Dose-Escalation Study of Thoracic Radiotherapy in Combination With Pemetrexed Plus Cisplatin Followed by Pemetrexed Consolidation Therapy in Japanese Patients With Locally Advanced Nonsquamous Non–Small-Cell Lung Cancer

BackgroundPemetrexed has radiosensitizing potential when evaluated in vitro in combination with platinum-containing compounds and radiation. We determined the recommended dose (RD) of thoracic radiotherapy (TRT) with a concurrent chemotherapy combination of pemetrexed and cisplatin in Japanese patients with nonsquamous non–small-cell lung cancer (NSCLC).Patients and MethodsEligible patients were histologically confirmed as having locally advanced nonsquamous NSCLC. Study treatment consisted of 2 phases: concurrent chemoradiation and consolidation. In the concurrent chemoradiation phase, all patients received pemetrexed 500 mg/m² plus cisplatin 75 mg/m² on day 1 of a 21-day interval for 3 cycles. The first 6 patients were given 60 Gy concurrently at level 1 dose (L1D). If dose-limiting toxicity (DLT) occurred in < 2 patients at L1D, radiation was escalated to 66 Gy (level 2 dose [L2D]).ResultsEighteen patients were treated and completed chemoradiotherapy; 12 completed the consolidation phase. In the concurrent chemoradiation phase, 1 patient experienced 2 DLTs [grade 3 anorexia and diarrhea] at L1D. Because no DLT was observed at L2D, it was determined to be the RD. Common toxicities ≥grade 3 were neutropenia and leukopenia. At L1D, 1 patient each experienced grade 2 and grade 3 pneumonitis, and 2 patients experienced grade 2 esophagitis. Six patients experienced grade 2 pneumonitis and 3 patients experienced grade 2 esophagitis at L2D. Fifteen patients achieved partial response (PR), 2 had stable disease (SD), and 1 had progressive disease (PD).ConclusionExpected toxicities from concurrent chemoradiation were not worsened with concurrent TRT at a total dose of 66 Gy combined with pemetrexed in Japanese patients with locally advanced (LA) nonsquamous NSCLC.     

Phase 2 Study of Nimotuzumab in Combination With Concurrent Chemoradiotherapy in Patients With Locally Advanced Non–Small-Cell Lung Cancer

BackgroundWe evaluated the tolerability and efficacy of nimotuzumab, a humanized IgG1 monoclonal anti–epidermal growth factor receptor antibody, with concurrent chemoradiotherapy in patients with unresectable locally advanced non–small-cell lung cancer.Patients and MethodsIn this multicenter, single-arm, open-label, phase 2 trial conducted in Japan (JapicCTI-090825), patients received thoracic radiotherapy (60 Gy, 2 Gy per fraction, 6 weeks) and four 4-week cycles of chemotherapy (day 1, cisplatin 80 mg/m²; days 1 and 8, vinorelbine 20 mg/m²). Nimotuzumab 200 mg was administrated weekly for 16 weeks. The primary endpoint was treatment completion rate, defined as the percentage of patients completing 60 Gy of radiotherapy within 8 weeks, 2 cycles of chemotherapy, and at least 75% of the required nimotuzumab dose during the initial 2-cycle concurrent chemoradiotherapy period.ResultsOf 40 patients enrolled, 39 received the study treatment, which was well tolerated, with a completion rate of 87.2%. Thirty-eight patients completed 60 Gy of radiotherapy within 8 weeks. Infusion reaction, grade 3 or higher rash, grade 3 or higher radiation pneumonitis, or grade 4 or higher nonhematologic toxicity were not observed. The objective response rate was 69.2%. The median progression-free survival (PFS) and 5-year PFS rate were 508 days and 29.0%, respectively. The 5-year PFS rate in patients with non–squamous cell carcinoma (n = 23) was 13.7% and in patients with squamous cell carcinoma (n = 16) was 50.0%. The 5-year overall survival rate was 58.4%.ConclusionAddition of nimotuzumab to the concurrent chemoradiotherapy regimen was well tolerated and showed potential for treating patients with locally advanced non–small-cell lung cancer, particularly squamous cell carcinoma.     

