Proteasome inhibitor bortezomib enhances the effect of standard chemotherapy in small cell lung cancer.

Small cell lung cancer (SCLC) is an aggressive cancer showing a very poor prognosis because of metastasis formation at an early stage and acquisition of chemoresistance. One key driver of chemoresistance is the transcription factor Forkhead box protein M1 (FOXM1) that regulates cell cycle proliferation, maintenance of genomic stability, DNA damage response, and cell differentiation in numerous tumor entities. In this study we investigated the role of FOXM1 in SCLC progression and analyzed the effect of FOXM1 inhibition using two proteasome inhibitors, bortezomib and siomycin A. FOXM1 was strongly expressed in patient-derived SCLC samples (n=123) and its nuclear localization was associated with the proliferation marker Ki-67. Both proteasome inhibitors successfully inhibited FOXM1 expression leading to a significantly reduced proliferation and a decreased mitotic rate along with cell cycle arrest and apoptosis induction. These effects were further enhanced by addition of bortezomib to standard chemotherapy. Treatment of mice bearing chemoresistant SCLC xenografts with bortezomib reduced the mean bioluminescence signal of tumors by 54%. Similarly, treatment with cisplatin as a standard chemotherapy reduced the mean bioluminescence signal of tumors by 58%. However, in combination with standard chemotherapy bortezomib further reduced the mean bioluminescence signal by 93% (p=0.0258). In conclusion, we demonstrate the effect of bortezomib in inhibiting FOXM1 expression and thus in sensitizing resistant SCLC cells to standard chemotherapy. Thus, addition of bortezomib to standard chemotherapy might potently improve SCLC therapy, particularly in an extensive cancer stage.

65Plus: open-label study of bevacizumab in combination with pemetrexed or pemetrexed/carboplatin as first-line treatment of patients with advanced or recurrent nonsquamous non-small-cell lung cancer.

BACKGROUND: The aim of the study was to investigate in terms of noninferiority the efficacy and safety of a monochemotherapy regimen of pemetrexed plus bevacizumab (BevPem) versus carboplatin/pemetrexed plus bevacizumab (BevCPem) in elderly patients as first-line treatment for advanced metastatic or recurrent nonsquamous non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: 65Plus was a Phase III, randomized, open-label study. In total, 253 patients received BevPem (n=119) or BevCPem (n=134). The primary outcome measure was progression-free survival. Secondary end points were overall survival, tumor response, and safety outcomes. Evaluations were performed for the whole study population and stratified according to Eastern Cooperative Oncology Group (ECOG) performance status (PS). RESULTS: Noninferiority of BevPem in comparison to BevCPem could not be demonstrated for the overall population (P=0.7864). Significant superiority of the combined treatment BevCPem was seen in patients of ECOG PS 0-1 (median PFS 5.1 vs 6.9 months, HR 1.353, 95% CI 1.03-1.777), while the opposite tendency was observed in patients with ECOG PS 2 (median PFS 2.9 vs 1.5 months, HR 0.628, 95% CI 0.195-2.025). Overall, better tolerability was found for the BevPem group, irrespective of ECOG PS. CONCLUSION: Results from the 65plus study give evidence that BevPem and BevCPem treatments may exert differential effects on PFS, depending on the patients ECOG PS. It appears that patients with better ECOG PS (0-1) benefited more from the combined treatment with carboplatin, while the group comprising more severely impaired patients (ECOG PS 2) benefited more from the monochemotherapy.

Phase III Trial of Ipilimumab Combined With Paclitaxel and Carboplatin in Advanced Squamous Non-Small-Cell Lung Cancer.

