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Our purpose was to evaluate the maximum tolerated dose of hypofractionated proton beam radiation therapy with concurrent weekly carboplatin/paclitaxel in patients with stage II-III non-small cell lung cancer.A phase I trial was designed using the time-to-event continuous reassessment method. Maximum tolerated dose was defined as the dose associated with a 20% probability of Common Terminology Criteria for Adverse Events protocol-specified serious adverse events (SAEs). Starting dose was 3.5 Gy/fx for 15 fractions with 2 potential escalation and de-escalation levels in 0.25 Gy/fx increments. Chemotherapy was weekly concurrent carboplatin/paclitaxel with 2 cycles of optional consolidation carboplatin/paclitaxel.From May 2015 to September 2016, 23 patients enrolled at a single institution. Of 20 evaluable, median age was 66.5 years (range, 54-89) and 12 were male (60%). Fourteen (70%) had squamous cell and 15 (75%) were stage IIIA. Nineteen (95%) completed all 3 cycles of concurrent chemotherapy, and 16 (80%) received at least 1 cycle of consolidation chemotherapy. Within the 6-month time-to-event continuous reassessment method assessment window, no SAEs were reported, and most patients were treated at the highest dose level. Dose level assignment was 52.5 Gy (n = 2), 56.25 Gy (n = 4), and 60 Gy (n = 14). The posterior probability of dose-limiting toxicity for 60 Gy was 5.3% (95% confidence interval, 1%-18.1%). Acute, nonserious AEs included grade 2 esophagitis in 7 patients (35%) and grade 2 pneumonitis in 1 patient (5%). At a median follow-up of 20.3 months for all and 44.9 months for living patients, there were no grade 4 or 5 AEs, though there were 3 (21% at 24 months) SAEs outside of the dose-escalation window. The 2-year overall survival, local, regional, and distant control rates were 48%, 84%, 77%, and 79%, respectively.Hypofractionated proton beam radiation therapy and chemotherapy up to 60 Gy in 15 fractions is acutely well tolerated, with high rates of locoregional control and overall survival, though late SAEs were noted.

Aim Aurora kinase A (AURKA) is a pleiotropic serine/threonine kinase that orchestrates mitotic progression. Paclitaxel stabilises microtubules and disrupts mitotic spindle assembly. The combination of AURKA inhibitor (alisertib) plus paclitaxel may be synergistic in rapidly proliferative cancers. We evaluated the safety and maximum tolerated dose (MTD) of alisertib in combination with nab-paclitaxel and its preliminary efficacy in patients with refractory high-grade neuroendocrine tumours (NETs). Method This is a two-part, Phase 1 study. In Part A (dose escalation), a standard 3 + 3 design was used to determine MTD. In Part B (dose expansion), patients with predominantly refractory high-grade NETs were enrolled. Results In total, 31 patients were enrolled and treated (16 in Part A and 15 in Part B). The MTD of alisertib was 40 mg BID on D1-3 per week and nab-paclitaxel 100mg/m2 weekly: 3 weeks, 1 week off. Dose-limiting toxicity was neutropenia, and other common side-effects included fatigue, mucositis, and diarrhoea. In Part A, a patient with small-cell lung cancer with partial response (PR) was treated for more than 2 years, whereas four other patients with pancreatic ductal adenocarcinoma (one patient), small cell lung cancer (SCLC) (two patients), or high-grade NET (one patient) achieved stable disease (SD). In Part B, 13 of 15 enrolled patients had high-grade NETs. Of these, one had PR, and four had SD for more than 10 months. Conclusions The combination of alisertib and nab-paclitaxel has manageable side-effect profile and showed promising preliminary efficacy in high-grade NETs, warranting further testing. Trial registration ClinicalTrials.gov identifier: NCT01677559 .