Phase Ib Study of Bavituximab With Carboplatin and Pemetrexed in Chemotherapy-Naive Advanced Nonsquamous Non–Small-Cell Lung Cancer

Introduction

Bavituximab is an immunomodulatory chimeric monoclonal antibody that inhibits phosphatidylserine signaling, which promotes innate and adaptive immune responses. In this phase Ib trial we evaluated the safety, tolerability, and preliminary antitumor activity of pemetrexed, carboplatin, bavituximab in advanced non–small-cell lung cancer (NSCLC).

An Open-Label,Multicenter, Randomized,Phase II Study of Cisplatin and Pemetrexed With or Without Cixutumumab (IMC-A12) as a First-Line Therapy in Patients With Advanced Nonsquamous Non–Small Cell Lung Cancer

IntroductionType 1 insulin-like growth factor receptor is deregulated in solid tumors. Cixutumumab, a monoclonal antibody that inhibits the activity of type 1 insulin-like growth factor receptor, was investigated in combination with pemetrexed/cisplatin in the frontline setting.MethodsIn this open-label, phase II study, patients with stage IV nonsquamous NSCLC and a performance status of 0 to 1 were randomized (1:1) to receive 20 mg/kg cixutumumab, 500 mg/m² pemetrexed, and 75 mg/m² cisplatin (cixutumumab [n = 87]) or pemetrexed and cisplatin (control [n = 85]). Eligible patients received pemetrexed-based maintenance therapy with cixutumumab (cixutumumab arm) or without it (control arm). The primary end point was progression-free survival. Secondary end points assessed overall survival, objective response rate, and safety. Survival was analyzed by the Kaplan-Meier method and Cox proportional hazard model. Exploratory correlative analyses were also performed.ResultsThe mean age of the intent-to-treat population (n = 172) was 59 years (range 32–83). Median progression-free survival was 5.45 months with cixutumumab versus 5.22 months in the control (hazard ratio = 1.15, 95% confidence interval: 0.81–1.61; p = 0.44). Median overall survival was 11.33 months with cixutumumab versus 10.38 months in the control (hazard ratio = 0.93, 95% confidence interval: 0.64–1.36). Objective response rate did not differ between treatments (p = 0.338). Grade 3 or 4 hyperglycemia occurred at a higher rate with cixutumumab than in the control (9.4% versus 1.2%). One death possibly related to cixutumumab occurred.ConclusionsEfficacy was not improved in patients with nonsquamous NSCLC when cixutumumab was added to pemetrexed/cisplatin. Combination therapy was well tolerated and no new safety concerns were reported.     

Randomized Phase III Study of Cisplatin With Pemetrexed and Cisplatin With Vinorelbine for Completely Resected Nonsquamous Non–Small-Cell Lung Cancer: The JIPANG Study Protocol

This trial report describes the background and design for the Japan Intergroup Trial of Pemetrexed Adjuvant Chemotherapy for Completely Resected Nonsquamous Non–Small-Cell Lung Cancer (JIPANG) study (University Hospital Medical Information Network database: UMIN000006737). Various randomized trials have shown the efficacy of postoperative adjuvant chemotherapy regimens that include cisplatin for resected non–small-cell lung cancer (NSCLC), but the optimal regimen is not known. The JIPANG study is a randomized study comparing cisplatin (75 mg/m², day 1) and pemetrexed (500 mg/m², day 1) with cisplatin (80 mg/m², day 1) and vinorelbine (25 mg/m², days 1 and 8) for nonsquamous NSCLC as postoperative adjuvant chemotherapy. A total of 804 patients with pathological stage II to IIIA completely resected nonsquamous NSCLC were enrolled in this study between March 2012 and August 2016. These patients have been randomized in a 1:1 ratio and stratified according to sex (female vs. male), age (< 70 years vs. ≥ 70 years), pathologic stage (II vs. IIIA), mutation of the epidermal growth factor receptor (mutant vs. wild) and institution. Each treatment will be undertaken every 3 weeks until 4 cycles have been completed. The primary endpoint is overall survival and the secondary endpoints are disease-free survival, rate of treatment completion, and incidence of adverse events. This design has 80% power to detect overall survival with a hazard ratio of 0.786 (α = 1-sided 0.05) with 5-year follow-up after registration of the final patient. This study will show a superior regimen for completely resected nonsquamous NSCLC. Biomarker analyses of the JIPANG study are ongoing.     

