Jorge Miguel Otero

Elderly patients with aggressive non-Hodgkin's lymphoma treated with CHOP chemotherapy plus granulocyte-macrophage colony-stimulating factor : Identification of two age subgroups with differing hematologic toxicity

PURPOSE Standard cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy repeated at 3-week intervals is difficult to deliver in elderly patients with non-Hodgkins lymphoma (NHL). The use of hemopoietic growth factors may decrease the hematologic toxicity of chemotherapy and allow the delivery of full-dose CHOP. PATIENTS AND METHODS We conducted a phase II trial with the addition of granulocyte-macrophage colony-stimulating factor (GM-CSF) to CHOP chemotherapy in NHL patients older than 60 years of age. Twenty-six previously untreated patients were assessable; median age was 67 years (range, 61 to 84 years). CHOP included cyclophosphamide 750 mg/m2 intravenously day 1; doxorubicin 50 mg/m2 intravenously day 1; vincristine 1.4 mg/m2 (2 mg total dose) intravenously day 1; and prednisone 100 mg orally days 1 through 5. GM-CSF 5 microg/kg was administered subcutaneously on days 4 through 13. Cycles were repeated every 21 days for six cycles. Results were analyzed for the total group and for two age subgroups: 61 to 69 years (n = 15) and 70 years or older (n = 11). RESULTS Sixteen patients (62%) achieved a complete response (CR), four patients (15%) achieved a partial response (PR), and six patients (23%) did not respond to therapy. After a median follow-up of 41 months, the median progression-free and overall survival were 19 and 30 months, respectively. Twenty patients completed six cycles. One hundred thirty-eight of the 156 planned cycles were delivered (88%). The relative dose-intensity was 95%. The chemotherapy-induced toxicity was important. Absolute neutrophil count was less than 500/mL in 43% of the cycles, platelet nadir was less than 20,000/mL in 19%, and febrile neutropenia occurred in 21%. There were no grades 3 to 4 mucositis. Treatment-related death occurred in two patients, and was associated with neutropenic septic shock. The toxicity related to GM-CSF was mild hypotension after the cytokine was administered in 7% of cycles. When the results of the study were analyzed by age subgroups, we observed that whereas response and median survival were similar in patients aged 61 to 69 years or 70 years or older, there were significant differences in dose delivery and toxicity. Chemotherapy was delivered in 86 of 90 planned cycles in patients aged 61 to 69 years, but in only 52 of 72 planned cycles in patients aged 70 to 84 years (P = .00008). Absolute neutrophil count was less than 500/mL in 24% of cycles in patients aged 61 to 69 years and 73% of cycles in patients aged 70 years or older (P = .00001). The platelet nadir of less than 20,000/mL occurred in 5% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P < .0001). Fever and neutropenia occurred in 8% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P < .0001). Mucositis (grades 1 to 2) occurred in 21% of patients aged 61 to 69 years and in 42% of patients aged 70 years or older (P = .006). CONCLUSION CHOP chemotherapy plus GM-CSF is an active regimen in elderly patients with NHL. Despite cytokine support, the toxicity of the regimen is elevated. We have identified two age subgroups (61 to 69 and > or = 70 years) that do not differ in treatment efficacy but show large differences in treatment-related toxicity.

Risk factors for treatment-related death in elderly patients with aggressive non-Hodgkin's lymphoma: results of a multivariate analysis.

PURPOSE It has been suggested that age is associated with chemotherapy-related death in patients with non-Hodgkins lymphoma (NHL) treated with doxorubicin-containing chemotherapy. The purpose of this study was to evaluate the relative influence of increasing age and other clinical parameters on the occurrence of treatment-related death in elderly patients with intermediate- or high-grade NHL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. METHODS A retrospective study of patients 60 years of age or older with intermediate- or high-grade NHL treated with CHOP chemotherapy in a single cancer center. The following variables were recorded: age (60 to 69, 70 to 79, and 80 to 94 years), histology (Working Formulation [WF] D, E, F, G, and H), Ann Arbor stage, B symptoms, extranodal involvement, bulky disease (> 7 cm), performance status (Eastern Cooperative Oncology Group [ECOG] scale), International Prognostic Index (IPI score), serum lactate dehydrogenase (LDH) level and doxorubicin relative dose-intensity (RDI). The relationship between these features and treatment-related death was assessed in univariate and multivariate logistic regression analysis. RESULTS From 1982 to 1991, 267 consecutive patients were treated. Median age was 70 years (range, 60 to 94 years). There were 35 toxic deaths. Sixty-three percent of the deaths occurred after the first cycle. Infection accounted for 82% of the toxic deaths. In the univariate analysis, the features associated with an increased risk of toxic death were ECOG performance status 2 to 4 (relative risk [RR], 7.82), B symptoms (RR, 3.38), diffuse large-cell histology (RR, 3.06), bulky disease (RR, 2.58), serum levels of LDH (RR, 2.53), and IPI score (RR, 2.46). The age groups did not show significance. In the regression model, performance status 2 to 4 was the only independent predictor of treatment-related death (RR, 3.52; 95% confidence interval [CI], 2.98 to 4.06). CONCLUSION Our results show that in elderly patients with NHL treated with doxorubicin-based chemotherapy the risk for treatment-related death is associated with poor performance status rather than with increasing chronologic age.