Introduction The mammalian target of rapamycin (mTOR) is a downstream mediator in the phosphatidylinositol 3-kinase/Akt signaling pathway, and plays a central role in cell proliferation, growth, differentiation, migration, and survival. Temsirolimus (CCI-779), a selective inhibitor of the mTOR, is an ester analog of rapamycin (sirolimus) with improved aqueous solubility and pharmacokinetic (PK) properties. Preclinical studies have confirmed additive and synergistic antitumor activity in cancer cell lines (breast, prostate cancer) with combinations of taxanes and mTOR inhibitors. We conducted a phase I open-label, dose-escalation study to determine the maximal tolerated dose (MTD) of docetaxel in combination with temsirolimus in patients with refractory solid tumors. Patients and methods Eligible patients had a diagnosis of a refractory solid malignancy, measurable disease, and adequate organ function. Patients were sequentially enrolled in 4 dose level intravenous combinations of docetaxel and temsirolimus. Temsirolimus was administered weekly with docetaxel administered every 3 weeks. Laboratory data for tumor markers and radiologic imaging were conducted prestudy and then after every 2 cycles of the treatment. Radiologic response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Blood samples for PK and pharmacodynamic analysis were planned to be drawn at MTD. Apart from the traditional 3+3 design, we also implemented Bayesian Optimal Interval design which uses isotonic regression method to select MTD. We proceeded with isotonic regression analysis by using 20% dose-limiting toxicity (DLT) rate as target. Results Twenty-six patients were treated in this study in 4 cohorts and dose levels. Fourteen males and 12 females were enrolled with a median age of 50 years (range of 27 to 72 y) and median Eastern Cooperative Oncology Group performance score of 1. Tumor histologies included pancreas (6), colon (5), rectum (3), gallbladder (2), non-small cell lung (2), endometrium (1), neuroendocrine (1), esophagus (1), stomach (1), pharynx (1), small intestine (1), and duodenum (1). Stable disease was observed in 2/4 (50%), 3/7 (43%), 4/10 (40%), and 3/5 (60%) patients in cohorts 1, 2, 3, and 4, respectively. Dose escalation in cohorts 2, 3, and 4 was complicated by DLTs such as grade 4 neutropenia and grade 3 diarrhea and an inability for patients to tolerate treatments during and beyond cycle 1 without dose reductions. Therefore, we could not determine an MTD or recommended phase II dose using the traditional 3+3 study analysis. Blood samples for PK and pharmacodynamic analysis were not collected since MTD was not determined. By using 20% DLT rate closest to the target, isotonic regression analysis showed identical estimated DLT rates in dose -1 (docetaxel 50 mg/m2 and temsirolimus 15 mg/m2) and dose level 1 (docetaxel 60mg/m2 and temsirolimus 15 mg/m2). Conclusions Dose escalation of docetaxel and temsirolimus was limited by severe myelosuppressive toxicity in this phase I study. Most of the DLTs occurred after cycle 1 of therapy hence, we were unable to determine MTD or collect blood samples for PK and pharmacodynamic analysis. Our trial did not meet its objectives due to significant DLTs with this chemotherapy combination. Although our novel use of Bayesian Optimal Interval design using isotonic regression method to select MTD showed identical estimated DLT rates in dose levels 1 and -1, clinically our patients were not able to complete 2 cycles of this regimen without dose reductions due to myelosuppressive toxicity in either of these dose levels, and hence, escaped clinical validity. This combination regimen should not be studied further at the dose levels and schedules tested in our study.

