Safety and tolerability of weekly docetaxel plus nintedanib: A phase I trial after first-line chemotherapy failure in NSCLC.

INTRODUCTION: Studies have shown improved tolerability with once-weekly versus three-weekly docetaxel in the second-line treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to evaluate the tolerability of nintedanib plus weekly docetaxel in patients with NSCLC. METHODS: This phase I, open-label, dose-escalation study (NCT02668393) enrolled patients with locally advanced/metastatic adenocarcinoma NSCLC that had progressed on first-line platinum chemotherapy. The primary endpoint was to determine the maximum tolerated dose of nintedanib (up to 200 mg twice daily [BID]) combined with weekly docetaxel (35 mg/m2) on days 1, 8, and 15 based on the occurrence of dose-limiting toxicities (DLTs) over a 28-day treatment cycle. Adverse events (AEs) were also evaluated. RESULTS: The trial terminated prematurely due to recruitment challenges. At termination, seven patients had received nintedanib 150 mg BID and seven nintedanib 200 mg BID, in combination with weekly docetaxel. In the first treatment cycle, DLTs were reported for 1/6 evaluable patients (16.7%) in each group. The disease control rates were 57.1% and 42.9%, respectively. Grade ≥3 treatment-related AEs affected three patients in each group (42.9%); neutropenia was reported in one patient (14.3%) in each group. Treatment-related serious AEs were reported in three patients (42.9%) receiving nintedanib 150 mg, and two patients (28.6%) receiving nintedanib 200 mg. CONCLUSIONS: Overall, nintedanib plus weekly docetaxel was well-tolerated in patients with locally advanced or metastatic lung adenocarcinoma who progressed on first-line platinum-based chemotherapy, without loss of efficacy. DLTs were manageable.

Retrospective Data Analysis of Patients With Metastatic Lung Adenocarcinoma With or Without KRAS-Mutation or TTF1-Expression.

INTRODUCTION: Patients with lung adenocarcinoma not expressing TTF1 and those with a KRAS mutation have worse prognosis. However, available data are limited and sometimes contradictory. Therefore, this retrospective cohort analysis aimed to clarify whether there was a difference in overall survival and progression-free survival between these groups of patients. METHODS: In total, data derived from 181 patients with metastatic lung adenocarcinoma treated at the Martha-Maria Halle-Dölau Hospital from 2016 to 2019 were analyzed. Kaplan-Meier curves were generated, and associated values, such as median survival and its confidence intervals, were determined using the log-rank test. RESULTS: A benefit in overall survival (OS) (8.4 vs 5.8 months; HR, .8; 95% CI, .53-1.19; P = .267) was associated with positive TTF1 expression, but this was not statistically significant. The same trend was shown with the progressive free survival (PFS) (6.5 vs 4.6 months; HR, .76; 95% CI, .51-1.20; P = .162). In patients with a KRAS mutation, there was no difference in OS compared to those with a wildtype KRAS. The median survival was almost identical at 7.5 months (KRAS mutation, 95% CI, 3.32-11.74) and 7.0 months (KRAS wildtype, 95% CI, 3.59-10.41). Additionally, in PFS, there was no difference between the 2 groups (5.8 vs 6.3 months). CONCLUSIONS: Our analysis did not show a worse prognosis in patients with a KRAS mutation or in those with missing TTF1 expression, which is most likely related to the new therapeutic options. As a result of the administration of immunotherapy in patients with a KRAS mutation and the change from a regimen containing pemetrexed to a regimen containing no pemetrexed, the corresponding patients no longer seem to have a worse prognosis.

Nintedanib plus docetaxel after progression on first-line immunochemotherapy in patients with lung adenocarcinoma: Cohort C of the non-interventional study, VARGADO.

