A Phase Ib,Dose-Finding Study of Erlotinib in Combination With a Fixed Dose of Pertuzumab in Patients With Advanced Non–Small-Cell Lung Cancer

BackgroundPertuzumab, a dimerization inhibitor of human epidermal growth factor receptor 2 (HER2), has demonstrated pharmacodynamic activity, with stable disease in non–small-cell lung cancer. Combining erlotinib and pertuzumab may enhance antitumor activity. This study aimed to establish the recommended dosing of the erlotinib and pertuzumab combination; assess safety, preliminary efficacy, and pharmacokinetics; and analyze biomarkers.Patients and MethodsFifteen patients with stage IIIb/IV non–small-cell lung cancer who failed chemotherapy were recruited. The patients received erlotinib (days ?8 to ?1), then combination therapy (21-day cycles for 6 cycles). Pertuzumab was given intravenous at 840 mg, then 420 mg once every three weeks, with erlotinib given daily (100 or 150 mg).ResultsNo dose-limiting toxicities were observed. Adverse events were generally grade 1/2 and manageable. The objective response rate was 20% (3/15 patients; 2 responders had mutant HER1, 1 responder had wild-type HER1), median overall progression-free survival was 9.3 weeks. High HER1, HER2, and HER3 messenger RNA expression correlated with increased progression-free survival. Combination therapy did not affect erlotinib's pharmacokinetics; however, pertuzumab mean exposures (maximum concentration, 231 mg/L; area under the concentration-time curve from 0 to 21 days, 1780 mg*d/L) were slightly higher than in previous studies.ConclusionsCombination therapy was well tolerated in patients with good performance status, with encouraging efficacy. A loading dose of pertuzumab 840 mg followed by 420 mg once every three weeks plus daily erlotinib 150 mg appears to be the most appropriate regimen for this combination.     

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

BackgroundPemetrexed 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 MethodsThe patients were randomized (1:1) to 2 parallel arms: pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) or pemetrexed (500 mg/m²) 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.ResultsSixty-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%]).ConclusionsBoth 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.     

Molecularly Targeted Therapies in Locally Advanced Non–Small-Cell Lung Cancer

Approximately a third of the patients with non-small cell lung cancer (NSCLC) present with locally advanced disease not amenable to curative resection. Concurrent chemoradiation is currently the treatment of choice for these patients. Outcomes in patients with locally advanced NSCLC treated with concurrent chemoradiation are modest at best. No significant progress has been made over the past decade in this subset of patients with NSCLC. Several trials have examined the role of molecular targeted therapies in this setting. We review the results of these trials and present the outline of a proposed prospective clinical trial to evaluate targeted drugs in molecularly selected group of patients with locally advanced NSCLC.     

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.     

Early Detection of Recurrence in Patients With Locally Advanced Non–Small-Cell Lung Cancer via Circulating Tumor Cell Analysis

BackgroundAssays to identify circulating tumor cells (CTCs) might allow for noninvasive and sequential monitoring of lung cancer. We investigated whether serial CTC analysis could complement conventional imaging for detecting recurrences after treatment in patients with locally advanced non–small-cell lung cancer (LA-NSCLC).Patients and MethodsPatients with LA-NSCLC (stage II-III) who definitively received concurrent chemoradiation were prospectively enrolled, with CTCs from peripheral blood samples identified using an adenoviral probe that detects elevated telomerase activity present in nearly all lung cancer cells. A “detectable” CTC level was defined as 1.3 green flourescent protein-positive cells per milliliter of collected blood. Samples were obtained before, during (at weeks 2, 4, and 6), and after treatment (post-radiation therapy [RT]; at months 1, 3, 6, 12, 18, and 24).ResultsForty-eight patients were enrolled. At a median follow-up of 10.9 months, 22 (46%) patients had disease recurrence at a median time of 7.6 months post-RT (range, 1.3-32.0 months). Of the 20 of 22 patients for whom post-RT samples were obtained, 15 (75%) had an increase in CTC counts post-RT. In 10 of these 15 patients, CTCs were undetectable on initial post-RT draw but were then detected again before radiographic detection of recurrence, with a median lead time of 6.2 months and mean lead time of 6.1 months (range, 0.1-12.0 months) between CTC count increase and radiographic evidence of recurrence. One patient with an early recurrence (4.7 months) had persistently elevated detectable CTC levels during and after treatment.ConclusionThese results indicate that longitudinal CTC monitoring in patients with LA-NSCLC treated with chemoradiation is feasible, and that detectable CTC levels in many patients meaningfully precede radiologic evidence of disease recurrence.     