Background Activation of the mTOR pathway has been implicated in the development of several malignancies and alterations in TSC1, TSC2, STK11 and NF1, can lead to the dysregulation of this pathway. Furthermore, mutations in TSC1 and NF2 are known to confer sensitivity to everolimus-an mTOR inhibitor. Based on these data, a single-arm, open label, single-institution phase II basket study was designed to assess the activity of everolimus in patients with solid malignancies whose tumors harbored mutations in TSC1, TSC2, NF1, NF2, or STK11. Methods A total of 12 patients with histologically confirmed diagnosis of advanced solid tumors (metastatic, recurrent, or unresectable) with mutations in TSC1, TSC2, NF1, NF2 or STK11 genes, who had failed at least one line of standard of care systemic therapy, were enrolled to this open label, single-arm study. Presence of mutations in TSC1, TSC2, NF1, NF2 or STK11 genes was assessed using targeted-next generation sequencing (NGS). All eligible patients were treated with everolimus at an initial dose of 10 mg orally once daily in cycles of 28 days. The primary endpoint of this study was overall response rate (ORR). Results Of 12 patients enrolled, 8 were evaluable for response at the end of 2 cycles. One complete response (CR) was observed (12.5%) and one patient (12.5%) had stable disease (SD), while six (75%) patients showed disease progression. Everolimus was overall well tolerated with anemia, decreased neutrophil and lymphocyte counts, peripheral edema and hyperglycemia representing the most common adverse events. One patient discontinued treatment due to a treatment related grade 4 pericardial effusion. Both patients with CR or SD had a diagnosis of lung adenocarcinoma with NF1 or STK11 mutations, respectively. Conclusions Although this study failed to meet its prespecified ORR threshold for success of 30% or higher, exploratory analyses suggest potential activity for everolimus in a subset of patients with lung adenocarcinomas with STK11 or NF1 mutations. Further studies are necessary to systematically explore the clinical activity of everolimus, potentially as a combination therapy, in these patients.

Purpose Vorolanib is a multi-target tyrosine kinase inhibitor with anti-angiogenic properties. This study aimed to evaluate the tolerability, safety and efficacy of vorolanib when added to checkpoint inhibitors (CPIs) in patients with advanced solid tumors. Methods We conducted a phase 1b study of vorolanib (300 or 400 mg orally once daily) plus pembrolizumab or nivolumab using a standard 3 + 3 design to determine the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). The endpoints included safety, toxicity and objective response rate, according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Results Sixteen patients (9 in pembrolizumab arm, 7 in nivolumab arm) with gastrointestinal or lung cancers were enrolled. All patients had at least 1 treatment-related adverse event (TRAE). The most common TRAEs across all cohorts were lymphopenia (n = 7), leukopenia (n = 5), fatigue (n = 5), and alanine aminotransferase elevation (n = 5); most toxicities were grade (G) 1–2. DLTs were reported in 3 patients at vorolanib 400 mg dose level, with G3 aspartate aminotransferase elevation, G3 rectal hemorrhage, and G3 rash. Of 13 total response-evaluable patients, 2 patients had confirmed partial responses (1 rectal squamous cell cancer and 1 small cell lung cancer). Two patients achieved prolonged stable disease. Vorolanib 300 mg daily was determined to be the RP2D for either pembrolizumab or nivolumab. Conclusion Combination vorolanib 300 mg orally once daily plus CPI appears to be a feasible regimen with manageable toxicity and promising efficacy in select tumor types. NCT03511222. Date of Registration: April 18, 2018.

BACKGROUND: Activation of the mTOR pathway has been implicated in the development of several malignancies and alterations in TSC1, TSC2, STK11 and NF1, can lead to the dysregulation of this pathway. Furthermore, mutations in TSC1 and NF2 are known to confer sensitivity to everolimus—an mTOR inhibitor. Based on these data, a single-arm, open label, single-institution phase II basket study was designed to assess the activity of everolimus in patients with solid malignancies whose tumors harbored mutations in TSC1, TSC2, NF1, NF2, or STK11. METHODS: A total of 12 patients with histologically confirmed diagnosis of advanced solid tumors (metastatic, recurrent, or unresectable) with mutations in TSC1, TSC2, NF1, NF2 or STK11 genes, who had failed at least one line of standard of care systemic therapy, were enrolled to this open label, single-arm study. Presence of mutations in TSC1, TSC2, NF1, NF2 or STK11 genes was assessed using targeted-next generation sequencing (NGS). All eligible patients were treated with everolimus at an initial dose of 10 mg orally once daily in cycles of 28 days. The primary endpoint of this study was overall response rate (ORR). RESULTS: Of 12 patients enrolled, 8 were evaluable for response at the end of 2 cycles. One complete response (CR) was observed (12.5%) and one patient (12.5%) had stable disease (SD), while six (75%) patients showed disease progression. Everolimus was overall well tolerated with anemia, decreased neutrophil and lymphocyte counts, peripheral edema and hyperglycemia representing the most common adverse events. One patient discontinued treatment due to a treatment related grade 4 pericardial effusion. Both patients with CR or SD had a diagnosis of lung adenocarcinoma with NF1 or STK11 mutations, respectively. CONCLUSIONS: Although this study failed to meet its prespecified ORR threshold for success of 30% or higher, exploratory analyses suggest potential activity for everolimus in a subset of patients with lung adenocarcinomas with STK11 or NF1 mutations. Further studies are necessary to systematically explore the clinical activity of everolimus, potentially as a combination therapy, in these patients.