Background: Immune checkpoint inhibitors (ICIs) with or without chemotherapy represent first-line standard of care for patients with advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. The most appropriate second-line therapy after failing immunochemotherapy remains an open question. Nintedanib, an oral triple angiokinase inhibitor that targets the vascular endothelial growth factor receptor, fibroblast growth factor receptor, and, platelet-derived growth factor receptor, in combination with docetaxel, is approved for treatment of advanced NSCLC (adenocarcinoma histology) following progression on first-line chemotherapy. Methods: VARGADO (NCT02392455) is an ongoing, prospective, non-interventional study investigating the efficacy and safety of nintedanib plus docetaxel following first-line chemotherapy with or without ICIs in patients with locally advanced, metastatic, or locally recurrent NSCLC of adenocarcinoma histology. This analysis focuses on Cohort C, which enrolled patients who had received prior first line chemotherapy with ICIs. Patients received second-line docetaxel (75 mg/m2) by intravenous infusion on Day 1, plus oral nintedanib (200 mg twice daily) on Days 2-21 of each 21-day cycle during routine clinical care. The primary endpoint is overall survival (OS) rate 1 year after the start of treatment with nintedanib plus docetaxel. Secondary endpoints include progression-free survival (PFS), OS, and disease control rate (DCR). Safety was also assessed. Results: Among 137 patients treated, the median age was 63 years (range, 37-84); 57 patients (41.6%) were female, most patients had Eastern Cooperative Oncology Group performance status of 0 (28.5%) or 1 (43.1%); 118 (86.1%) had stage IV NSCLC and 27 (19.7%) had brain metastases. Most (n=120, 87.6%) patients had received pembrolizumab/pemetrexed/platinum-based chemotherapy as first-line treatment. In 80 patients with available response data, the DCR was 72.5% (complete response: 1.3%; partial response: 36.3%; stable disease: 35.0%). Median progression-free survival was 4.8 months (95% confidence interval: 3.7-6.6). OS data were immature. Grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs leading to treatment discontinuation were reported in 62 (45.3%), 50 (36.5%), and 40 patients (29.2%), respectively. Conclusions: This analysis indicates that nintedanib plus docetaxel represents an effective second-line treatment option in patients with advanced adenocarcinoma NSCLC following progression on first-line immunochemotherapy. The safety profile was manageable with no unexpected signals.

[30- and 90-day Lethality in Patients with Stage IV Lung Cancer Depending on the Primary Therapy]. / 30- und 90-Tage-Letalität bei Patienten mit Lungenkarzinom im Stadium IV in Abhängigkeit der Primärtherapie.

Early lethality after initiation of therapy in patients with stage IV lung cancer has rarely been the focus of scientific studies yet. The little time remaining between diagnosis, start of therapy and onset of death, as well as any influencing factors, are of special interest for both, patients and physician. Accordingly, the aim of this work was to analyze the 30- and 90-day morbidity after initiation of systemic therapy and to determine possible factors influencing early lethality. For this purpose, the data of 225 patients with stage IV lung cancer and treatment at the Martha-Maria Halle-Dölau Lung Cancer Center between 01/01/2017 and 05/18/2020 were retrospectively analyzed. Forms of therapy and patient characteristics were analyzed with a frequency distribution and the probability of survival was estimated using the Kaplan-Meier method. The analysis of the early morbidity of all tumor-specifically treated patients showed a morbidity of 8.5 % at day 30 after the start of therapy and a rate of 23.5 % after 90 days. In a direct comparison of the different therapy groups, the patients receiving mono-checkpointinhibition had higher lethality (16.6 % after 30 days and 44.3 % after 90 days). In contrast, the morbidity of patients in the other therapy groups remained below 10 % after 30 days and below 23.3 % after 90 days. A poor general condition, an advanced tumor disease, polymetastasis and a positive history of smoking could be determined as predictors for higher early lethality. In contrast, there was no relevant difference in morbidity between the different tumor entities, gender, PD-L1 and mutation status. With this analysis, very high early lethality, comparable to other studies, could be detected in patients with lung cancer. Relevant differences between the forms of therapy illustrate the importance of individual patient selection for the respective therapy options and the rapid decision to initiate therapy.

Efficacy and Safety of Rovalpituzumab Tesirine Compared With Topotecan as Second-Line Therapy in DLL3-High SCLC: Results From the Phase 3 TAHOE Study.

