Hernán Carranza

Updated Frequency of EGFR and KRAS Mutations in NonSmall-Cell Lung Cancer in Latin America: The Latin-American Consortium for the Investigation of Lung Cancer (CLICaP)

Introduction: Previously, we reported the frequency of epidermal growth factor receptor (EGFR) and KRAS mutations in nonsmall-cell lung cancer (NSCLC) patients in Latin America. The EGFR mutation frequency was found between Asian (40%) and Caucasian (15%) populations. Here, we report the updated distribution of NSCLC mutations. Methods: A total of 5738 samples from NSCLC patients from Argentina (1713), Mexico (1417), Colombia (1939), Peru (393), Panama (174), and Costa Rica (102) were genotyped for EGFR and KRAS. Results: The median patient age was 62.2 ± 12.3 years; 53.5% were women, 46.7% had a history of smoking, and 95.2% had adenocarcinoma histology. The frequency of EGFR mutations was 26.0% (95% confidence interval [CI], 24.9–27.1; Argentina, 14.4% [12.8–15.6]; México, 34.3% [31.9–36.7]; Colombia, 24.7% [22.8–26.6]; Peru, 51.1% [46.2–55.9]; Panamá, 27.3 [20.7–33.9]; and Costa Rica, 31.4% [22.4–40.4]). The frequency of KRAS mutations was 14.0% (9.1–18.9). In patients with adenocarcinoma, EGFR mutations were independently associated with gender (30.7% females vs. 18.4% males; p < 0.001), nonsmoker status (27.4% vs. 17.1%, p < 0.001), ethnicity (mestizo/indigenous, 35.3% vs. Caucasian, 13.7%, p < 0.001), and the absence of KRAS mutation (38.1% vs. 4.7%; p < 0.001). The overall response rate to EGFR tyrosine kinase inhibitors was 60.6% (95% CI, 52–69), with a median progression-free survival and overall survival of 15.9 (95% CI, 12.420.6) and 32 months (95% CI, 26.5–37.6), respectively. Conclusion: Our findings support the genetic heterogeneity of NSCLC in Latin America, confirming that the frequency of EGFR mutations is intermediate between that observed in the Asian and Caucasian populations.

The impact of common and rare EGFR mutations in response to EGFR tyrosine kinase inhibitors and platinum-based chemotherapy in patients with non-small cell lung cancer

OBJECTIVES In non-small cell lung cancer (NSCLC), the association between common EGFR mutations (Del EX19/L858R) with EGFR tyrosine kinase inhibitors (EGFR-TKIs) has been well established. However, this has not been investigated for rare EGFR mutations or their impact on treatment response and outcome to EGFR TKIs (primary objective) and chemotherapy (secondary objective). MATERIALS AND METHODS In an observational prospective cohort, we analyzed 188 NSCLC patients from Mexico, Colombia and Costa Rica with EGFR mutations. As a first line of treatment, 66.5% received platinum-based chemotherapy. All patients received TKIs in first-line treatment or after progression to chemotherapy. The clinical-pathological characteristics as well as the f of common and rare EGFR mutations associated with treatment response were analyzed. RESULTS Of all patients, 79.5% had common and 20.5% had rare EGFR mutations. Lepidic and acinar adenocarcinomas were associated with common EGFR mutations (p=0.010). Patients with common EGFR mutations had higher response rates to EGFR-TKIs than those who had rare EGFR mutations (63.8 vs 32.4%, p<0.001). Women had increased progression-free survival (PFS) to EGFR-TKIs than men (16.4 vs 9.5 months, p=0.02). The median PFS and overall survival (OS) were better in patients with common EGFR mutations (15.5 vs 3.9 months, p<0.001; and 37.3 vs 17.4 months, p<0.001) respectively. CONCLUSION Our findings suggested that only patients with rare EGFR mutations could receive platinum-based chemotherapy as a first-line treatment, due to their low response rates and short PFS in response to EGFR-TKIs. Consequently, EGFR-TKIs could be reserved as a second- or third-line treatment. In patients with EGFR mutations, women have better PFS to EGFR-TKIs than men, and rare EGFR mutations are more frequent in high grade adenocarcinomas than in low grade tumors.

Distribution and trends of hematology and oncology research in Latin America: A decade of uncertainty

Although hematology and oncology research is a highly relevant and evolving field, research contributions by Latin American countries, apart from Brazil, remain unclear.

Epithelial-mesenchymal transition, proliferation, and angiogenesis in locally advanced cervical cancer treated with chemoradiotherapy.

