolled patients with diagnosis of advanced NSCLC. Clinicopathological information on age, sex, smoking history, histologic type, stage, Eastern Cooperative Oncology Group (ECOG) performance status, clinical outcomes and evaluation of symptoms of dyspnea at diagnosis using modified Medical Research Council (mMRC) scores from each patient were recorded. Result: A total of 120 patients with diagnosis of NSCLC were identified, of these only in 65 patients (54%) the symptom of dyspnea were detected and evaluate using modified Medical Research Council (mMRC) scores at initial diagnosis. The median age was 58 years. Among those patient with dyspnea and mMRC scores available at diagnosis, 29 (45%) patients had an mMRC score 2, while 36 (55 %) had an mMRC score < 2. In multivariate analysis, poor performance status and an mMRC score 2 were found to be significant prognostic factors for patient survival. The overall median survival for all patients was 18 months. The overall survival of patients with dyspnea (mMRC grade 2 or higher) was significantly lower than that for patients without or low grade dyspnea (median survival, 17 months vs. 35 months, p<0.036). Conclusion: In conclusion, this study showed that the dyspnea mMRC mMRC grade 2 or higher in Hispanic patient with NSCLC were significantly associated with poor prognosis. Therefore, clinicians should pay more attention to evaluation and management of dyspnea.