INTRODUCTION: DLL3, an atypical Notch ligand, is expressed in SCLC tumors but is not detectable in normal adult tissues. Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate containing a DLL3-targeting antibody tethered to a cytotoxic agent pyrrolobenzodiazepine by means of a protease-cleavable linker. The efficacy and safety of Rova-T compared with topotecan as second-line therapy in patients with SCLC expressing high levels of DLL3 (DLL3-high) was evaluated. METHODS: The TAHOE study was an open-label, two-to-one randomized, phase 3 study comparing Rova-T with topotecan as second-line therapy in DLL3-high advanced or metastatic SCLC. Rova-T (0.3 mg/kg) was administered intravenously on day 1 of a 42-day cycle for two cycles, with two additional cycles available to patients who met protocol-defined criteria for continued dosing. Topotecan (1.5 mg/m2) was administered intravenously on days 1 to 5 of a 21-day cycle. The primary end point was overall survival (OS). RESULTS: Patients randomized to Rova-T (n = 296) and topotecan (n = 148) were included in the efficacy analyses. The median age was 64 years, and 77% had the extensive disease at initial diagnosis. The median OS (95% confidence interval) was 6.3 months (5.6-7.3) in the Rova-T arm and 8.6 months (7.7-10.1) in the topotecan arm (hazard ratio, 1.46 [95% confidence interval: 1.17-1.82]). An independent data monitoring committee recommended that enrollment be discontinued because of the shorter OS observed with Rova-T compared with topotecan. Safety profiles for both drugs were consistent with previous reports. CONCLUSIONS: Compared with topotecan, which is the current standard second-line chemotherapy, Rova-T exhibited an inferior OS and higher rates of serosal effusions, photosensitivity reaction, and peripheral edema in patients with SCLC. A considerable unmet therapeutic need remains in this population.

Erlotinib treatment after platinum-based therapy in elderly patients with non-small-cell lung cancer in routine clinical practice - results from the ElderTac study.

BACKGROUND: In this prospective non-interventional study, the effectiveness and tolerability of erlotinib in elderly patients with non-small-cell lung cancer (NSCLC) after ≥1 platinum-based chemotherapy were assessed. METHODS: A total of 385 patients ≥65 years of age with advanced NSCLC receiving erlotinib were observed over 12 months. The primary endpoint was the 1-year overall survival (OS) rate. RESULTS: Patients were predominantly Caucasian (99.2%), a mean of 73 years old; 24.7% had an Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2. Most common tumor histologies were adenocarcinoma (64.9%) and squamous cell carcinoma (22.3%). Of 119 patients tested, 15.1% had an activating epidermal growth factor receptor gene (EGFR) mutation. The 1-year OS rate was 31% (95% CI 25-36) with a median OS of 7.1 months (95% CI 6.0-7.9). OS was significantly better in females than males (p = 0.0258) and in patients with an EGFR mutation compared to EGFR wild-type patients (p = 0.0004). OS was not affected by age (p = 0.3436) and ECOG PS (p = 0.5364). Patients with squamous NSCLC tended to live longer than patients with non-squamous EGFR wild-type tumors (median OS: 8.6 vs 5.5 months). Cough and dyspnea improved during the observation period. The erlotinib safety profile was comparable to that in previous studies with rash (45.2%) and diarrhea (22.6%) being the most frequently reported adverse events. CONCLUSIONS: Erlotinib represents a suitable palliative treatment option in further therapy lines for elderly patients with advanced NSCLC. The results obtained under real-life conditions add to our understanding of the benefits and risks of erlotinib in routine clinical practice. TRIAL REGISTRATION: BfArM ( https://www.bfarm.de ; ML23023); ClinicalTrials.gov (NCT01535729; 20 Feb 2012).

Treatment decisions, clinical outcomes, and pharmacoeconomics in the treatment of patients with EGFR mutated stage III/IV NSCLC in Germany: an observational study.

BACKGROUND: We evaluated treatment decisions and outcomes in a cohort of predominately Caucasian patients with EGFR mutation-positive (EGFR Mut+) non-small-cell lung cancer (NSCLC). METHODS: REASON (NCT00997230) was a non-interventional study in German patients with stage IIIB/IV NSCLC. Secondary endpoints for EGFR Mut + NSCLC included progression-free survival (PFS), overall survival (OS), adverse event (AE) management, and pharmacoeconomic outcomes. RESULTS: Among 334 patients with EGFR Mut + NSCLC, tyrosine kinase inhibitors (TKIs) were the most common first-line therapy (56.6%, 53.0% gefitinib). Among patients who received TKIs/gefitinib before first disease progression, PFS was longer compared with those who did not receive a TKI (median 10.1/10.0 vs. 7.0 months; HR 0.67/0.69; log-rank p = 0.012/p = 0.022). OS was longer for those patients who ever received a TKI/gefitinib during their complete therapy course compared with those who never received a TKI (median 18.4/18.1 vs. 13.6 months; HR 0.53/0.55; p = 0.003/p = 0.005). Total mean first-line treatment healthcare costs per person were higher for those receiving TKIs (€46,443) compared with those who received chemotherapy (€27,182). Mean outpatient and inpatient costs were highest with chemotherapy. Rash, diarrhea, and dry skin were the most commonly reported AEs for patients receiving gefitinib. CONCLUSIONS: In REASON, TKI therapy was the most common first- and second-line treatment for EGFR Mut + NSCLC, associated with increased drug costs compared with chemotherapy. Patients who received gefitinib or a TKI ever during their complete therapy course had prolonged PFS and OS compared with patients who did not receive a TKI. TRIAL REGISTRATION: The trial was registered on October, 2009 with ClinicalTrials.gov : https://clinicaltrials.gov/ct2/show/NCT00997230?term=NCT00997230&rank=1.