Purpose Patients with squamous non-small-cell lung cancer (NSCLC) have poor prognosis and limited treatment options. This randomized, double-blind, phase III study investigated the efficacy and safety of first-line ipilimumab or placebo plus paclitaxel and carboplatin in advanced squamous NSCLC. Patients and Methods Patients with stage IV or recurrent chemotherapy-naïve squamous NSCLC were randomly assigned (1:1) to receive paclitaxel and carboplatin plus blinded ipilimumab 10 mg/kg or placebo every 3 weeks on a phased induction schedule comprising six chemotherapy cycles, with ipilimumab or placebo from cycles 3 to 6 and then, after induction treatment, ipilimumab or placebo maintenance every 12 weeks for patients with stable disease or better. The primary end point was overall survival (OS) in patients receiving at least one dose of blinded study therapy. Results Of 956 randomly assigned patients, 749 received at least one dose of blinded study therapy (chemotherapy plus ipilimumab, n = 388; chemotherapy plus placebo, n = 361). Median OS was 13.4 months for chemotherapy plus ipilimumab and 12.4 months for chemotherapy plus placebo (hazard ratio, 0.91; 95% CI, 0.77 to 1.07; P = .25). Median progression-free survival was 5.6 months for both groups (hazard ratio, 0.87; 95% CI, 0.75 to 1.01). Rates of grade 3 or 4 treatment-related adverse events (TRAEs), any-grade serious TRAEs, and TRAEs leading to discontinuation were numerically higher with chemotherapy plus ipilimumab (51%, 33%, and 28%, respectively) than with chemotherapy plus placebo (35%, 10%, and 7%, respectively). Seven treatment-related deaths occurred with chemotherapy plus ipilimumab, and one occurred with chemotherapy plus placebo. Conclusion The addition of ipilimumab to first-line chemotherapy did not prolong OS compared with chemotherapy alone in patients with advanced squamous NSCLC. The safety profile of chemotherapy plus ipilimumab was consistent with that observed in previous lung and melanoma studies. Ongoing studies are evaluating ipilimumab in combination with nivolumab in this population.

Experience with afatinib in patients with non-small cell lung cancer progressing after clinical benefit from gefitinib and erlotinib.

BACKGROUND: Afatinib, an irreversible ErbB family blocker, demonstrated superiority to chemotherapy as first-line treatment in patients with EGFR-mutated non-small cell lung cancer (NSCLC). Afatinib is also active in patients progressing on EGFR tyrosine kinase inhibitors (EGFR-TKIs). We report the results of a large cohort of NSCLC patients receiving afatinib within a compassionate-use program (CUP). PATIENTS AND METHODS: Patients with advanced NSCLC progressing after one line or more of chemotherapy and one line or more of EGFR-TKI treatment with either an EGFR mutation or documented clinical benefit were enrolled. Data collection was not monitored or verified by central review. The intention of this CUP was to provide controlled preregistration access to afatinib for patients with life-threatening diseases and no other treatment option. RESULTS: From May 2010 to October 2013, 573 patients (65% female; median age: 64 years [range: 28-89 years]) were enrolled, with strong participation of community oncologists. Comorbidities were allowed, including second malignancies in 11% of patients. EGFR mutation status was available in 391 patients (72%), and 83% tested mutation positive. Median time to treatment failure (TTF) of 541 patients treated with afatinib was 3.7 months (range: 0.0 to >29.0 months). Median TTF was 4.0 and 2.7 months in patients with adenocarcinomas and squamous cell carcinomas, respectively, and 4.6 months in patients with EGFR-mutated NSCLC. Adverse events were generally manageable. CONCLUSION: Afatinib was able to be given in a real-world setting to heavily pretreated patients with EGFR-mutated or EGFR-TKI-sensitive NSCLC. Acknowledging the constraints of data collection in a CUP, afatinib appears to be safe and to confer some clinical benefit in this population.

Motesanib plus carboplatin/paclitaxel in patients with advanced squamous non-small-cell lung cancer: results from the randomized controlled MONET1 study.