Phase II Study of Cetuximab,Docetaxel, and Gemcitabine in Patients With Previously Untreated Advanced Non–Small-Cell Lung Cancer

BackgroundTargeting epidermal growth factor receptors (EGFRs) has been a novel strategy in treating non–small-cell lung cancer (NSCLC). This multicenter, community-based trial was designed to examine the role of cetuximab in combination with a nonplatinum regimen.Patients and MethodsEligibility criteria were newly diagnosed unresectable stage III/IV NSCLC, all histologies, measurable disease, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2. Treatment premedication included dexamethasone 20 mg orally 12 and 6 hours before treatment, and 4 mg 12 hours following treatment; diphenhydramine 50 mg intravenously (I.V.) and cimetidine 300 mg I.V. before cetuximab. Treatment medication included docetaxel 30 mg/m² I.V. days 1 and 8; gemcitabine 1000 mg/m² I.V. days 1 and 8; and cetuximab 400 mg/m² I.V. day 1, then 250 mg/m² I.V. weekly. Patients received up to 6 cycles with restaging every 6 weeks. The primary endpoint was an overall response rate (ORR) ≥ 25%.ResultsSixty-nine patients enrolled from July 2005 to October 2007. Patients had a median age of 69 years; 70% were male and 30% were female; ECOG PS was 0 in 42%, 1 in 51%, and 2 in 7%; patients had adenocarcinoma (42%), squamous cell (30%), large cell (6%), mixed (1%), and not otherwise specified (20%) disease. The ORR was 17% (95% CI, 9%-29%). Thirty-five patients (54%) had stable disease; 14 patients (22%) had progressive disease. With a median follow-up of 17.8 months, the median progression-free and overall survivals were 4 months and 9.4 months, respectively. The most common (> 10%) grade 3/4 toxicities were neutropenia (25%), rash (22%), and fatigue (12%). Accrual in our middle Tennessee offices was temporarily suspended and ultimately stopped because of a higher-than-anticipated rate of cetuximab-related severe hypersensitivity reactions (HSRs) in 4 patients among the first 12 enrolled, including 1 fatal event.ConclusionCetuximab/docetaxel/gemcitabine was relatively well-tolerated and associated with efficacy similar to chemotherapy alone. Additional study with cetuximab/chemotherapy in NSCLC should focus on new potentially predictive biomarkers. Also, additional study is needed to better understand and prevent the severe HSRs that appear to be endemic to specific regions of the United States.     

Prognostic Significance of Weight Gain During Definitive Chemoradiotherapy for Locally Advanced Non–Small-Cell Lung Cancer

BackgroundThe successful treatment of locally advanced non–small-cell lung cancer (NSCLC) with chemoradiotherapy (CRT) is still compromised by poor locoregional and distant control rates. Given the morbidity associated with treatment, it is critical to determine clinical prognostic factors to risk stratify patients before and after aggressive therapy. This study aimed to discern the prognostic value of weight gain during CRT in patients with locally advanced NSCLC.Patients and MethodsThis was a retrospective analysis of 92 patients treated with definitive split-course CRT between 2004 and 2010 at Rush University Medical Center. Weight gain was defined as a weight change greater than the highest quartile of change between the start and finish of CRT (4.5 lb). Overall survival (OS), locoregional progression-free survival (PFS), and distant metastasis-free survival (DMFS) were determined using Kaplan-Meier analysis, and the cumulative incidences of locoregional and distant recurrence were calculated. Cox regression (multivariate analysis) was used to determine independent predictors of OS.ResultsWith a median follow-up of 50 months for surviving patients, the median, 3- and 5-year OS probabilities were 25 months, 37%, and 29%, respectively. The 3-year cumulative risks of locoregional and distant metastases were 51% and 64%. Patients who experienced weight gain were significantly more likely to survive (3-year OS, 55% vs. 31%; P = .04) and prolonged DMFS resulted. Weight gain was the only significant predictor of survival on multivariate analysis.ConclusionsWeight gain during split-course CRT was associated with superior OS and DMFS. The presence of weight gain may have utility in risk stratification after CRT as well as in identifying novel treatment approaches for patients with locally advanced NSCLC.     

Use of Cetuximab After Failure of Gefitinib in Patients With Advanced Non–Small-Cell Lung Cancer

BackgroundGefitinib and cetuximab are both epidermal growth factor receptor (EGFR) target therapies used to treat patients with non–small-cell lung cancer (NSCLC) with different mechanisms. To clarify the effectiveness of cetuximab after failure of gefitinib treatment, we investigated the clinical features of patients with NSCLC who received cetuximab-containing chemotherapy after failure of gefitinib.Patients and MethodsWe analyzed the clinical data and mutational studies of patients with NSCLC in the National Taiwan University Hospital who had received gefitinib and, after failure of gefitinib, cetuximab-containing chemotherapy.ResultsFifteen patients who received cetuximab-containing chemotherapy after failure of gefitinib were identified. Four were responders to gefitinib therapy, and 3 were responders to cetuximab-containing chemotherapy. Ten were sequenced for EGFR and KRAS mutations. Six of the 10 patients had EGFR mutations, and all 10 patients had wild-type (WT) KRAS. In the 4 patients who had the gefitinib-resistant EGFR T790M mutation, 2 were responders to cetuximab-containing chemotherapy. The other cetuximab responder had WT EGFR.ConclusionCetuximab might add benefit in treatment after failure of gefitinib, regardless of EGFR mutational status. Treatment with cetuximab should be further explored, even in patients who have previously received gefitinib treatment.     

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).