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.

Meta-analysis of pemetrexed plus carboplatin doublet safety profile in first-line non-squamous non-small cell lung cancer studies.

OBJECTIVES: This meta-analysis compared safety profiles (selected drug-related treatment-emergent adverse events [TEAEs]) of first-line pemetrexed plus carboplatin (PCb) area under the concentration-time curve 5 mg/min•mL (PCb5) or 6 mg/min•mL (PCb6), two widely used regimens in clinical practice for advanced non-squamous non-small cell lung cancer. METHODS: All patients received pemetrexed 500 mg/m2 every 21 days with either of two carboplatin doses for up to 4-6 cycles. Safety profiles of PCb doses were compared using three statistical analysis methods: frequency table analysis (FTA), generalized linear mixed effect model (GLMM), and the propensity score method. Efficacy outcomes of PCb5 and PCb6 regimens were summarized. RESULTS: A total of 486 patients mainly from the US, Europe, and East Asia were included in the analysis; 22% (n = 105) received PCb5 in one trial and 78% (n = 381) received PCb6 in four trials. The FTA comparison demonstrated that PCb5 vs PCb6 was associated with a statistically significantly lower incidence of TEAEs, including all-grade thrombocytopenia, anemia, fatigue, and vomiting, and grade 3/4 thrombocytopenia. In the GLMM analysis, PCb5 patients were numerically less likely to experience all-grade and grade 3/4 neutropenia, anemia, and thrombocytopenia. The propensity score regression analysis showed PCb5 group patients were significantly less likely than PCb6 group patients to experience all-grade hematologic TEAEs and grade 3/4 thrombocytopenia and anemia. After applying propensity score 1:1 matching, FTA analysis showed that the PCb5 group had significantly less all-grade and grade 3/4 hematologic toxicities. Overall efficacy outcomes, including overall survival, progression-free survival, and response rate, were similar between the two carboplatin doses. CONCLUSIONS: Acknowledging the limitations of this meta-analysis of five trials, heterogeneous in patient's characteristics and trial designs, the results show that the PCb5 regimen was generally associated with a better safety profile than PCb6 across three statistical approaches, with no apparent impact on survival outcomes.

EGFR mutation status and first-line treatment in patients with stage III/IV non-small cell lung cancer in Germany: an observational study.

INTRODUCTION: EGFR mutations confer sensitivity to EGFR tyrosine kinase inhibitors (TKI) in advanced non-small cell lung cancer (NSCLC). We investigated the clinicopathologic characteristics associated with EGFR mutations and their impact on real-world treatment decisions and outcomes in Caucasian patients with advanced NSCLC. METHODS: REASON (NCT00997230) was a noninterventional multicenter study in patients (≥18 years) with stage IIIb/IV NSCLC, who were candidates for EGFR mutation testing and first-line systemic treatment, but not eligible for surgery or radiotherapy. Patients were followed up according to normal clinical practice and assessed for primary (correlation of mutation status with baseline characteristics) and secondary endpoints (first-line treatment decision). RESULTS: Baseline data were obtained for 4,200 patients; 4,196 fulfilled the inclusion criteria; EGFR mutations were detected in 431 patients; no EGFR mutations were detected in 3,590 patients; mutation status was not evaluable in 175 patients. In multivariate analysis, the odds of EGFR mutations were significantly higher (P < 0.0001) in females versus males (odds ratio: 1.85; 95% confidence interval, 1.48-2.32), never-smokers versus smokers (3.64; 2.91-4.56), and patients with adenocarcinoma versus other histologic subtypes (2.94; 2.17-4.08). The most commonly prescribed first-line systemic treatments were: EGFR-TKIs in EGFR mutation-positive NSCLC (56.6%) and combination chemotherapy in EGFR mutation-negative NSCLC (78.5%). CONCLUSIONS: This represents the largest dataset for EGFR mutations in Caucasian patients and shows EGFR mutations to be most prevalent in females with adenocarcinoma who had never smoked. IMPACT: These findings add to our understanding of the prognostic and predictive factors of NSCLC, supporting future improved treatment selection.