In non-small cell lung cancer (NSCLC), platelet-derived growth factor receptor (PDGFR) mediates angiogenesis, tissue invasion, and tumor interstitial pressure. Olaratumab (IMC-3G3) is a fully human anti-PDGFRα monoclonal antibody. This Phase II study assessed safety and efficacy of olaratumab+paclitaxel/carboplatin (P/C) versus P/C alone for previously untreated advanced NSCLC.Patients received up to six 21-day cycles of P 200mg/m131 patients were: 67 with olaratumab+P/C and 64 with P/C; 74% had nonsquamous NSCLC. Median PFS was similar between olaratumab+P/C and P/C (4.4 months each) (HR 1.29; 95% CI [0.86-1.93]; p=0.21). Median OS was similar between olaratumab+P/C (11.8 months) and P/C (11.5 months) (HR 1.04; 95% CI [0.68-1.57]; p=0.87). Both arms had similar toxicity profiles. All evaluable cases were PDGFR-negative by immunohistochemistry. Tumor stroma PDGFR expression was evaluable in 23/131 patients, of which 78% were positive.The addition of olaratumab to P/C did not result in significant prolongation of PFS or OS in advanced NSCLC. Olaratumab studies in other patient populations, including soft tissue sarcoma (NCT02783599), pancreatic cancer (NCT03086369), and pediatric malignancies (NCT02677116) are underway.

Patients with epidermal growth factor receptor (EGFR)-positive (EGFR+) non-small-cell lung cancer (NSCLC) show improved response rates when treated with tyrosine kinase inhibitors (TKIs) such as erlotinib. However, standard daily dosing of erlotinib often does not reach therapeutic concentrations within the cerebrospinal fluid (CSF), resulting in progression of central nervous system (CNS) disease. Intermittent, high-dose administration of erlotinib reaches therapeutic concentrations within the CSF and is well tolerated in patients. Experience with "pulsatile" dosing, however, is limited. We review the literature on the pharmacology and clinical outcomes of pulsatile erlotinib in the treatment of EGFR+ NSCLC with brain and leptomeningeal metastases, and include available data on the use of next-generation TKIs in CNS progression. We also provide our institution's experience with patients treated with pulsatile erlotinib for CNS metastasis, and propose clinical criteria for its use. Pulsatile erlotinib is a reasonable alternative in EGFR+ patients with new or worsening CNS disease, without evidence of systemic progression, and without confirmed T790M resistance mutations within the CNS.

