Trastuzumab Emtansine (T-DM1) in Patients with Previously Treated HER2-Overexpressing Metastatic Non-Small Cell Lung Cancer: Efficacy, Safety, and Biomarkers.

PURPOSE: HER2-targeted therapy is not standard of care for HER2-positive non-small cell lung cancer (NSCLC). This phase II study investigated efficacy and safety of the HER2-targeted antibody-drug conjugate trastuzumab emtansine (T-DM1) in patients with previously treated advanced HER2-overexpressing NSCLC. PATIENTS AND METHODS: Eligible patients had HER2-overexpressing NSCLC (centrally tested IHC) and received previous platinum-based chemotherapy and targeted therapy in the case of EGFR mutation or ALK gene rearrangement. Patients were divided into cohorts based on HER2 IHC (2+, 3+). All patients received T-DM1 3.6 mg/kg intravenously every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was investigator-determined overall response rate (ORR) using RECIST v1.1. RESULTS: Forty-nine patients received T-DM1 (29 IHC 2+, 20 IHC 3+). No treatment responses were observed in the IHC 2+ cohort. Four partial responses were observed in the IHC 3+ cohort (ORR, 20%; 95% confidence interval, 5.7%-43.7%). Clinical benefit rates were 7% and 30% in the IHC 2+ and 3+ cohorts, respectively. Response duration for the responders was 2.9, 7.3, 8.3, and 10.8 months. Median progression-free survival and overall survival were similar between cohorts. Three of 4 responders had HER2 gene amplification. No new safety signals were observed. CONCLUSIONS: T-DM1 showed a signal of activity in patients with HER2-overexpressing (IHC 3+) advanced NSCLC. Additional investigation into HER2 pathway alterations is needed to refine the target population for T-DM1 in NSCLC; however, HER2 IHC as a single parameter was an insufficient predictive biomarker.

Final results of the large-scale multinational trial PROFILE 1005: efficacy and safety of crizotinib in previously treated patients with advanced/metastatic ALK-positive non-small-cell lung cancer.

PURPOSE: Crizotinib is a potent, orally administered tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC). We report final results from PROFILE 1005, the largest clinical trial to date for an ALK inhibitor in ALK-positive NSCLC. PATIENTS AND METHODS: PROFILE 1005 (NCT00932451) was a multicenter, single-arm phase 2 trial of the efficacy, safety and tolerability of crizotinib (250 mg twice daily; 3 week continuous treatment cycles) in patients with ALK-positive NSCLC after failure of ≥1 lines of systemic treatment for locally advanced/metastatic disease. Patients' tumour ALK status was initially determined by a central laboratory until a protocol amendment permitted enrolment of patients based on locally determined ALK status. Co-primary endpoints were objective response rate (ORR), evaluated using Response Evaluation Criteria in Solid Tumours V.1.1 and adverse events (AEs). Cancer-specific patient-reported outcomes (PROs) were also assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 and its lung cancer module QLQ-LC13. RESULTS: 1069 patients were enrolled; 1066 received crizotinib. The as-treated population comprised 908 and 158 patients, in whom tumour positive ALK-status was determined centrally (± locally) or locally only, respectively. At baseline, a majority of patients were <65 years (84%), 66% were never smokers and 46% were Asian. Derived investigator-assessed ORR was 54% (95% CI 51 to 57) and 41% (95% CI 33 to 49) in the central-testing and local-testing subgroups, respectively. The most common treatment-related AEs in the overall population (any grade) were vision disorder (58%), nausea (51%), diarrhoea (47%) and vomiting (47%). PRO scores demonstrated clinically meaningful improvement in lung cancer symptoms and global quality of life. CONCLUSION: The efficacy, safety and PRO profiles of crizotinib in this cohort of 1066 patients with ALK-positive NSCLC are consistent with previous reports. TRIAL REGISTRATION NUMBER: Phase 2 trial (NCT00932451); Results.

Cisplatin and carboplatin-based chemotherapy in the first-line treatment of non-small cell lung cancer: Analysis from the European FRAME study.

OBJECTIVES: To explore patient and disease factors, and reasons behind the physician's choice of platinum backbone for the first-line treatment of non-small cell lung cancer (NSCLC), as observed in a European prospective observational study of patients receiving platinum-based chemotherapy as first-line treatment for advanced or metastatic NSCLC (the FRAME study). Additionally, overall survival (OS) for patients who received cisplatin or carboplatin was evaluated. MATERIALS AND METHODS: A post-hoc analysis of the prospective study population was conducted. Baseline characteristics of patients receiving cisplatin versus carboplatin were compared and summarized by propensity score. Survival for matched patients was summarized using the Kaplan-Meier approach. RESULTS: Of the 1564 patients who were included in the prospective study, 1520 received either cisplatin (54%) or carboplatin (46%) in combination with pemetrexed, gemcitabine, taxanes or vinorelbine. Patients treated with carboplatin were older than patients receiving cisplatin (mean age 67 versus 61 years; p<0.001), had poorer performance status (p<0.001), and more comorbidities (p<0.001). Cisplatin was most frequently combined with pemetrexed (47%), and carboplatin most frequently with taxanes (31%). Unadjusted median OS estimates for patients from the total prospective study sample were 11.5 months (95% confidence interval [CI] 10.1-12.9) for cisplatin recipients and 9.0 months (95% CI 8.1-10.6) for carboplatin recipients. Median (95% CI) overall survival for the matched cohorts was 10.8 months (8.8-14.3) for cisplatin versus 9.5 months (8.2-11.3) for carboplatin; p=0.086. CONCLUSION: This post-hoc analysis illustrated real-life differences in patients with NSCLC prescribed platinum-based first-line treatment, and suggested that baseline patient and disease characteristics were associated with physician's choice of platinum agent, with cisplatin being more frequently prescribed to younger and fitter patients.