CHAMP: A Phase II Study of Panitumumab With Pemetrexed and Cisplatin Versus Pemetrexed and Cisplatin in the Treatment of Patients With Advanced-Stage Primary Nonsquamous Non-Small-Cell Lung Cancer With Particular Regard to the KRAS Status.

INTRODUCTION: The aim of the study was to investigate the efficacy and tolerability of panitumumab, a fully human antiepidermal growth factor receptor monoclonal antibody, in combination with pemetrexed/cisplatin in patients with stage IIIB to IV primary nonsquamous non-small-cell lung cancer and wild type V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS). Results were compared with those obtained in a control group of patients who received a pemetrexed/cisplatin regimen only. PATIENTS AND METHODS: This was a phase II, randomized, open-label study with 2 treatment arms. In total, 96 patients received panitumumab at a dose of 9 mg/kg in combination with pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) (n = 49) or pemetrexed/cisplatin alone (n = 47). The primary outcome measure was progression-free survival at 6 months. Secondary end points of the study included overall survival, tumor response, quality of life, and safety outcomes. The CHAMP study is registered with ClinicalTrials.gov, number NCT01088620. RESULTS: Progression-free survival at 6 months did not indicate a benefit of panitumumab as a supplement to the standard therapy of pemetrexed/cisplatin whereas the overall survival showed a clear difference between the treatment groups in favor of the standard therapy. Results might be affected by the higher rates of serious adverse events and higher death rates within the panitumumab arm. CONCLUSIONS: Results from the present study indicate that combination of cisplatin/pemetrexed with panitumumab should not be recommended for patients with adenocarcinoma and KRAS wild type because of lack of efficacy, lack of improvement of quality of life, and because of the increase in toxicity rates compared with patients in the control arm, who received standard chemotherapy of pemetrexed/cisplatin.

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.

A Prospective Phase I/II Study: Combination Chemotherapy with Docetaxel and Pemetrexed as Second-Line Treatment in Patients with Stage IIIB/IV Non-Small Cell Lung Cancer.

INTRODUCTION: Two standard single-agent chemotherapy treatments (docetaxel and pemetrexed) were combined in this trial and administered as second-line treatment in patients with non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the safety and feasibility of combining docetaxel with pemetrexed. METHODS: Six patients were enrolled between August 2007 and March 2009 with stage IIIB/IV NSCLC. The dose-escalation model included a pemetrexed infusion on day 1 of 200-300 mg/m(2) followed by infusion of docetaxel on days 1, 8 and 15 at doses from 20 to 30 mg/m(2). Primary study endpoints included efficacy and safety variables, also progression-free, overall and 1-year survival and time to progression. RESULTS: The study was abandoned due to adverse effects defined in the protocol. The major toxicities were all of grade 3 and included fatigue, stomatitis/mucositis, diarrhea and in one case, an episode of febrile neutropenia. Two patients died during the study, but not as a direct result of the treatment. CONCLUSIONS: We recommend that docetaxel or pemetrexed monotherapies should continue to be considered the standard second-line chemotherapy treatment against NSCLC. The results of this study warrant no further investigation into this particular combination treatment due to the severe toxicity effects encountered.

Phase II study of pemetrexed and cisplatin plus cetuximab followed by pemetrexed and cetuximab maintenance therapy in patients with advanced nonsquamous non-small cell lung cancer.

