Victoria Soldatenkova

Second-line therapy for NSCLC in clinical practice: baseline results of the European SELECTTION observational study.

Abstract Objective: Although the efficacy of a number of drugs for the second-line treatment of non-small cell lung cancer (NSCLC) has been demonstrated in Phase III trials, very limited evidence exists on optimal duration of second-line treatment or the reasons why this treatment is stopped in standard clinical practice. SELECTTION (Survey in European Lung Cancer Evaluating Choice of Treatment and Tolerability In Observed NSCLC) was designed to assess the time from initiation of second-line treatment for NSCLC to treatment discontinuation for any reason, the reasons for discontinuation, and the impact of discontinuation on outcomes. Methods: From October 2006 to January 2008, 1012 patients with advanced/metastatic NSCLC who completed or discontinued first-line treatment were enrolled in a multi-national, prospective observational cohort study (SELECTTION). Treatment cohorts were constructed based on the patients’ distribution across second-line treatments that were assigned by physician decision (pemetrexed, docetaxel, erlotinib, other treatments). This report presents a descriptive analysis of the baseline data collected, including patient/disease characteristics, treatment history and planned second-line treatments. Factors that may have affected treatment choice, selected by physicians from a range of options, were also identified. Results: Overall, 468 patients (46.2%) were enrolled in the pemetrexed cohort, 232 (22.9%) in docetaxel cohort, 206 (20.4%) in erlotinib cohort and 106 (10.5%) received other treatments. The profile of patients enrolled in the erlotinib cohort differed from those of patients enrolled in the pemetrexed or docetaxel cohorts in that erlotinib was more frequently planned for women, never-smokers and patients with adenocarcinomas. The primary reasons physicians gave for selection of the second-line treatment were tolerance and efficacy for pemetrexed, and preferred regimen for the particular patient and efficacy for the other treatments. Conclusions: In this observational study, pemetrexed, then docetaxel and erlotinib were the most frequently prescribed second-line treatments, which is in line with international guidelines. Erlotinib was most commonly prescribed to that subset of patients expected to gain the greatest benefit (those with adenocarcinoma, never-smokers and females). Pemetrexed was more frequently prescribed than docetaxel, with physicians most commonly choosing to prescribe the former agent because of its tolerability profile.

A randomized phase II non-comparative study of pemetrexed‑carboplatin and gemcitabine‑vinorelbine in anthracycline- and taxane-pretreated advanced breast cancer patients

Pemetrexed-carboplatin and gemcitabine‑vinorelbine combination therapies were efficacious in phase II and phase III studies as first-line breast cancer treatment. Thus, Arm A and Arm B combinations were investigated in patients pretreated with anthracycline and taxanes. Women with advanced breast cancer, with ≥1 measurable lesion per RECIST, were stratified by line of treatment (1st, 2nd), visceral disease (yes/no), ECOG PS (0-1 vs. 2) and randomized 1:1 to Arm A (pemetrexed 600 mg/m², D1 i.v. q21; carboplatin, AUC 5, D1 i.v. q21) or Arm B (gemcitabine 1,200 mg/m² D1, D8 i.v. q21; vinorelbine 30 mg/m² D1, D8 i.v. q21). Treatment continued until progression. The primary endpoint was objective response rate (RR). Secondary endpoints were duration of response (DoR), time-to-response (TTR), time-to-progressive disease (TTPD), time-to-treatment failure (TTTF) and safety. A two-stage design was employed independently for each arm. Of 135 randomized patients, 125 (Arm A, n=64; Arm B, n=61) qualified for tumor-response analysis. The mean (standard deviation) number of cycles administered was 6.3 (4.13) in Arm A and 6.2 (4.39) in Arm B. Efficacy in Arm A and Arm B were: RR (95% CI), 26.6 (16.3-39.1) and 29.5 (18.5-42.6); time-to-events (months), DoR 7.7 and 7.5; TTPD, 5.1 and 5.6; TTR, 1.8 and 1.8; TTTF, 4.8 and 5.1; respectively. Most common grade 3/4 adverse events possibly related to study-drug were neutropenia, thrombocytopenia, anemia and leucopenia in Arm A and neutropenia, leucopenia and fatigue in Arm B. In this study, both combinations showed moderate activity as predefined RR was not reached and were well tolerated.