Influence of histology and biomarkers on first-line treatment of advanced non-small cell lung cancer in routine care setting: baseline results of an observational study (FRAME).

FRAME is a prospective observational study of first-line treatments for advanced non-small cell lung cancer (NSCLC). This interim analysis examines the influence of histology and biomarkers on therapeutic decisions. Baseline characteristic, treatment, and diagnostic procedure data were collected on European patients with stage IIIB/IV NSCLC who were treated with any first-line platinum-based doublet, with or without targeted agents, in routine clinical practice. A total of 1567 patients were observed in 11 countries between April 2009 and February 2011. Patients were mostly non-Asian (96.4%), male (71.5%), smokers (84.4%) with stage IV NSCLC (76.6%) and a performance status of 0-1 (82.2%). Median age was 64 years (range, 33-87). First-line treatments were platinum-based combinations with pemetrexed (36.3%), gemcitabine (23.0%), vinorelbine (19.2%), taxanes (18.9%), or other (2.6%), with concurrent targeted agents in 8.4% of patients (mainly bevacizumab, 7.3%). Diagnosis was based on histology in 70.6%, cytology in 20.3%, and both in 9.1% of patients. The final diagnosis was nonsquamous in 72.2% (including 'not otherwise specified [NOS]' in 11.0%), squamous in 24.4%, and other in 3.4% of patients, with the most common reasons for NOS diagnosis being 'subtyping not technically possible' (42.9%) and 'not important for treatment decision' (40.5%). Only 1.1% (6 patients) in the pemetrexed cohort and 0.9% (1 patient) of patients who received bevacizumab had squamous cell carcinoma. At least one immunohistochemical (IHC) marker was used in 53.5% of patients (thyroid transcription factor-1 [TTF-1]: 47.5%, cytokeratin 7 [CK7]: 38.6%, cytokeratin 5/6 [CK5/6]: 17.9%, p63: 8.8%, cluster of differentiation 56 [CD56]: 4.2%, cytokeratin 14 [CK14]: 1.9%, and other: 24.2%). Testing for additional biomarkers was less common, with the most common being for epidermal growth factor receptor (EGFR) mutation status (26.0%). Physician-reported key factors influencing treatment choice were 'histopathological/cytological diagnosis' (77.4%), 'performance status' (63.2%), and 'age' (52.8%). Similar factors were identified using logistic regression models. Frequent histological testing was observed, likely resulting in few NOS diagnoses. In addition, IHC and predictive biomarkers were routinely assessed. Histology, performance status, and age were key factors influencing first-line treatment choice in the routine care of patients with advanced NSCLC. Clinical Trials. gov registry identifier number: NCT01067794.

An indirect comparison of the efficacy of bevacizumab plus carboplatin and paclitaxel versus pemetrexed with cisplatin in patients with advanced or recurrent non-squamous adenocarcinoma non-small cell lung cancer.

OBJECTIVE: There are two new treatment options available for the treatment of adenocarcinoma histology non-small cell lung cancer (NSCLC) which offer improved benefit in terms of progression-free (PFS) and overall survival (OS) over chemotherapy. Both bevacizumab and pemetrexed when combined with chemotherapy significantly increase PFS and OS in patients with advanced NSCLC versus chemotherapy alone. The aim of this analysis was to compare the efficacy for patients with non-squamous adenocarcinoma NSCLC treated with bevacizumab, carboplatin and paclitaxel (BCP) to pemetrexed and cisplatin (PC) by using indirect comparison (ITC) methodology. EXPERIMENTAL DESIGN: In the absence of head-to-head trials, ITC was performed on patients with adenocarcinoma histology non-squamous NSCLC to compare the relative benefit of first-line therapies BCP vs. PC by hazard ratios (HR). Subsequently, these HRs were used in a decision-analytic Markov model with a lifelong time horizon to extrapolate the long-term effectiveness of the two treatments. RESULTS: ITC estimated HRs for the primary endpoints in the bevacizumab study E4599 showed that BCP treatment in non-squamous adenocarcinoma NSCLC patients resulted in a BCP HR of 0.82 versus PC. The long-term predictions from the Markov model yielded a mean survival of 1.48 years (95% CI 1.34, 1.62 years) (or 17.7 months) for BCP compared with 1.29 years (95% CI 1.16, 1.42 years) (or 15.4 months) for PC. CONCLUSIONS: Based on our decision analysis, triplet BCP targeted therapy in patients with advanced non-squamous adenocarcinoma NSCLC compared with doublet PC chemotherapy results in improved expected values for overall long-term survival. Therefore, from the efficacy perspective, bevacizumab in combination with platinum-based chemotherapy can be considered as the targeted therapy of choice for patients with advanced non-squamous adenocarcinoma NSCLC.