OBJECTIVES: The aim was to determine if combined pemetrexed, cisplatin, and cetuximab was efficacious and safe as first-line treatment in advanced nonsquamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In this single-arm, multicenter clinical trial, patients with Stage IIIB/IV nonsquamous NSCLC received first-line therapy consisting of pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) on Day 1 (21-day cycles) plus weekly cetuximab (400 mg/m(2) loading dose, then 250 mg/m(2)) for 4-6 cycles. Non-progressing patients received maintenance therapy consisting of pemetrexed and cetuximab as above until disease progression. All patients received vitamin supplementation, dexamethasone, and antihistamine prophylaxis. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), 1-year survival rate, translational research (TR) and safety. RESULTS: Of the 113 patients receiving study drug, 109 were protocol-qualified. All patients completed ≥1 cycle of induction, and 51 (45%) and 49 (43%) patients completed ≥1 cycle of maintenance with pemetrexed and cetuximab, respectively. The ORR (n = 109) was 38.5% (80% confidence interval [CI], 32.3-45.1%), all partial responses. Median PFS was 5.8 (80% CI, 4.4-6.7) months. One-year survival rate was 45% (80% CI, 39-51%). In exploratory analyses, there was some preliminary evidence of potential prognostic relationships with efficacy outcomes for epidermal growth factor receptor and thyroid transcription factor-1 protein expression, but not for KRAS mutation or for thymidylate synthase or folate receptor-alpha protein expression. Seventy-three (64.6%) patients had study drug-related Grade 3/4 adverse events (AEs). Drug-related serious AEs were reported in 31 (27.4%) patients. There were 3 (2.7%) potentially drug-related deaths on-study or within 30 days of follow up. CONCLUSION: Pemetrexed, cisplatin, and cetuximab appeared efficacious and tolerable in advanced nonsquamous NSCLC patients. The TR outcomes are hypothesis-generating given the study's size and nonrandomized nature.

A randomized phase II study of pemetrexed in combination with cisplatin or carboplatin as first-line therapy for patients with locally advanced or metastatic non-small-cell lung cancer.

BACKGROUND: Pemetrexed plus cisplatin was approved for first-line treatment of non-small-cell lung cancer (NSCLC) in patients with nonsquamous histology after initiation of this study. This phase II study evaluated pemetrexed plus cisplatin and pemetrexed plus carboplatin as first-line treatments for stage IIIB/IV NSCLC. PATIENTS AND METHODS: The patients were randomized (1:1) to 2 parallel arms: pemetrexed (500 mg/m(2)) plus cisplatin (75 mg/m(2)) or pemetrexed (500 mg/m(2)) plus carboplatin (area under the curve 6) day 1 every 3 weeks (maximum, 6 cycles). Progression-free survival (PFS) was the primary objective; secondary objectives included overall survival (OS), 1-year survival, and safety. RESULTS: Sixty-five patients were randomized to each treatment arm. The patients treated with pemetrexed plus cisplatin had a median age of 64 years and were predominantly men (42 [64.6%]) with nonsquamous histology (53 [81.5%]), stage IV (61 [92.4%]) disease, and a performance status of 0 (40 [61.5%]). Median PFS was 6.0 months, 6-month PFS rate was 50.5%, median OS was 11.7 months, and 1-year survival rate was 47.5%. Drug-related grade 3/4 toxicities included neutropenia (11 [16.9%]), anemia (5 [7.7%]), thrombocytopenia (2 [3.1%]), and nausea (3 [4.6%]). Patients treated with pemetrexed plus carboplatin had a median age of 63 years, were predominantly men (46 [70.8%]) with nonsquamous histology (52 [80.0%]), stage IV (58 [86.6%]) disease, and a performance status of 0 (45 [69.2%]). The median PFS was 4.7 months, the 6-month PFS rate was 34.9%, median OS was 8.9 months, and 1-year survival rate was 39.2%. Drug-related grade 3/4 toxicities included neutropenia (17 [26.2%]), thrombocytopenia (11 [16.9%]), anemia (7 [10.8%]), and nausea (5 [7.7%]). CONCLUSIONS: Both the pemetrexed plus cisplatin and pemetrexed plus carboplatin arms met their primary endpoints and demonstrated efficacy and tolerability as first-line therapy in patients with advanced NSCLC. http://ClinicalTrials.gov: NCT00402051.

Six-minute walk distance and dyspnoea scores to assess the course of COPD exacerbation in elderly patients.