Introduction The aim of this study was to evaluate efficacy of maintenance sunitinib after first-line chemotherapy for stage IIIB/IV NSCLC. Methods Cancer and Leukemia Group B 30607 trial was a randomized, double-blind, placebo-controlled, phase III study that enrolled patients without progression after four cycles of first-line platinum-based doublet chemotherapy with or without bevacizumab. Bevacizumab was allowed only during the four cycles of chemotherapy. Patients were randomized to receive sunitinib, 37.5 mg/d, or placebo and were treated until unacceptable adverse event(s), progression, or death. The primary end point was progression-free survival (PFS). Results A total of 210 patients were enrolled, randomized, and included in the intent-to-treat analysis. Ten patients did not receive maintenance therapy (four who received placebo and six who received sunitinib). Grade 3/4 adverse events affecting more than 5% of the patients were fatigue (25%), thrombocytopenia (12%), hypertension (12%), rash (11%), mucositis (11%), neutropenia (7%), and anemia (6%) for sunitinib and none for placebo. There were three grade 5 events in patients receiving sunitinib (one pulmonary hemorrhage, one other pulmonary event, and one death not associated with a Common Terminology Criteria for Adverse Events term) and two grade 5 events in patients receiving placebo (one other pulmonary event and one thromboembolism). Median PFS was 4.3 months for sunitinib and 2.6 months for placebo (hazard ratio = 0.62, 95% confidence interval: 0.47–0.82, p = 0.0006). Median overall survival was 11.7 months for sunitinib versus 12.1 months for placebo (hazard ratio = 0.98, 95% confidence interval: 0.73–1.31, p = 0.89). Conclusions Maintenance sunitinib was safe and improved PFS as maintenance therapy in stage IIIB/IV NSCLC but had no impact on overall survival. There is no room for future investigations of sunitinib in this setting.

Introduction The purpose of this study was to evaluate the efficacy and tolerability of carfilzomib plus irinotecan (C/I) in patients with relapsed small-cell lung cancer (SCLC). Patients and Methods Patients with SCLC who progressed after 1 platinum-containing regimen for recurrent or metastatic disease were eligible. Patients were stratified as: sensitive (SS) (progressive disease > 90 days after chemotherapy) or refractory (RS) (progressive disease 30 to 90 days after chemotherapy) and received up to 6 cycles of C/I; imaging was performed every 2 cycles. The primary endpoint was 6-month overall survival (OS). Results All 62 patients enrolled were evaluable for efficacy and adverse events. 6-month OS was 59% in the platinum SS and 54% in the platinum RS. The overall response rate was 21.6% (2.7% complete response, 18.9% partial response) in SS (n = 37) and 12.5% (all partial response) in RS (n = 25). The disease control rate was 68% (SS) and 56% (RS). Progression-free survival and OS were 3.6 months (95% confidence interval [CI], 2.6-4.6 months) and 6.9 months (95% CI, 4.3-12.3 months) in SS, and 3.3 months (95% CI, 1.8-3.9 months) and 6.8 months (95% CI, 4.1-11 months) in RS. Twenty-nine (47%) patients experienced ≥ grade 3 adverse events; 8 (12.9%) subjects had grade 4 toxicities. Three treatment-related deaths occurred: myocardial infarction (possible), lung infection (possible), and sepsis (probable). Conclusion In patients with relapsed SCLC, C/I was effective in the treatment of SS and RS. With 4.8% grade 5 toxicity, C/I is a viable option for relapsed patients with SCLC with performance status 0 to 1, particularly in platinum-resistant patients, or subjects who cannot receive immunotherapy.