Second-line therapy for non-small cell lung cancer in clinical practice: final results and treatment pathways from the SELECTTION observational study

Abstract Objectives: SELECTTION was a multinational, prospective observational study to assess the choice of and the time from initiation of second-line treatment to treatment discontinuation for any reason in patients with non-small cell lung cancer. Methods: Treatment cohorts were constructed based on prescribed second-line treatments that were at the discretion of the treating physicians, for 1013 patients enrolled in 11 countries. Propensity score analysis was conducted to assess whether the cohorts were comparable. Time from initiation of second-line treatment to treatment discontinuation was the primary endpoint. Reasons for treatment discontinuation, overall survival, progression-free survival and choice of second-line treatment were secondary endpoints. Results: The treatment cohorts were pemetrexed (46.2%), docetaxel (22.9%), erlotinib (20.4%) and other treatments (10.5%). Analyses of baseline data and propensity scores showed that the erlotinib cohort comprised substantially different patients compared with the pemetrexed and docetaxel cohorts: patients in the erlotinib cohort were more likely to be women, never-smokers, have adenocarcinoma and worse performance status. Therefore, comparisons of outcomes between cohorts were not appropriate. Although disease progression was the most common reason for treatment discontinuation in all cohorts, erlotinib patients tended to continue treatment after disease progression, whereas in the docetaxel and pemetrexed cohorts, discontinuation occurred soon after disease progression. Conclusions: In real-world clinical practice the profiles of patients assigned to erlotinib were distinctly different from those assigned to pemetrexed or docetaxel. The most common reason for treatment discontinuation was progressive disease, reflecting adherence to clinical recommendations. It is difficult to extrapolate these findings to the present, as both clinical practice and the approved indications for NSCLC treatments have evolved substantially.

The Effect of Necitumumab in Combination with Gemcitabine plus Cisplatin on Tolerability and on Quality of Life: Results from the Phase 3 SQUIRE Trial

Introduction: Necitumumab, a second‐generation, recombinant human immunoglobulin G1 epidermal growth factor receptor antibody in the phase 3 SQUIRE trial (NCT00981058), increased survival benefit for patients randomized to receive necitumumab plus gemcitabine‐cisplatin compared with those who received gemcitabine‐cisplatin. Here we characterize health‐related quality of life (HRQoL) and tolerability results. Methods: A total of 1093 patients with stage IV squamous non–small cell lung cancer were randomized 1:1 to receive necitumumab (800 mg absolute dose intravenously [IV]) plus gemcitabine‐cisplatin (gemcitabine = 1250 mg/m2 IV on days 1 and 8; cisplatin = 75 mg/m2 IV on day 1) or gemcitabine‐cisplatin alone (every 21 days) for up to six cycles. Patients receiving necitumumab plus gemcitabine‐cisplatin without disease progression continued necitumumab until progression. HRQoL was measured by Eastern Cooperative Oncology Group performance status, the Lung Cancer Symptom Scale (LCSS), and the European Quality of Life Five‐Dimensions questionnaire. Efficacy and LCSS outcomes were analyzed using the baseline maximum severity score of the LCSS. Tolerability was measured in terms of exposure to the study treatment and adverse events. Hospitalization rates were collected. Results: Most patients in both study arms similarly maintained Eastern Cooperative Oncology Group performance status and comparable LCSS and European Quality of Life Five‐Dimensions questionnaire assessments. Patients with a higher baseline LCSS had a greater survival benefit on the necitumumab arm. Chemotherapy exposure was similar in both treatment arms; 51% of patients on the necitumumab plus gemcitabine‐cisplatin arm continued on single‐agent necitumumab. The most frequent grade 4 adverse events were neutropenia (6.1% versus 7.9%) and thrombocytopenia (3.2% versus 4.3%) in the necitumumab plus gemcitabine‐cisplatin versus gemcitabine‐cisplatin arms, respectively. Hospitalizations were slightly higher with necitumumab plus gemcitabine‐cisplatin (36.4%) than with gemcitabine‐cisplatin (34.0%). Conclusions: The addition of necitumumab to gemcitabine‐cisplatin was well tolerated, did not negatively affect HRQoL or toxicity, and particularly benefited patients with more severe baseline symptoms or lower HRQoL.