A Phase II Study of Neoadjuvant Gemcitabine Plus Doxorubicin in Stage IIIB Breast Cancer: A Preliminary Report

The purpose of this ongoing study is to determine the response and safety of a combination of gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) plus doxorubicin as neoadjuvant therapy for stage IIIB breast cancer. Thirty-nine chemotherapy-naive patients were enrolled in the study. The median age was 54 years (range, 32 to 74 years), and the median Karnofsky performance status was 100. Gemcitabine 1,200 mg/m(2) was given on days 1 and 8, and doxorubicin 60 mg/m(2) on day 1, followed by surgery or radiotherapy. Ninety-seven of 117 cycles (83%) were administered at full dose. An overall response rate of 95% was obtained, with a complete response in 18% (seven patients) and a partial response in 77% (30 patients). Twenty-eight patients (72%) underwent breast surgery after a maximum of three cycles of neoadjuvant therapy. World Health Organization grade 3/4 toxicities included leukopenia in nine cycles (8%), neutropenia in 16 cycles (14%), febrile neutropenia in 11 cycles (9%), and anemia in two cycles (2%). The most important nonhematologic toxicity was grade 2/4 mucositis in 16 cycles (14%), and/or grade 2/3 diarrhea in 10 cycles (9%). Neoadjuvant therapy with gemcitabine plus doxorubicin results in a high tumor response rate with moderate oral and hematologic toxicity. Semin Oncol 28 (suppl 10):57-61.

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.

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.

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

Background: X-396 is a novel, potent anaplastic kinase lymphoma (ALK) small tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1, SLK. It has demonstrated significant anti-tumor activity in both ALK TKI-naive and crizotinib-resistant models of ALK fusion-positive NSCLC. Method: In this multicenter phase I/II study, patient (pts) with advanced solid tumors enrolled in the phase I dose escalation portion of the study and given X-396 on a continuous 28-day schedule (NCT01625234). Doses from 25 up to 250 mg once daily were evaluated and 225 mg was selected for further evaluation in the phase II expansion. Patients in this phase were required to have ALK + NSCLC and measurable disease. Cohorts included pts who were 1) ALK-TKI naive, 2) Pts who progressed on prior crizotinib and had not received a second generation ALK TKI, 3) Pts who progressed on a second generation ALK TKI (may also have received crizotinib), 4) Pts with central nervous system (CNS) metastases, 5) Pts with leptomeningeal disease. All pts were assessed for adverse events (AEs) using CTCAE version 4.03, response to therapy was assessed using RECIST 1.1. Results: As of December 09, 2015 data cutoff, 57 pts (31 men, 26 women) have been enrolled. Median age is 56 (20-79) years, the majority of pts had ECOG performance status 1 (67%). The most common drugrelated AEs included rash (49%), nausea (28%), vomiting (25%), and fatigue (23%). Most AEs were grade (G) 1-2. The G3 treatment-related AEs were rash (7 pts), fatigue (1 pt), decreased appetite (1 pt), dehydration (1 pt), pruritus (1 pt), and face edema (1 pt). In particular, no G3 treatment-related gastrointestinal toxicity or liver enzyme elevation has been reported. To date 27 ALK+ NSCLC pts treated at doses 200 mg or greater are evaluable for response; partial response (PR) was achieved in 19 pts (70%) and stable disease (SD) in 2 pts (7%). In the crizotinib-naive pts (n1⁄48), responses were observed in 7 pts (88%). In the 12 pts with prior crizotinib, but no other ALK TKIs, 10 pts (83%) achieved PR and 1 (8%) SD. CNS responses have been observed in both crizotinib-naive and crizotinib resistant pts. The median duration of treatment in the 27 evaluable ALK+ pts is 16+ weeks, with the longest being 128+ weeks. Conclusion: X-396 is well tolerated and induces responses in both crizotinib-naive and crizotinib-resistant ALK+ NSCLC pts, as well as patients with CNS lesions. Enrollment is ongoing in the expansion cohorts.

P2.04: Characteristics and Long Term Outcomes of Advanced Pleural Mesothelioma in Latin America (MeSO-CLICaP): Track: SCLC, Mesothelioma, Thymoma

(HR 0.72; p1⁄40.02), and FL-TTP 12 months (HR 0.48; p<0.001). OS was significantly related to ECOG 0-1 (HR 0.43; p1⁄40.011) and to FL-TTP 12 months (HR 0.66; p1⁄40.05). Fifty-two patients (42%) receive a TL achieving a disease control rate of 62% with a PFS of 5.9 months (95%CI 5.0-6.8). Conclusion: SL-chemotherapy appears to be active in Hispanic MPM-patients, particularly in younger patients with good PS and prolonged disease control with FL chemotherapy. Considering the important limitations of this study, due to retrospective nature and the possible selection bias, prospective clinical trials are warranted to clarify these issues.