IMPORTANCE: Erlotinib is a standard first-line therapy for patients with epidermal growth factor receptor (EGFR)–mutant non–small cell lung cancer (NSCLC). Median progression-free survival (PFS) with erlotinib is approximately 10 months. OBJECTIVE: To determine whether adding bevacizumab to erlotinib treatment results in superior progression-free survival compared with erlotinib alone. DESIGN, SETTING, AND PARTICIPANTS: This phase 2 randomized clinical trial compared erlotinib plus bevacizumab with erlotinib alone in EGFR-mutant NSCLC. The trial was conducted in 17 US academic and community medical centers among 88 patients with EGFR exon 19 deletion or exon 21 L858R mutation based on local testing and stage 4 NSCLC who were eligible for bevacizumab. Patients were enrolled between November 2, 2012, and August 22, 2016, and followed up for a median (range) of 33 (0.7-62.5) months. Data were analyzed on August 28, 2018, and included data from November 2, 2012, to August 20, 2018. INTERVENTIONS: Patients were randomized with equal allocation to 150 mg of oral erlotinib daily alone or with 15 mg/kg of intravenous bevacizumab every 3 weeks. Study therapy continued until disease progression, unacceptable adverse event, or withdrawal of consent. MAIN OUTCOMES AND MEASURES: The primary outcome was PFS as assessed by the investigator; secondary outcomes were objective response rate (ORR), adverse events, and overall survival (OS). Analysis was designed to detect a hazard ratio (HR) of 0.667 for PFS (an improvement from a median PFS of 10 to 15 months). RESULTS: Among 88 patients enrolled, the median (range) age was 63 (31-84) years; 62 patients (70%) were female; 75 (85%) were white, 8 (9%) were African American, 3 (3%) were Asian, and for 2 (2%), data on race were not available. Forty-eight patients (55%) were never smokers, 45 patients (51%) were of Eastern Cooperative Oncology Group performance status 1, and 59 patients (67%) had EGFR exon 19 deletion. Compared with erlotinib, the combination did not result in a significant difference in PFS (HR, 0.81; 95% CI, 0.50-1.31; P = .39; median PFS 17.9 [combination] and 13.5 months [erlotinib]), ORR (81% vs 83%; P = .81), and OS (HR, 1.41; 95% CI, 0.71-2.81; P = .33; median OS, 32.4 months [combination] and 50.6 months [erlotinib]). Adverse events of grade 3 or higher observed in 5 or more patients in the combination and erlotinib arms were skin eruption in 11 (26%) vs 7 (16%) patients, diarrhea in 4 (9%) vs 6 (13%) patients, hypertension in 17 (40%) vs 9 (20%) patients, and proteinuria in 5 (12%) vs 0 (0%) patients. CONCLUSIONS AND RELEVANCE: Erlotinib plus bevacizumab compared with erlotinib did not result in a significant improvement in PFS in EGFR-mutant NSCLC. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01532089.

Adjuvant chemotherapy improves survival in patients with completely resected stage II and III NSCLC. However, its role in patients with stage IB NSCLC disease remains unclear. We evaluated the role of adjuvant chemotherapy in a large data set of patients with completely resected T2N0M0 NSCLC.Patients with pathologic stage T2N0M0 NSCLC who underwent complete (R0) resection between 2004 and 2011 were identified from the National Cancer Data Base and classified into four groups based on tumor size: 3.1 to 3.9 cm, 4 to 4.9 cm, 5 to 5.9 cm, and 6 to 7 cm. Patients who died within 1 month after their operation were excluded. Survival curves were estimated by the Kaplan-Meier product-limit method and compared by log-rank test.Among the 25,267 patients who met the inclusion criteria, there were 4996 (19.7%) who received adjuvant chemotherapy. Adjuvant chemotherapy was associated with improved median and 5-year overall survival compared with observation for all tumor size groups. In patients with T2 tumors smaller than 4 cm, adjuvant chemotherapy was associated with improved median and 5-year overall survival in univariate (101.6 versus 68.2 months [67% versus 55%], hazard ratio [HR] = 0.66, 95% confidence interval [CI]: 0.61-0.72, p0.0001) and multivariable analysis (HR = 0.77, 95% CI: 0.70-0.83, p 0.001) as well as propensity-matched score (101.6 versus 78.9 months [68% versus 60%], HR = 0.75, 95% CI: 0.70-0.86; p0.0001).In patients with completely resected T2N0M0, adjuvant chemotherapy is associated with improved survival in all tumor size groups. The benefit in patients with tumors smaller than 4 cm strongly suggests a role for chemotherapy in this patient population and counters its current status as an exclusion criteria for adjuvant trials.