INTRODUCTION: The phase 3 MONET1 study evaluated motesanib (a small-molecule inhibitor of vascular endothelial growth factor receptors) plus carboplatin/paclitaxel versus placebo plus carboplatin/paclitaxel as first-line therapy for advanced non-small-cell lung cancer (NSCLC). Treatment and enrollment of patients with squamous histology were permanently discontinued following higher early mortality and gross hemoptysis in those with squamous NSCLC who received motesanib. Enrollment of patients with nonsquamous histology was temporarily halted, but resumed following a protocol amendment (Scagliotti et al. J Clin Oncol. 2012;30:2829-2836). Herein, we report data from the squamous cohort. METHODS: Patients with stage IIIB/IV or recurrent squamous NSCLC (without prior systemic therapy for advanced disease) received up to six 3-week cycles of chemotherapy (carboplatin, area under the curve 6 mg/mL•min/paclitaxel, 200 mg/m) and were randomized 1:1 to receive motesanib 125 mg (Arm A) or placebo (Arm B) once daily. The primary end point was overall survival. RESULTS: Three-hundred and sixty patients with squamous NSCLC were randomized (Arm A, n = 182; Arm B, n = 178) between July 2007 and November 2008. Twenty-three patients (13%) in Arm A and 10 (6%) in Arm B had fatal adverse events within the first 60 days of treatment. Among these, six patients in Arm A, but none in Arm B, had fatal bleeding events. At final analysis, serious adverse events had occurred in 47% of patients in Arm A and 29% of patients in Arm B. Median overall survival was similar in Arms A and B (11.1 versus 10.7 months). CONCLUSIONS: Motesanib plus carboplatin/paclitaxel had unacceptable toxicity compared with carboplatin/paclitaxel alone in patients with advanced squamous NSCLC.

Randomized phase II study of ixabepilone or paclitaxel plus carboplatin in patients with non-small-cell lung cancer prospectively stratified by beta-3 tubulin status.

PURPOSE: Retrospective studies have reported that tumor expression of the beta-3 tubulin (ß3T) isoform is an unfavorable prognostic factor in non-small-cell lung cancer (NSCLC) treated with tubulin-inhibiting chemotherapy. Ixabepilone is a tubulin-inhibiting agent with low susceptibility to multiple resistance mechanisms including ß3T isoform expression in several tumor models. This randomized phase II study evaluated ixabepilone-based chemotherapy in stage IIIb/IV NSCLC, compared with paclitaxel-based chemotherapy. Tumor specimens were prospectively evaluated for ß3T expression. PATIENTS AND METHODS: Patients were stratified by ß3T status (positive v negative) and randomly assigned at a ratio of 1:1 to receive ixabepilone (32 mg/m(2)) and carboplatin (area under concentration-time curve [AUC], 6) or paclitaxel (200 mg/m(2)) and carboplatin (AUC, 6) for up to six cycles. The primary end point was progression-free survival (PFS) in the ß3T-positive subgroup. RESULTS: Ninety-five patients (ß3T positive, 52; ß3T negative, 43) received ixabepilone plus carboplatin; 96 patients (ß3T positive, 49; ß3T negative, 47) received paclitaxel plus carboplatin. No significant differences in median PFS were observed between arms for either subgroup (ß3T positive, 4.3 months in both arms; ß3T negative, 5.8 v 5.3 months). Ixabepilone did not significantly improve overall survival (OS) for the ß3T-positive subset or the overall population. Adverse events were similar between the two arms and comparable with those in previous studies. CONCLUSION: There was no predictive value of ß3T in differentiating clinical activity of ixabepilone- or paclitaxel-containing regimens. Ixabepilone did not improve PFS or OS in patients with ß3T-positive tumors. ß3T-positive patients had worse PFS relative to ß3T-negative patients, regardless of treatment; hence, ß3T expression seems to be a negative prognostic factor, but not a predictive factor, in advanced NSCLC treated with either ixabepilone or paclitaxel platinum-based doublets.

Peptide receptor radionuclide therapy of Merkel cell carcinoma using (177)lutetium-labeled somatostatin analogs in combination with radiosensitizing chemotherapy: a potential novel treatment based on molecular pathology.