INTRODUCTION: While the severity of stable chronic obstructive pulmonary disease (COPD) has been defined in a valid and relevant prognostic manner, parameters that describe the course of COPD exacerbations are not yet established. Physical performance and dyspnoea are of prognostic relevance in stable COPD. The issue investigated was to assess the course of COPD exacerbations to find parameters that describe this situation better. METHODS: In 82 hospitalised patients with acute exacerbation of COPD who responded to intensified medical treatment (age 67.3 ± 9.5 years; forced expiratory volume in 1 s 1.0l, 40% predicted), we measured the 6-min walk distance and the visual analogue scale dyspnoea scores before the start of treatment, prior to discharge and after a 4-week stable period. Additionally, the conventional clinical parameters of COPD and quality of life were documented. RESULTS: The 6-min walk distance was significantly increased from 97 ± 114 m to 290 ± 106 m. After 4 weeks of outpatient treatment in clinically stable patients, the 6-min walk distance fell non-significantly to 270 ± 120 m. The increment in walk distance fell significantly with advancing severity of COPD: from 112 ± 68 m for grade I and II to 56 ± 88 m for grade IV. Resting as well as exertional dyspnoea scores were significantly reduced (resting dyspnoea from 4 to 2 and exertional dyspnoea from 8 to 6). CONCLUSION: We were able to demonstrate that 6-min walk test and dyspnoea scores, but not pulmonary function test, are suitable parameters to assess the course of COPD exacerbations.

Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer.

INTRODUCTION: This multicenter, open-label, phase II study was carried out to compare the efficacy and safety of cilengitide (EMD 121974), a selective inhibitor of the cell-surface integrins αVß3 and αVß5, with that of docetaxel in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: Patients (n = 140) with advanced NSCLC who had failed first-line chemotherapy were randomized to cilengitide 240, 400, or 600 mg/m(2) twice weekly, or docetaxel 75 mg/m(2) once every 3 weeks for eight cycles. Non-progressing patients could continue cilengitide for up to 1 year. The primary endpoint was progression-free survival (PFS). No statistical tests were performed since the study was exploratory in nature and the number of patients enrolled was relatively small. RESULTS: Median PFS was 54, 63, 63, and 67 days for cilengitide 240, 400, and 600 mg/m(2), and docetaxel 75 mg/m(2), respectively. One-year survival rates were 13 %, 13 %, 29 %, and 27 %, respectively. The response rate (partial response only) with docetaxel was 15 %. No responses were reported in any cilengitide arm. The most frequent grade 3/4 treatment-related adverse events in the docetaxel group were leukopenia and neutropenia (experienced by 13 % of patients). Hematologic toxicity of this severity did not occur in cilengitide-treated patients. CONCLUSION: With the highest dose of cilengitide (600 mg/m(2)), median PFS and 1-year survival were similar to those in patients treated with docetaxel 75 mg/m(2) and there were fewer grade 3/4 treatment-related adverse events.

Second-line treatment of stage III/IV non-small-cell lung cancer (NSCLC) with pemetrexed in routine clinical practice: evaluation of performance status and health-related quality of life.

BACKGROUND: Second-line treatment of advanced non-small-cell lung cancer (NSCLC) improves overall survival. There is a lack of data regarding the impact on patients' overall health condition. This prospective, non-interventional study evaluated performance status (PS) and health-related quality of life (HR-QoL) during second-line pemetrexed treatment in routine clinical practice. METHODS: Stage III/IV NSCLC patients who initiated second-line pemetrexed (standard vitamin and dexamethasone supplementation) were observed for a maximum of 9 treatment cycles. The primary objective was to evaluate the proportion of patients achieving improvement of Karnofsky Index (KI) of ≥ 10% (absolute) or maintaining KI ≥ 80% after the second treatment cycle ("KI benefit response"). HR-QoL was self-rated using the EuroQoL-5D questionnaire (EQ-5D). Factors potentially associated with KI benefit response were evaluated using logistic regression models. RESULTS: Of 521 eligible patients (73.5% Stage IV, median age 66.3 yrs, 36.1% ≥ 70 yrs, 62.0% with KI ≥ 80%), 471 (90.4%) completed at least 2 treatment cycles. 58.0% (95%CI 53.6%;62.2%) achieved KI benefit response after the second cycle. Patients with baseline KI ≥ 80%, no Grade 3/4 toxicities during the first 2 cycles, or combination regimen as prior first-line therapy were more likely to achieve a KI benefit response. EQ-5D scores improved over time. Grade 3/4 toxicities were reported in 23.8% of patients (mainly fatigue/asthenia 15.9%, neutropenia 8.7%). CONCLUSIONS: In this large prospective, non-interventional study of second-line pemetrexed treatment in patients with advanced NSCLC, including 36% elderly patients ( ≥ 70 years), physician-rated PS and self-rated HR-QoL were maintained or improved in the majority of patients. TRIAL REGISTRATION: Registered on ClinicalTrials.gov (NCT00540241) on October 4, 2007.