A Multicenter Double-blind Phase II Study of Metformin With Gefitinib as First-line Therapy of Locally Advanced Non–Small-cell Lung Cancer

We present the rationale and study design of the CGMT (combined gefitinib and metformin therapy) trial (www.ClinicalTrials.gov Identifier: NCT01864681), which is aimed at treating locally advanced non–small-cell lung cancer. The CGMT trial is a multicenter, phase II randomized, double-blinded, and placebo-controlled study, which is designed to evaluate the safety and efficacy of metformin in combination with gefitinib as first-line therapy in patients presenting with stage IIIb-IV non–small-cell lung cancer expressing the epidermal growth factor receptor mutant. Two therapies are proposed for this trial. The first regimen is comprised of gefitinib plus metformin. The second therapy is comprised of gefitinib plus placebo. The primary objective of this trail is to compare the progression-free survival rate at year 1 of the study. The secondary objective of this trial is to compare the 2-year overall survival, the 2-year progression-free survival, the objective response rate, and the disease-control rate, and to evaluate the relative safety of both therapies. Based on the statistical design, we plan to enroll approximately 200 patients.     

Carboplatin/Pemetrexed/Bevacizumab in the Treatment of Patients With Advanced Non–Small-Cell Lung Cancer: A Single-Institution Experience

PurposeThe purpose of this study was to determine the efficacy and tolerability of carboplatin, pemetrexed, and bevacizumab in patients with advanced, nonsquamous non–small-cell lung cancer (NSCLC).Patients and MethodsThe charts of consecutive patients with stage IIIB/IV nonsquamous NSCLC were reviewed. All patients receiving at least 1 cycle of the 3-drug regimen (pemetrexed 500 mg/m², carboplatin area under the curve of 5-6, bevacizumab 15 mg/kg intravenously), were included for assessment of response, safety, and toxicity.ResultsA total of 27 patients received this regimen between February 2008 and July 2009; 63% were women. Median follow-up was 6.3 months (range, 1.6-21.1 months). Median number of cycles was 6 (range, 1-6 cycles); 67% completed 6 cycles; 83% went on to receive maintenance bevacizumab/pemetrexed. Among those who received maintenance, the median number of cycles administered was 4.5 (range, 1-18 cycles). Response rate was 52%; stable disease was observed in another 40%. On the basis of Kaplan-Meier analysis, actuarial overall survival was 83% at 12 months; actuarial progression-free survival was 83% and 63% at 6 and 12 months, respectively. Clinical improvement was noted in 41% of the patients, with clinical stability in another 48%. Grade 2 and 3 toxicities from the regimen included anemia (11% and 15%), fatigue (37% and 7.4%), febrile neutropenia (7.4%; grade 3 only), thrombocytopenia (7.4% and 0), and thromboembolic disorders (3.7% and 3.7%). Bevacizumab-induced side effects (any grade) included headaches (22.2%), epistaxis (30%), hemoptysis (3.7%), and hypertension (11%). No grade 4 or 5 toxicities were seen.ConclusionCombination carboplatin/pemetrexed and bevacizumab followed by maintenance therapy with pemetrexed/bevacizumab is effective, with response rates > 50%, acceptable toxicity, and promising early survival in patients with advanced nonsquamous NSCLC.     

A Phase I/II Study of Biweekly Carboplatin and Nab-paclitaxel With Concurrent Radiotherapy for Patients With Locally Advanced Unresectable Stage III Non–small-cell Lung Cancer

BackgroundConcurrent chemoradiotherapy (CCRT) is the standard treatment for patients with locally advanced non–small-cell lung cell cancer (LA-NSCLC). We conducted a phase I/II study of biweekly carboplatin and nab-paclitaxel (nab-PTX) with radiotherapy (RT).Materials and MethodsIn the phase I part, patients with inoperable stage IIIA/IIIB NSCLC were treated with carboplatin (area under the time-concentration curve, 4) and nab-PTX (60-100 mg/m²) on days 1, 15, and 29. Thoracic RT was administered from day 1 to a total dose of 60 Gy in 30 fractions. In the phase II part, patients were administered carboplatin and nab-PTX on days 1, 15, and 29 at the recommended dose (RD). The primary endpoint of the phase I part was to determine the maximum tolerated dose and the RD. In the phase II part, the primary endpoint was 2-year overall survival (OS) rate, and secondary endpoints were the objective response rate, progression-free survival, OS, and safety profile.ResultsIn the phase I part, although maximum tolerated dose was not obtained, the RD was carboplatin (area under the time-concentration curve, 4) and nab-PTX (100 mg/m²). Of the evaluable 28 patients, the rate of 2-year OS was 67.8% (95% confidence interval, 49.3%-82.1%). The objective response rate was 96.4%, and the median follow-up time was 33.2 months. The median progression-free survival was 18.2 months (95% confidence interval, 13.1 months to not reached). The most common toxicities of grade 3 or higher were neutropenia (60.5%), anemia (14.2%), thrombocytopenia (7.2%), and pneumonitis (3.6%).ConclusionsThis study achieved the primary endpoint. Biweekly carboplatin and nab-PTX with concurrent RT was well-tolerated and exerted promising antitumor activity.     