Few studies have been published on the safety and feasibility of synchronous use of peptide receptor radionuclide therapy (PRRNT), as source of internal radiation therapy, in combination with chemotherapy. In this study we reported a 53-year-old man with stage IV Merkel cell carcinoma (MCC), who underwent synchronous internal radiation therapy and chemotherapy. Based on presumable poor prognosis with chemotherapy only, functional similarities of MCC with other neuroendocrine tumors and available evidence of effectiveness and safety of synchronous use of external beam radiation therapy and chemotherapy in treatment of high-risk MCC patients, our interdisciplinary neuroendocrine tumor board recommended him to add PRRNT to his ongoing chemotherapy. He received 2 courses of (177)Lu-DOTATATE(1, 4, 7, 10-Tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid-1-D-Phe1-Tyr3-Thr8-octreotide) in combination with ongoing 8 cycles of liposomal doxorubicin based on standard protocols. Response to therapy was evaluated by (18)F-FDG and (68)gallium-somatostatin-receptor PET/CT. There was an impressive improvement of the clinical symptoms. However, follow-up PET/CT studies showed mixed pattern of response. Synchronous use of PRRNT and radiosensitizing chemotherapy seems safe and feasible in high risk MCC patients, however, further prospective studies and clinical trials are warranted to provide reliable evidence of possible pitfalls and effectiveness of PRRNT and (68)Ga-somatostatin-receptor PET/CT in the management of MCC.

Safety and efficacy of first-line bevacizumab plus chemotherapy in elderly patients with advanced or recurrent nonsquamous non-small cell lung cancer: safety of avastin in lung trial (MO19390).

INTRODUCTION: Safety of Avastin in Lung (MO19390) was an international, open-label, single-arm study, which assessed the safety and efficacy of first-line bevacizumab (Avastin®) in combination with standard chemotherapy in patients (n = 2212) with advanced or recurrent non-small cell lung cancer (NSCLC). A preplanned subgroup analysis was performed to examine these outcomes in elderly patients older than 65 years. METHODS: Eligible patients with nonsquamous NSCLC received up to six cycles of bevacizumab (7.5 or 15 mg/kg) plus any standard of care chemotherapy. Patients who did not experience disease progression after induction therapy continued bevacizumab therapy until disease progression or unacceptable toxicity. The primary end point was safety; secondary end points included time to disease progression (TTP) and overall survival (OS). RESULTS: Data were evaluated for 623 patients older than 65 years (mean age 70.6). The majority were Whites (86.2%) with stage IV disease (79.7%) and had adenocarcinoma (83.5%). The incidence of adverse events (AEs) of special interest was similar for elderly and younger patients (any grade bleeding 38.2% versus 38.3%; any grade hypertension 33.1% versus 30.6%; any grade proteinuria 33.4% versus 29.3%). Most AEs were grade less than or equal to 2. Serious AEs were reported in 45.3 and 34.7% of elderly and younger patients, respectively. Median OS was similar in elderly and younger patients (14.6 months in both age groups), as were TTP (8.2 versus 7.6 months), response rate (49.3% versus 52.4%), and disease control rate (89.3% versus 88.4%). Similar results were seen in a post hoc comparison of the older than 70 years and 70 years or younger subgroups: TTP was 8.6 months versus 7.7 months, respectively; OS was 14.6 months in both subgroups; response rate was 49% and 52%, respectively; incidence of AEs of special interest was comparable. CONCLUSION: Patients older than 65 years with nonsquamous NSCLC derive a similar clinical benefit from first-line bevacizumab-based therapy as their younger counterparts and do not experience increased toxicity.

Randomized phase II study of erlotinib in combination with placebo or R1507, a monoclonal antibody to insulin-like growth factor-1 receptor, for advanced-stage non-small-cell lung cancer.