BACKGROUND. Seribantumab (MM‐121) is a fully human IgG2 monoclonal antibody that binds to human epidermal growth factor receptor 3 (HER3/ErbB3) to block heregulin (HRG/NRG)‐mediated ErbB3 signaling and induce receptor downregulation. This open‐label, randomized phase 1/2 study evaluated safety and efficacy of seribantumab plus erlotinib in advanced non‐small cell lung cancer (NSCLC). Here, we report the activity of seribantumab plus erlotinib, versus erlotinib alone, in patients with EGFR wild‐type tumors and describe the potential predictive power of HRG. MATERIALS AND METHODS. Patients with EGFR wild‐type NSCLC were assigned randomly to receive seribantumab + erlotinib or erlotinib alone. Patients underwent pretreatment core needle biopsy and archived tumor samples were collected to support prespecified biomarker analyses. RESULTS. One hundred twenty‐nine patients received seribantumab + erlotinib (n = 85) or erlotinib alone (n = 44). Median estimated progression‐free survival (PFS) in the unselected intent‐to‐treat (ITT) population was 8.1 and 7.7 weeks in the experimental and control arm, respectively (hazard ratio [HR], 0.822; 95% confidence interval [CI], 0.37–1.828; p = 0.63), and median estimated overall survival was 27.3 and 40.3 weeks in the experimental and control arm, respectively (HR, 1.395; 95% CI, 0.846 to 2.301; p = .1898) In patients whose tumors had detectable HRG mRNA expression, treatment benefit was observed in the seribantumab + erlotinib combination (HR, 0.35; 95% CI, 0.16–0.76; p = .008). In contrast, in patients whose tumors were HRG negative, the HR was 2.15 (95% CI, 0.97–4.76; p = .059, HRG‐by‐treatment interaction, p value = .0016). CONCLUSION. The addition of seribantumab to erlotinib did not result in improved PFS in unselected patients. However, predefined retrospective exploratory analyses suggest that detectable HRG mRNA levels identified patients who might benefit from seribantumab. An ongoing clinical trial of seribantumab, in combination with docetaxel, is underway in patients with advanced NSCLC and high HRG mRNA expression (NCT02387216). IMPLICATIONS FOR PRACTICE. The poor prognosis of patients with non‐small cell lung cancer (NSCLC) underscores the need for more effective treatment options, highlighting the unmet medical need in this patient population. The results of this study show that a novel biomarker, heregulin, may help to identify patients with advanced NSCLC who could benefit from treatment with seribantumab. On the basis of the observed safety profile and promising clinical efficacy, a prospective, randomized, open‐label, international, multicenter phase II trial (SHERLOC, NCT02387216) is under way to investigate the efficacy and safety of seribantumab in combination with docetaxel in patients with heregulin‐positive advanced adenocarcinoma.

Purpose Tumor overexpression of cyclooxygenase-2 (COX-2) has been associated with worse outcome in non–small-cell lung cancer (NSCLC). In Cancer and Leukemia Group B (CALGB) 30203, we found that the selective COX-2 inhibitor celecoxib in addition to chemotherapy in advanced NSCLC improved progression-free and overall survival in patients with moderate to high COX-2 expression by immunohistochemistry (IHC). CALGB 30801 (Alliance) was designed to prospectively confirm that finding. Patients and Methods Patients with NSCLC (stage IIIB with pleural effusion or stage IV according to American Joint Committee on Cancer [sixth edition] criteria) were preregistered, and biopsy specimens were analyzed for COX-2 by IHC. Patients with COX-2 expression ≥ 2, performance status of 0 to 2, and normal organ function were eligible. Chemotherapy was determined by histology: carboplatin plus pemetrexed for nonsquamous NSCLC and carboplatin plus gemcitabine for squamous histology. Patients were randomly assigned to celecoxib (400 mg twice per day; arm A) or placebo (arm B). The primary objective was to demonstrate improvement in progression-free survival in patients with COX-2 index ≥ 4 with hazard ratio of 0.645 with approximately 85% power at two-sided significance level of .05. Results The study was halted for futility after 312 of the planned 322 patients with COX-2 index ≥ 2 were randomly assigned. There were no significant differences between the groups (hazard ratio, 1.046 for COX-2 ≥ 4). Subset analyses evaluating histology, chemotherapy regimen, and incremental COX-2 expression did not demonstrate any advantage for COX-2 inhibition. Elevation of baseline urinary metabolite of prostaglandin E2, indicating activation of the COX-2 pathway, was a negative prognostic factor. Values above the third quartile may have been a predictive factor. Conclusion COX-2 expression by IHC failed to select patients who could benefit from selective COX-2 inhibition. Urinary metabolite of prostaglandin E2 may be able to identify patients who could benefit from COX-2 inhibition.