Phase 1b/2 Randomized Study of MEDI-575 in Combination With Carboplatin Plus Paclitaxel Versus Carboplatin Plus Paclitaxel Alone in Adult Patients With Previously Untreated Advanced Non–Small-Cell Lung Cancer

IntroductionPlatinum doublet chemotherapy has represented the standard of care in advanced non–small-cell lung cancer for decades. Targeting platelet-derived growth factor receptors (PDGFR) is a potential mechanism to improve the efficacy of first-line therapy. This randomized phase 1b/2 trial investigated the addition of the anti-PDGFRα monoclonal antibody MEDI-575 to first-line carboplatin/paclitaxel (CP) chemotherapy.Patients and MethodsThe phase 1b component was a dose-escalation study combining MEDI-575 with carboplatin area under the plasma concentration versus time curve 6 and paclitaxel 200 mg/m² (CPM), with the end point of identifying a recommended phase 2 dose. The phase 2 component randomized patients to CPM or CP, with primary end point of progression-free survival. Secondary end points included overall survival, overall response rate, and adverse event rates.ResultsOverall, 99 patients were enrolled and received either CPM (n = 53; 4 phase 1b, 49 phase 2) or CP (n = 46). Demographics were as follows: 63/36 male/female, 78/21 aged ≤ 70/> 70 years; 37/62 squamous/nonsquamous, 42/53 Eastern Cooperative Oncology Group performance status 0/1. The phase 2 portion of the trial did not meet its primary end point: progression-free survival was shorter with CPM (4.6 vs. 5.5 months) than CP. No significant difference was seen in overall response rate (31.7% vs. 22.5%) or median overall survival (10.0 vs. 11.8 months). More serious adverse events were observed in patients receiving CPM (47% vs. 40%); in particular, 9 patients in the CPM group had significant gastrointestinal or respiratory adverse events (including abscess, perforation, and pneumothorax).ConclusionThe addition of MEDI-575 to CP chemotherapy as first-line treatment of advanced non–small-cell lung cancer did not improve efficacy and resulted in increased toxicity.     

Oxaliplatin in First-line Therapy for Advanced Non–Small-Cell Lung Cancer

Platinum doublets are the recommended standard first-line chemotherapy for stage IIIB/IV non–small-cell lung cancer (NSCLC). As efficacy outcomes associated with currently approved agents (cisplatin and carboplatin) are broadly similar, the decision about which platinum-based doublet to use is based on other factors such as toxicity. The goals for new platinum agents are to maintain and perhaps improve current efficacy and to improve toxicity. The aim of this article is to review the available clinical data from studies investigating the third-generation platinum analogue oxaliplatin in patients with advanced NSCLC. Information was obtained from the PubMed database and from recent presentations at national and international meetings. Oxaliplatin has been studied as monotherapy and in combination with a wide range of other chemotherapies (vinca alkaloids, taxanes, gemcitabine, and pemetrexed), mainly in phase II trials. Preliminary results from studies in which oxaliplatin-based doublets have been combined with targeted agents (eg, bevacizumab) are now available. In general, the clinical activity observed with oxaliplatin-based therapy is similar to that seen with other currently used platinum regimens, although outcomes vary between individual trials (response rates, 23%-48%; median progression-free survival, 2.7-7.3 months; median overall survival, 7.3-13.7 months). The toxicity profile of oxaliplatin, particularly when compared with cisplatin, makes it an alternative treatment, especially in patients unable to tolerate cisplatin. However, well-conducted randomized phase III trials will be needed to clarify which particular groups of patients with NSCLC may benefit from oxaliplatin-based therapy.