Randomized phase II study of palifermin for reducing dysphagia in patients receiving concurrent chemoradiotherapy for locally advanced unresectable non-small cell lung cancer.

INTRODUCTION: Dysphagia is a common, dose-limiting toxicity of combined chemoradiotherapy (CT/RT) in patients with locally advanced non-small cell lung cancer (NSCLC). This study assessed the efficacy and safety of palifermin in reducing dysphagia from CT/RT followed by consolidation chemotherapy (CT). METHODS: This randomized, double-blind, phase II trial enrolled adults with unresectable stage III NSCLC. Subjects received weekly paclitaxel (50 mg/m2) and carboplatin (AUC 2.0) with concurrent daily radiation (RT) of 6000 to 6600 cGy, followed by consolidation CT. Palifermin (n = 49) or placebo (n = 46) was administered before starting concurrent CT/RT and once weekly for 6 weeks. The primary end points were the incidence of grade ≥ 2 dysphagia and safety. RESULTS: The incidence of grade ≥ 2 and ≥ 3 dysphagia was numerically lower in palifermin subjects versus placebo subjects (61% versus 70%; p = 0.36; 22% versus 28%, p = 0.50, respectively). Mean duration of dysphagia (grade ≥ 2) was 25 days for palifermin subjects and 32 days for placebo subjects (p = 0.32). The incidence of adverse events was similar in the two treatment groups, and median overall survival and progression-free survival were not adversely affected by palifermin treatment (overall survival: 513 versus 319 days; progression-free survival: 262 versus 235 days for palifermin versus placebo arms, respectively). The palifermin arm received more doses of CT per study design and significantly more patients received RT doses ≥ 6000 cGy (84% versus 61%, p = 0.01). CONCLUSIONS: The results of this exploratory trial suggest that additional larger studies may be warranted to further evaluate the effect of palifermin on dysphagia, exposure to CT/RT, and long-term survival.

Randomized phase III trial of docetaxel plus carboplatin with or without levofloxacin prophylaxis in elderly patients with advanced non-small cell lung cancer: the APRONTA trial.

PURPOSE: To examine the effect of levofloxacin prophylaxis on infection rates during chemotherapy with docetaxel plus carboplatin in elderly patients with advanced non-small cell lung cancer. METHODS: In a randomized, double-blind, phase III study, patients (≥65 years) with untreated, histologically/cytologically proven stage IIIB/IV non-small cell lung cancer received docetaxel (75 mg/m) plus carboplatin (area under the curve 6) on day 1 every 3 weeks, plus once-daily levofloxacin (500 mg orally) or placebo on days 5 to 11. The primary end point was the rate of grade 3/4 infections or grade 1/2 infections treated with additional antibiotics. Secondary end points included overall infection rate, toxicity, overall survival, and progression-free survival. RESULTS: In total, 187 patients were randomized to levofloxacin (n = 95) or placebo (n = 92). The rate of grade 3/4 infections or grade 1/2 infections treated with additional antibiotics (intent-to-treat population) was 27.5% (95% confidence interval, 19.3-39.0%) for levofloxacin versus 36.7% (95% confidence interval, 27.1-48.0%) for placebo. Median time to first infection was 67 days for levofloxacin versus 46 days for placebo. Grade 3/4 infections occurred in 8.8% of patients in the levofloxacin group versus 26.7% for placebo. There was one grade 5 infection in each group. Grade ≥3 toxicities (levofloxacin versus placebo) included leukopenia (63.2 versus 52.2%), neutropenia (62.1 versus 51.1%), dyspnea (12.6 versus 8.7%), and pain (10.5 versus 9.8%). There was no significant difference in overall survival or progression-free survival between groups. CONCLUSIONS: Levofloxacin prophylaxis reduces the rate of infection compared with placebo and is well tolerated in elderly patients receiving docetaxel plus carboplatin.