PURPOSE: R1507 is a selective, fully human, recombinant monoclonal antibody (immunoglobulin G1 subclass) against insulin-like growth factor-1 receptor (IGF-1R). The strong preclinical evidence supporting coinhibition of IGF-1R and epidermal growth factor receptor (EGFR) as anticancer therapy prompted this study. PATIENTS AND METHODS: Patients with advanced-stage non-small-cell lung cancer (NSCLC) with progression following one or two prior regimens, Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2, and measurable disease were eligible. Patients were randomly assigned to receive erlotinib (150 mg orally once a day) in combination with either placebo, R1507 9 mg/kg weekly, or R1507 16 mg/kg intravenously once every 3 weeks. Treatment cycles were repeated every 3 weeks. The primary end point was comparison of the 12-week progression-free survival (PFS) rate. RESULTS: In all, 172 patients were enrolled: median age, 61 years; female, 33%; never-smokers, 12%; and performance status 0 or 1, 88%. The median number of R1507 doses was six for the weekly arm and 3.5 for the every-3-weeks arm. Grades 3 to 4 adverse events occurred in 37%, 44%, and 48% of patients with placebo, R1507 weekly, and R1507 every 3 weeks, respectively. The 12-week PFS rates were 39%, 37%, and 44%, and the median overall survival was 8.1, 8.1, and 12.1 months for the three groups, respectively, with statistically nonsignificant hazard ratios. The 12-week PFS rate in patients with KRAS mutation was 36% with R1507 compared with 0% with placebo. CONCLUSION: The combination of R1507 with erlotinib did not provide PFS or survival advantage over erlotinib alone in an unselected group of patients with advanced NSCLC. Predictive biomarkers are essential for further development of combined inhibition of IGF-1R and EGFR.

Epidermal growth factor receptor-related tumor markers and clinical outcomes with erlotinib in non-small cell lung cancer: an analysis of patients from german centers in the TRUST study.

INTRODUCTION: Relationships between clinical outcomes and epidermal growth factor receptor (EGFR)-related tumor markers were investigated in patients with advanced non-small cell lung cancer. METHODS: Patients with stage IIIB/IV non-small cell lung cancer (0-2 prior regimens) received erlotinib (150 mg PO per day). Response and survival were evaluated, and tumor samples were assessed by immunohistochemistry (EGFR, phosphorylated mitogen-activated protein kinase, and phosphorylated AKT protein expression), fluorescence in situ hybridization (FISH; EGFR gene copy number), and DNA sequencing (EGFR, KRAS gene mutations). RESULTS: Among 311 patients, 8% had a complete/partial response; the disease control rate was 66%. Median Overall survival (OS) was 6.1 months; 1-year survival rate was 27.2%. Two of 4 patients with EGFR mutations had tumor responses, versus 2/68 with wild-type EGFR (p = 0.014). Progression-free survival (PFS) (HR = 0.31) and OS (HR = 0.33) were significantly prolonged in patients with EGFR mutations. Response rate was significantly higher in patients with EGFR FISH-positive (17%) than FISH-negative tumors (6%), and both PFS (HR = 0.58) and OS (HR = 0.63) significantly favored patients with EGFR FISH-positive tumors; median OS was 8.6 months in the EGFR FISH-positive group. None of 17 patients with a KRAS mutation had a tumor response, but the impact of KRAS mutation status on survival outcomes was of borderline statistical significance. Neither phosphorylated mitogen-activated protein kinase nor phosphorylated AKT immunohistochemistry status had a significant effect on PFS and OS with erlotinib. CONCLUSIONS: The presence of EGFR mutations and EGFR FISH-positive tumors may predispose patients to achieving better outcomes on erlotinib, but may have a beneficial impact on prognosis (irrespective of treatment). Prospective, placebo-controlled studies are needed to determine the predictive value of the putative biomarkers.

Randomized, multicenter, open-label phase II study of gemcitabine plus single-dose versus split-dose carboplatin in the treatment of patients with advanced-stage non-small-cell lung cancer.