Final results from a Phase II study of pemetrexed and cisplatin with concurrent thoracic radiation after Pem-Cis induction in patients with unresectable locally advanced non-squamous non-small cell lung cancer (NSCLC).

OBJECTIVES This single-arm multicenter Phase II study investigated the efficacy and safety of pemetrexed (Pem) and cisplatin (Cis) induction chemotherapy (CT) followed by full-dose Pem-Cis plus concurrent radiotherapy (RT) in patients with locally advanced non-squamous NSCLC. MATERIALS AND METHODS Patients with unresectable Stage III non-squamous NSCLC received two 21-day cycles of Pem 500 mg/m(2) (vitamin/folic acid supplementation and dexamethasone prophylaxis per Pem-label)+Cis 75 mg/m(2) on Day 1. Eligible patients who had not progressed continued with 2 further cycles of full-dose Pem-Cis plus concurrent RT (2 Gy/fraction, 5 days/week, 66 Gy total). Primary endpoint was the 1-year progression-free survival (PFS) rate. RESULTS Of 90 patients enrolled (all treated; median age 61 years, male/female 57%/43%, ECOG performance status 0/1 66%/34%, adenocarcinoma 90%, Stage III 36%/62%), 75 (83%) completed induction CT and started concurrent CT+RT. 64 (71%) patients received all 4 CT cycles and an RT dose ≥60 Gy. The 1-year PFS rate was 51.3% (95%CI: 42.0, 60.5). Median PFS was 10.6 months (95%CI: 8.6, 17.3), median OS was 26.2 months (95%CI: 16.7, not estimable). One patient died from enteritis (treatment-related) during Cycle 4. Four patients discontinued due to treatment-related adverse events, 1 on induction CT (renal failure), 3 on concurrent CT+RT (1 hypoacusis, 2 acute esophagitis). During induction CT, 18.9% of patients reported Grade 3/4 CTCAEs, only neutropenia (2.2%) and syncope (2.2%) were reported by >1 patient. During concurrent CT+RT, 41.3% of patients reported G3/4 CTCAEs, mainly esophagitis (12.0%), neutropenia (10.7%), and leukopenia (9.3%). CONCLUSION In this study of Pem-Cis induction CT followed by full-dose Pem-Cis with concurrent RT, median PFS was 10.6 months and toxicity was manageable, in line with previous data on Pem-Cis plus RT.

A randomized Phase 2 study of pemetrexed in combination with cisplatin or carboplatin as adjuvant chemotherapy in patients with completely resected stage IB or II Non-Small-Cell Lung Cancer

OBJECTIVES We investigated the feasibility of cisplatin or carboplatin combined with pemetrexed as adjuvant treatment in patients with completely resected Stage IB/II Non-Small-Cell Lung Cancer (NSCLC). MATERIALS AND METHODS Patients in this multicenter, open-label, parallel-group, non-comparative Phase 2 study were randomized (1:1) to pemetrexed (500 mg/m(2)) with either cisplatin (75 mg/m(2)) or carboplatin (AUC5) for 4 cycles of 21 days. The primary endpoint was treatment feasibility (defined as 4 cycles completed with no cycle delay >42 days and ≤2 dose reductions, with a median relative dose intensity (RDI) ≥95% [overall]; and no Grade ≥3 toxicities at the follow-up visit 30 days after last drug administration). Secondary objectives included overall survival (OS) and safety. RESULTS We randomized 122 patients and treated 118. 71.9% (46/64) of patients in pemetrexed+cisplatin and 88.9% (48/54) in pemetrexed+carboplatin completed 4 cycles (median RDI >97% for all compounds). Neither treatment met the pre-defined feasibility level >60% of patients: 59.4% (95% confidence interval [CI]: 46.4;71.5) pemetrexed+cisplatin; 50.0% (95%CI: 36.1;63.9) in pemetrexed+carboplatin. In a post-hoc analysis considering only safety, both regimens were feasible with 81.3% (95%CI: 69.5;89.9) in pemetrexed+cisplatin and 90.7% (95%CI: 79.7;96.9) in pemetrexed+carboplatin. OS rates for both groups were 82-83% after 3 years and 80-83% after 5 years. Treatment-related Grade ≥3 adverse events (mostly hematological) were experienced by approximately 30% of patients in each group. CONCLUSION Although the study did not meet the primary objective, both treatment groups demonstrated good safety-related feasibility and tolerability as adjuvant treatment in patients with completely resected Stage IB/II NSCLC.