Phase 2 Study of Afatinib Alone or Combined With Bevacizumab in Chemonaive Patients With Advanced Non–Small-Cell Lung Cancer Harboring EGFR Mutations: AfaBev-CS Study Protocol

Afatinib, a second-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), has demonstrated a significant survival benefit over platinum-based chemotherapy in a first-line setting in advanced non–small-cell lung cancer (NSCLC) harboring EGFR exon 19 deletion. In addition, we and other groups have shown there to be favorable progression-free survival (PFS) outcomes, with acceptable toxicity profiles, with bevacizumab and first-generation EGFR-TKI combination therapy. On the basis of the above, we hypothesized that a combination of bevacizumab and afatinib could potentially improve efficacy. In our phase 1 study, a daily 30 mg dose of afatinib and 15 mg/kg intravenous bevacizumab every 3 weeks was well tolerated and was defined as the recommended dose. We have initiated a randomized phase 2 trial comparing afatinib (30 mg daily) and bevacizumab (15 mg/kg every 3 weeks) with afatinib (40 mg daily) alone for nonsquamous NSCLC harboring EGFR common mutations as a first-line therapy. A total of 100 patients will be enrolled onto this study and randomized in a 1:1 ratio. Patients will continue to receive treatment until disease progression or unacceptable toxicity. The primary end point is PFS, and the secondary end points are overall survival, tumor response, and time to treatment failure. The power is greater than 50% under the assumptions of a median PFS of 12 months for the afatinib group and a hazard ratio of 0.6 for the combination group (2-sided α = 0.05). We hypothesize that the combination therapy will be more efficacious than standard therapies for EGFR-mutant NSCLC patients.     

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 II Study of Topotecan and Bevacizumab in Advanced,Refractory Non–Small-Cell Lung Cancer

BackgroundThis clinical trial evaluated whether topotecan in combination with bevacizumab improved progression-free survival (PFS) in patients with advanced, refractory non–small-cell lung cancer in a second-line setting.Patient and MethodsPatients aged 18 years old and older received topotecan (4.0 mg/m²) on days 1, 8, and 15, and bevacizumab (10 mg/kg) on days 1 and 15 as intravenous infusions on a 28-day treatment cycle. Available tumor specimens were analyzed for ISG15 gene expression as a biomarker of response to topotecan.ResultsForty-two patients were enrolled in the study, with a median age of 62.5 years and a median of 3 (range, 1-7) prior treatment regimens. Almost half (n = 18, 42.9%) of the patients received prior bevacizumab therapy. PFS was 5.1 months (95% CI, 3.7-7.8 months), and overall survival was 11.5 months (95% CI, 6.8-15.5 months). Response rates were as follows: 14.3% partial response, 54.8% stable disease, and 28.6% progressive disease. Hematologic toxicities included grade 3 thrombocytopenia (n = 7, 16.7%), neutropenia (n = 4, 9.5%), and anemia (n = 2, 4.8%). One toxic death occurred due to pulmonary hemorrhage, and one patient experienced a grade 4 pulmonary embolism. Grade 3 nonhematologic adverse events were uncommon (< 8%). There was a trend for improved median PFS, 3.5 months vs. 1.8 months (P = .26), in patients with high ISG15 expression.ConclusionBevacizumab in combination with topotecan as a salvage therapy for metastatic non–small-cell lung cancer is well tolerated and is worthy of further investigation.     

Gefitinib-Related Interstitial Lung Disease in Taiwanese Patients With Non–Small-Cell Lung Cancer

BackgroundGefitinib (Iressa; AstreZeneca, Wilmington, DE) is effective in the treatment of NSCLC, especially in the Asian population. However, ILD is usually a serious pulmonary adverse effect and almost leads to cessation of gefitinib treatment. In this study, we investigated the incidence, clinical features, and prognosis of gefitinib-related ILD in Taiwanese patients with NSCLC.Patients and MethodsThis was a retrospective observational study conducted in 2 medical centers and a local teaching hospital.ResultsA total of 1080 patients with NSCLC, who received at least 1 dose (250 mg per day) of gefitinib treatment, were enrolled. Of these, 42 patients were diagnosed with ILD. Twenty-five of the 42 patients were diagnosed with gefitinib-related ILD (incidence, 2.3%). The main manifestations of ILD included dyspnea, cough, and hypoxemia. Six of the 25 patients (24%) with gefitinib-related ILD required invasive mechanical ventilation and all patients were treated with steroids. Twenty-two patients (88%) discontinued gefitinib treatment without further rechallenge. Ten (40%) patients died directly from ILD and in-hospital mortality was 52%. Eleven patients received subsequent cytotoxic chemotherapy with a mean of 33.5 days after ILD events. Kaplan-Meier analysis demonstrated that gefitinib nonresponder and gefitinib use rather than first-line treatment were associated with poor prognosis when ILD developed during gefitinib treatment.ConclusionTaiwanese patients with NSCLC had a relatively high incidence of ILD during gefitinib treatment. Gefitinib-related ILD is usually life-threatening, especially in gefitinib nonresponders and gefitinib use rather than first-line treatment.