BACKGROUND: Gemcitabine/carboplatin is a convenient and effective treatment for advanced-stage non-small-cell lung cancer (NSCLC), but modification of the schedule to diminish thrombocytopenia is worthwhile. PATIENTS AND METHODS: One hundred fifty-eight chemotherapy-naive patients with stage IIIB/IV NSCLC were randomized from 15 centers in Germany to receive gemcitabine 1250 mg/m(2) on days 1 and 8 plus carboplatin area under the curve 5 on day 1 (arm A) or carboplatin area under the curve 2.5 on days 1 and 8 (arm B), every 21 days for 4 cycles. RESULTS: The 2 arms (A vs. B) were well balanced with regard to patient baseline characteristics: stage IV 72.5% versus 69%, median Eastern Cooperative Oncology Group performance status 1 versus 1. The incidence of grade 3/4 hematologic toxicity was as follows (percentage of patients in arm A vs. B): leukopenia 37.5% versus 27% (P = 0.075), granulocytopenia 36% versus 36%, and thrombocytopenia 51% versus 35% (P = 0.017). Nonhematologic toxicity was modest and comparable with both schedules. The overall response rate was 46% versus 36% (P = 0.12), and 24% versus 42% had stable disease. Median progression-free survival (5.8 months vs. 6.1 months) and overall survival (11.7 months vs. 10.7 months) were not significantly different between arms A and B. CONCLUSION: Splitting the dose of carboplatin between days 1 and 8 on the same days as gemcitabine results in a significantly decreased incidence of severe thrombocytopenia, without compromising the activity of the combination.

Standardized quantification of circulating peripheral tumor cells from lung and breast cancer.

Detection and quantitation of circulating tumor cells from solid epithelial tumors could become a valuable tool for therapy monitoring if the procedure can be standardized. In the present work we assessed the influence of pre-analytical handling, storage and white blood cell isolation on analysis of a population of spiked tumor cell-line cells and intrinsically present epithelial cells in the peripheral blood of breast and lung cancer patients and the sensitivity of their detection. Sucrose density separation did not enrich epithelial cells, and even depleted them, leading to a gross underestimation of their numbers (3/13 positive, between 2.9 and 50 cells/mL) in comparison to red blood cell lysis (13/13 positive, between 77,200 and 800 cells/mL). Short-term storage of whole blood samples for up to 7 days had little influence on the number of epithelial cells recovered. The effectiveness of magnetic bead enrichment was dependent on the number of relevant cells and the volume used for enrichment. Red blood cell lysis and fluorochrome-labeled antibody staining in a no-wash procedure with subsequent laser scanning cytometry allowed the detection of circulating epithelial cells in 92% of breast and lung cancer patients. Two examples of how this method can be applied for the longitudinal analysis in individual patients are shown, with an increase in numbers preceding relapse and a decrease paralleling tumor reduction. The proposed simple and easy method allows close monitoring, which may help in real-time analysis of the response of solid tumors, especially their systemic component, to therapy and hopefully will contribute to more individually tailored therapy.

A multicenter phase II study of gemcitabine and oxaliplatin for malignant pleural mesothelioma.

We conducted a phase II multicenter trial to evaluate the activity of combined gemcitabine and oxaliplatin in malignant pleural mesothelioma. Twenty-five patients were recruited between May 1999 and December 2001 and received gemcitabine 1000 mg/m2 intravenously over 30 minutes and oxaliplatin 80 mg/m2 intravenously over 3 hours on days 1 and 8 of a 21-day cycle for a maximum of 6 cycles. Eligibility criteria included an Eastern Cooperative Oncology Group performance status of 0-2 and no prior chemotherapy. Best objective responses achieved were as follows: partial response, 10 patients (40%, 95% CI, 21%-61%); stable disease, 6 patients (24%, 95% CI, 9%-45%); and progressive disease, 9 patients (36%, 95% CI, 18%-57%). Median time to disease progression was 7 months, and median survival was 13 months. One-year survival was 60% (95% CI, 31%-72%). There were 2 deaths from disease progression. Toxicity was mainly hematologic. Grade 3/4 nausea and vomiting occurred in 8% of patients, neuropathy occurred in 8% of patients, and diarrhea occurred in 4% of patients. The combination of gemcitabine and oxaliplatin was shown to be active in malignant pleural mesothelioma and to exhibit tolerable toxicity in an outpatient setting.