Taxane-based mono- or combination therapy for managing metastatic breast cancer (MBC) in routine practice: a multinational prospective observational study

Abstract Objectives: Taxanes are standard for first-line chemotherapy of metastatic breast cancer (MBC), but indications for single-agent versus combination treatment remain controversial. This non-interventional study in 12 different countries explored treatment patterns and progression-free survival (PFS) in routine practice. Research design and methods: The prospective study was designed to determine factors associated with the choice of taxane-based regimens for MBC. Data were collected at the start of first-line treatment planned by the physician (baseline), and at subsequent routine practice visits. Patients were followed up until death, disease progression or change of treatment regimen, for a maximum of 8 months. Upon analysis, patients were classified into taxane single-agent (TM) or taxane-based combination (TC) cohorts according to scheduled first-line therapy. Logistic regression was used to investigate the relationship between choice of TM vs. TC and baseline factors. Results: Among the 465 patients enrolled (22.4% HER2+), 160 were prescribed TM (69% docetaxel, 31% paclitaxel) and 305 TC, frequently combined with gemcitabine (39%) or capecitabine (24%). HER2+ status was the only factor associated with choosing TC (p < 0.001). Median PFS [95% CI] was 11.5 [8.7–13.3] months for TM and 10.3 [8.4–14.4] months for TC. Among HER2+ patients (N = 104), only 59% received trastuzumab, none had previous adjuvant trastuzumab. Median PFS was 19.7 [9.3–unestimated] months for TC including trastuzumab, 18.8 [5.0–22.0] months for TC and 6.1 [3.8–13.3] months for TM without trastuzumab. Conclusions: In patients from 12 different countries treated during routine practice, TCs were prescribed more frequently than single agents. HER2+ status was significantly associated with TC use. 41% of HER2+ patients received no anti-HER2 treatment; PFS results for TC with and without trastuzumab (19.7 and 18.8 months) suggested TCs without trastuzumab might be worth further investigation in these patients. However, the study was not randomized; treatment evaluation bias can therefore not be excluded.

Efficacy and Safety of First-Line Necitumumab Plus Gemcitabine and Cisplatin Versus Gemcitabine and Cisplatin In East Asian Patients with Stage IV Squamous Non-Small Cell Lung Cancer: A Subgroup Analysis of the Phase 3, Open-Label, Randomized SQUIRE Study.

Purpose The phase 3 randomized SQUIRE study revealed significantly longer overall survival (OS) and progression-free survival (PFS) for necitumumab plus gemcitabine and cisplatin (neci+GC) than for gemcitabine and cisplatin alone (GC) in 1,093 patients with previously untreated advanced squamous non-small cell lung cancer (NSCLC). This post hoc subgroup analysis assessed the efficacy and safety of neci+GC among East Asian (EA) patients enrolled in the study. Materials and Methods All patients received up to six 3-week cycles of gemcitabine (days 1 and 8, 1,250 mg/m²) and cisplatin (day 1, 75 mg/m²). Patients in the neci+GC arm also received necitumumab (days 1 and 8, 800 mg) until disease progression or unacceptable toxicity. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from stratified Cox proportional hazards models. Results In EA patients, there were improvements for neci+GC (n=43) versus GC (n=41) in OS (HR, 0.805; 95% CI, 0.484 to 1.341) and PFS (HR, 0.720; 95% CI, 0.439 to 1.180), consistent with the results for non-EA patients observed in the present study. The overall safety data were consistent between EA and non-EA patients. A numerically higher proportion of patients experienced serious adverse events (AEs), grade ≥ 3 AEs, and AEs with an outcome of death for neci+GC versus GC in EA patients and EA patients versus non-EA patients for neci+GC. Conclusion Although limited by the small sample size and post hoc nature of the analysis, these findings are consistent with those of the overall study and suggest that neci+GC offers a survival advantage and favorable benefit/risk for EA patients with advanced squamous NSCLC.