Human recombinant erythropoietin does not promote cancer growth in presence of functional receptors expressed in cancer cells.

Human recombinant erythropoietin (hrEPO) therapy might be associated with tumor progression and death. This effect has been suggested to be secondary to rhEPO binding to its receptor (EPOR) expressed on cancer cells. However, there are several concerns about EPOR functionality when expressed on cancer cells. In this paper we have provided evidence that EPOR expressed in cancer cells could be implicated in proliferation events because a transfection of EPOR siRNA to EPOR-expressing bladder cancer cells resulted in a marked reduction in cell growth. However, these cell lines do not grow in the presence of hrEPO. Furthermore, bladder cancer patients that expressed EPOR in tumor samples had a reduced survival in absence of rhEPO treatment. Therefore, EPOR is implicated in bladder cancer growth but this effect appears to be independent from rhEPO supplementation. Reports which suggest that rhEPO promotes cancer growth due to the expression of EPOR in cancer cells must be observed with caution since in the presence of functional EPOR rhEPO does not promote growth.

Long term responses with cetuximab therapy in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is responsible for most of the deaths associated with primary brain tumors. Standard treatment includes maximal surgical resection followed by chemotherapy and concomitant radiotherapy. Most patients, however, recur shortly after treatment. Second line treatment has little efficacy and the majority of patients die soon from the disease. Recent advances in molecular biology have implicated the epidermal growth factor receptor (EGFR) signaling pathways in the progression and resistance to standard therapies for GBM. This has prompted the evaluation of EGFR tyrosine- kinase inhibitors with encouraging results. Cetuximab is a monoclonal antibody targeted against the extra cellular domain of the EGFR with activity against different tumor types, either alone or in combination with chemotherapy and/or radiation therapy. Here we describe three patients with recurrent, heavily pretreated, EGFR expressing GBM who responded to treatment with single agent cetuximab.

Efficacy of preoperative radiation therapy for resectable rectal adenocarcinoma when combined with oral tegafur-uracil modulated with leucovorin: results from a phase II study.

PURPOSE: The aim of this study was to evaluate the efficacy of preoperative radiation therapy for resectable rectal adenocarcinoma (T3-T4) when delivered in combination with chemotherapy (oral tegafur-uracil modulated with leucovorin). METHODS: Thirty-eight patients (23 males; mean age, 62 years.) with histologically proven rectal adenocarcinoma with primary tumor clinical classification T3-T4 (resectable) and N0 or N1-N2, according to TNM staging system, took part in the present clinical trial. After tumor and metastasis resectability confirmation, radiation therapy was administered by delivering a dose of 45 Gy in 25 fractions for 5 weeks. Chemotherapy treatment was initiated on the same day as radiotherapy and consisted of intravenous infusion of 6S-steroisomer of leucovorin 250 mg/m /day in 2 hours on Day 1, followed by oral 350 or 300 mg/m /day of tegafur (a 5-fluorouracil prodrug) plus uracil on Days 1 to 14 divided into 2 daily doses, and oral 6S-steroisomer of leucovorin 7.5 mg/12 hours on Days 2 to 14, with a total of 102 courses of neoadjuvant chemotherapy (, mean of 2.7 courses per patient). Six additional courses of tegafur-uracil were given postoperatively to all 38 patients but 1 who refused. RESULTS: As a result of preoperative chemoradiation treatment, 4 (10.5 percent) complete responses, 20 (52.6 percent) partial responses, and 14 (36.8 percent) patients with disease stabilization were observed. No patients had preoperative disease progression. Histologically proven downstaging was observed in 23 (60 percent) patients. On initial evaluation, only 39 percent of patients were considered as being good candidates for sphincter-preserving surgery; however, on preoperative chemoradiation completion this figure increased up to 60 percent. For the 23 patients eventually undergoing sphincter-preserving surgery, postoperative sphincter function assessment showed excellent function in 15 (65 percent) patients, good in 5 (22 percent), fair in 2 (9 percent), and poor in 1(4 percent). With a median follow-up of 37 (range, 10-62) months, local failure was found in 3 (8 percent) patients and distant failure in 2 (5 percent). Three-year actuarial disease-free survival and 3-year overall survival rates were 83 and 90 percent, respectively. Local control rate was 92 percent. Toxicity and postoperative complication rates were reasonable. CONCLUSIONS: Our neoadjuvant radiation therapy protocol is efficient for the preoperative treatment of resectable rectal adenocarcinoma when combined with chemotherapy (oral tegafur-uracil modulated with leucovorin). this protocol needs to be tested in a phase-III clinical trial with a larger sample size.