We evaluated the association between epithelial–mesenchymal transition (EMT)‐derived markers and expression of proteins associated with cell proliferation and tumor growth, as well as their prognostic roles, in 61 patients (mean age 52 ± 10 years) with locally advanced cervical cancer, all of whom were treated with chemoradiation and intracavitary brachytherapy. We used immunohistochemical analysis to assess the expression of proteins targeted in our investigation. Various statistical analyses were then conducted to assess protein marker associations with survival outcomes. Forty‐six percent of the patients were positive for human papilloma virus. Median progression‐free survival (PFS) was 6.6 months (95% confidence interval [CI]: 4.0–9.1, whereas overall survival (OS) was 30.0 months (95% CI: 11–48). Multivariate analysis demonstrated that vascular endothelial growth factor (VEGF) (P = 0.002), epidermal growth factor receptor (EGFR) (P = 0.001), and TWIST2 (P = 0.001) expression levels, as well as a tumor size <6 cm (P = 0.02), influenced OS. Changes in TWIST2 levels and loss of E‐cadherin expression were correlated with VEGF and EGFR levels; furthermore, patients with high TWIST2 expression had shorter OS (P = 0.0001), as those with loss of E‐cadherin (P = 0.02). OS was even shorter when positive EGFR or VEGF expression was related with EMT markers (positive EGFR + negative E‐cadherin: median 14 months, 95% CI: 3–24; negative EGFR + positive E‐cadherin: median 31 months, 95% CI: 14–NA; P = 0.02.). The presence of EMT markers was associated with proliferative and pro‐angiogenic protein expression and influenced the prognosis of locally advanced cervical cancer.

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.

BIM deletion polymorphisms in Hispanic patients with non-small cell lung cancer carriers of EGFR mutations

Background Germline alterations in the proapoptotic protein Bcl-2-like 11 (BIM) can have a crucial role in diverse tumors. To determine the clinical utility of detecting BIM deletion polymorphisms (par4226 bp/ par363 bp) in EGFR positive non-small-cell lung cancer (NSCLC) we examined the outcomes of patients with and without BIM alterations. Results BIM deletion was present in 14 patients (15.7%). There were no significant differences between patients with and without BIM-del in clinical characteristics or EGFR mutation type; however, those with BIM-del had a worse overall response rate (ORR) to erlotinib (42.9% vs. 73.3% in patients without BIM-del; p=0.024) as well as a significantly shorter progression-free survival (PFS) (10.8 BIM-del+ vs. 21.7 months for patients without BIM-del; p=0.029) and overall survival (OS) (15.5 BIM-del+ vs. 34.0 months for patients without BIM-del; p=0.035). Multivariate Cox regression analysis showed that BIM-del+ was an independent indicator of shorter PFS (HR 3.0; 95%CI 1.2-7.6; p=0.01) and OS (HR 3.4; 95%CI 1.4-8.3; p=0.006). Methods We studied 89 NSCLC Hispanic patients with EGFR mutation who were treated with erlotinib between January 2009 and November 2014. BIM deletion polymorphisms (BIM-del) was analyzed by PCR in formalin-fixed paraffin-embedded (FFPE) tissues of tumor biopsies. We retrospectively analyzed clinical characteristics, response rate, toxicity, and outcomes among patients with and without BIM-del. Conclusions The incidence of BIM-del found in Hispanic patients is similar to that previously described in Asia. This alteration is associated with a poor clinical response to erlotinib and represents an independent prognostic factor for patients who had NSCLC with an EGFR mutation.

P1.42 (also presented as PD2.04): PEM/CBP/BEV Followed by Maintenance PEM/BEV in Hispanic Patients With NSCLC: Outcomes According to TS, ERCC1 and VEGF: Track: Advanced NSCLC

The primary and secondary outcomes, Overall Survival (OS) and Progression Free Survival (PFS), respectviely, were evaluated in terms of (i) posterior surface under cumulative ranking curve (SUCRA), (ii) probability of being best treatment, (iii) probability of outperforming no maintenance, and (iv) posterior median hazard ratios with 95% credible intervals, in an unselected population, as well as by EGFR mutation status, histology, and response to induction. Secondary outcomes were overall survival (OS) and adverse events. Results: Twelve trials evaluating eight maintenance treatments in 3,850 patients were included in NMA. Selected maintenance treatments showed substantial PFS and OS benefits with probabilities 99% and 92% respectively of outperforming no maintenance. Results suggest the following strategy for optimal OS and PFS: (i) switch to or continue pemetrexed or switch to anti-EGFR TKI for nonsquamous patients, (ii) continue gemcitabine for squamous patients, (iii) switch to docetaxel or continue gemcitabine for responders to previous induction, and (iv) switch to or continue pemetrexed or switch to anti-EGFR TKI for patients with stable disease postinduction. Conclusion: Maintenance treatments improve PFS and OS in good performance status patients with stage IIIb/ IV NSCLC not progressing after first-line chemotherapy. Benefits are optimized by targeting specific maintenance treatments to selected patient groups guided by histology and response to previous induction.