A phase II single-arm study of induction chemotherapy with cisplatin and gemcitabine followed by concurrent cisplatin and gemcitabine with thoracic radiation for unresectable locally advanced non-small cell lung cancer

Objectives: The aim of this study was to evaluate the efficacy and tolerability of the combination of cisplatin–gemcitabine with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). Methods: This was a phase II, multicenter, open-label, single-arm trial in treatment-naïve patients with stage IIIA and IIIB LA-NSCLC. After three induction cycles with gemcitabine 1250 mg/m2 plus cisplatin 80 mg/m2, two concurrent chemoradiotherapy cycles with gemcitabine 300 mg/m2, cisplatin 80 mg/m2, and radiotherapy (63 Gy) were administered. The primary endpoint was response rate after induction chemotherapy followed by concurrent chemoradiotherapy. Secondary endpoints included time to progressive disease (TtPD), overall survival (OS), and safety. Results: Overall, 49 patients (median age 63.4 years; 73.5% male; Karnofsky performance status scores of 80, 85, 90, and 100 [16.3%, 2.0%, 49.0%, and 32.7%, respectively]; disease stage IIIA or IIIB 28.6% and 71.4%, respectively) were enrolled and treated. Response rate was 38.8% (95% confidence interval [CI] 25.2–53.8%). Median TtPD was 11.4 months (95% CI 9.4–12.9). Median OS was 21.8 months (95% CI 17.5–26.0), with 1- and 2-year survival rates of 70.8% and 43.7%, respectively. Overall, six patients discontinued from study treatment due to adverse events (AEs), of which two were serious AEs. The most relevant grade 3/4 AEs were neutropenia and thrombocytopenia in induction chemotherapy and chemoradiotherapy, and grade 3 events related to radiation in acute chemoradiotherapy, e.g. dysphagia, radiation pneumonitis, and radiation esophagitis. Conclusions: Induction chemotherapy followed by concurrent chemoradiotherapy with gemcitabine (300 mg/m2) and cisplatin was associated with acceptable toxicity. The observed median OS time was 21.8 months. Response evaluation was difficult as in many cases it was not possible to differentiate tumor progression from local radiofibrosis.

Venous thromboembolism with EGFR monoclonal antibody necitumumab in stage IV non-small cell lung cancer: A retrospective cohort analysis

INTRODUCTION Metastatic non-small cell lung cancer (NSCLC) is a recognized risk factor for VTE. Some systemic treatments may increase this risk further. Here, we present the risk of VTE and its prognostic significance for patients treated with chemotherapy (chemo) and the EGFR monoclonal antibody necitumumab (neci) for metastatic NSCLC. METHODS Four trials of 1st-line treatment for Stage IV NSCLC were analyzed: two randomized phase 3 studies of cisplatin/gemcitabine ±neci in squamous NSCLC (SQUIRE: N = 1079) and cisplatin/pemetrexed ±neci in non-squamous NSCLC (INSPIRE: N = 616); JFCL (N = 161), a randomized phase 2 trial of carboplatin/paclitaxel ±neci in squamous NSCLC; and JFCK (N = 61), a single arm phase 2 trial of cisplatin/gemcitabine +neci in squamous NSCLC. A Cox proportional hazards model with VTE as a time-dependent covariate was used for overall survival (OS) analyses. RESULTS Neci + chemo was associated with an increased risk of VTE (Relative Risk [RR]: 1.579; 95% CI: 1.155-2.158). History of VTE (RR: 1.899; 95% CI: 1.142-3.156) and prior cardiac/cardiovascular events (RR: 1.514; 95% CI: 1.102-2.082) were associated with increased risk of VTE. Decreased VTE risk was seen with: male sex (RR: 0.696; 95% CI: 0.502-0.964), eastern European geographic region (RR: 0.387; 95% CI: 0.267-0.562) and squamous cell pathology (RR: 0.653; 95% CI: 0.483-0.883). VTE occurrence showed no association with OS (HR: 1.121; 95% CI: 0.930-1.351). CONCLUSION Our data suggest that certain patient characteristics such as prior history of VTE and non-squamous histology might be associated with an increased risk of on-treatment VTE in NSCLC, although in this study, overall survival was not affected. Further studies to develop measures for identifying high-risk patients are needed to inform treatment decisions as well as VTE management and prophylaxis.