O.01: Acquired Resistance to EGFR-TKIs in EGFR-Mutant Lung Adenocarcinoma Among Hispanics (RBIOP-CLICaP)

PRESIDENTIAL SYMPOSIUM FRIDAY, AUGUST 26 e 08:00 e 09:15 O.01 Acquired Resistance to EGFR-TKIs in EGFR-Mutant Lung Adenocarcinoma Among Hispanics (RBIOP-CLICaP) Andrés F. Cardona, Oscar Arrieta, Martín I. Zapata, Leonardo Rojas, Beatriz Wills, Hernán Carranza, Noemi Reguart, Carlos Vargas, Jorge Otero, Luis Corrales-Rodriguez, Claudio Martin, Pilar Archila, Mauricio Cuello, Carlos Ortiz, Rafael Rosell Clinical And Translational Oncology Group, Clínica del Country, Bogotá/COLOMBIA, Thoracic Oncology Unit, Instituto Nacional de Cancerología, Mexico DF/MEXICO, Internal Medicine Department, Fundación Santa Fe de Bogotá, BOGOTA/COLOMBIA, Oncology Department, Hospital Universitario San Ignacio, Bogotá/COLOMBIA, Internal Medicine Department, Johns Hopkins Hospital, Baltimore/ UNITED STATES OF AMERICA, Medical Oncology, Hospital Clinic, Barcelona/SPAIN, Medical Oncology, CIMCA / Hospital San Juan de Dios, San José/COSTA RICA, Thoracic Oncology Unit, Instituto Alexander Fleming, CIUDAD DE BUENOS AIRES/ARGENTINA, Foundation for Clinical and Applied Cancer Research, Bogota/COLOMBIA, Hospital De Clínicas, Universidad de la República (UdeLAR), Montevideo/URUGUAY, Cancer Biology & Precision Medicine Program, Catalan Institute of Oncology, Barcelona/SPAIN Background: Patients with epidermal growth factor receptor (EGFR)-mutant lung carcinoma eventually develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). In 50% of these cases, a secondary EGFR mutation, T790M, underlies the acquired resistance. Other alterations include amplification of MET, PI3K mutations, changes in MAPK1, Her2, AXL and even transformation to small cell lung carcinoma (SCLC). We assessed histological, clinical characteristics and survival outcomes in Hispanic patients with EGFR mutation after disease progression. Method: 34 EGFR-mutant lung cancer patients with acquired resistance to EGFR TKIs were identified as part of a prospective registry (active between January 2011 and January 2015) in which post-progression tumor specimens were collected for molecular analysis using Journal of Thoracic Oncology Vol. 11 No. 10S: S168-S170 SNaPshot tumor genotyping assay to detect mutations in EGFR, KRAS, BRAF, PI3KCA, TP53, MET and Her2, and FISH for MET, ALK and EGFR. Samples also underwent immunohistochemistry analysis for E-cadherin, synaptophysin, CD56 and PDL1. Post-progression interventions, response and survival were assessed and compared to those with and without T790M. Results: Mean age was 59.4±13.9 years; 62% were female, 65% were never-smokers and 53% had a performance status 80%; main metastatic sites were lung (16/47%), bone (20/58%), brain (18/52%) and liver (13/38%). All patients received erlotinib as firstline treatment and documented mutations were: 60% DelE19 (Del746e750) and 40% L858R. Overall response rate (ORR) with first line TKI was 61.8% and progression free survival (PFS) was 16.8 months (range, 13.7e19.9 m). After progressing to TKI, all patients were re-biopsied, of whom 16 had the T790M mutation (47.1%); 5 had PI3K mutations (14.7), 5 had EGFR amplification (14.7%), 2 had a KRAS mutation (5.9%), 3 had MET amplification (8.8%), 2 had Her2 alterations (5.8%, deletions/insertions in e20), and one had SCLC transformation (2.9%). 79.4% received treatment after progression. ORR for post-TKI treatments was 47.1% (CR 2/PR 14) and median PFS was 8.3 months (CI95% 2.2e36.6). There were no differences in PFS according to gender (p1⁄40.10) or type of acquired alteration (p1⁄40.63). Median survival was 32.9 months (CI95% 30.4e35.3), and only the use of postprogression therapy affected OS in multivariate analysis (p1⁄40.05). Conclusion: Hispanic patients with acquired resistance to EGFR TKIs continued to be sensitive to other treatments after progression. Proportion of T790M+ patients appears to be similar to previously reported results in Caucasians.

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.