BACKGROUND A clinical assay was implemented to perform next-generation sequencing (NGS) of genes commonly mutated in multiple cancer types. This report describes the feasibility and diagnostic yield of this assay in 381 consecutive patients with non–small cell lung cancer (NSCLC). METHODS Clinical targeted sequencing of 23 genes was performed with DNA from formalin-fixed, paraffin-embedded (FFPE) tumor tissue. The assay used Agilent SureSelect hybrid capture followed by Illumina HiSeq 2000, MiSeq, or HiSeq 2500 sequencing in a College of American Pathologists–accredited, Clinical Laboratory Improvement Amendments–certified laboratory. Single-nucleotide variants and insertion/deletion events were reported. This assay was performed before methods were developed to detect rearrangements by NGS. RESULTS Two hundred nine of all requisitioned samples (55%) were successfully sequenced. The most common reason for not performing the sequencing was an insufficient quantity of tissue available in the blocks (29%). Excisional, endoscopic, and core biopsy specimens were sufficient for testing in 95%, 66%, and 40% of the cases, respectively. The median turnaround time (TAT) in the pathology laboratory was 21 days, and there was a trend of an improved TAT with more rapid sequencing platforms. Sequencing yielded a mean coverage of 1318×. Potentially actionable mutations (ie, predictive or prognostic) were identified in 46% of 209 samples and were most commonly found in KRAS (28%), epidermal growth factor receptor (14%), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (4%), phosphatase and tensin homolog (1%), and BRAF (1%). Five percent of the samples had multiple actionable mutations. A targeted therapy was instituted on the basis of NGS in 11% of the sequenced patients or in 6% of all patients. CONCLUSIONS NGS-based diagnostics are feasible in NSCLC and provide clinically relevant information from readily available FFPE tissue. The sample type is associated with the probability of successful testing. Cancer 2015;121:631–639. © 2014 American Cancer Society.

Lung cancer is the leading cause of cancer-related mortality and is responsible for more deaths than breast cancer, prostate cancer, and colon cancer combined. The majority of patients diagnosed with lung cancer are over the age of 65. Despite the prevalence of lung cancer in older adults, they have been notoriously underrepresented in clinical trials designed to help guide clinicians in the management of treatment. In the past 15 years, there have been many improvements that collectively have extended the lives of patients with metastatic lung cancer an average of one year after diagnosis. It is now well-established that age does not diminish the benefit of cancer treatment. However, certain toxicities are more common and may be less tolerated in this age group. It is therefore of paramount importance that clinicians work together to tease out which patients will benefit the most from treatment and to minimize toxicity.

8513 Background: Relapsed small cell lung cancer (SCLC) is incurable with limited therapeutic options. This phase II study evaluated efficacy and tolerability of carfilzomib + irinotecan in SCLC pts who progressed after prior platinum-based therapy, based on expected synergy of proteosome inhibitor carfilzomib and topisomerase 1 inhibitor irinotecan. Methods: SCLC pts who progressed after one platinum-containing regimen (no maintenance therapy allowed) for recurrent/metastatic disease were eligible. Pts were stratified by response to platinum-based therapy: sensitive (progressive disease (PD) > 90 days after chemo) versus refractory (PD 30 to 90 days after chemo). Pts were treated with up to 6 cycles of carfilzomib (20/36 mg.m2 D1, 2, 8, 9, 15, 16 q28D) and irinotecan (125 mg/m2 D1, 8, 15 q28D), imaging was performed every 2 cycles. The primary efficacy endpoint was 6-month overall survival (OS). Results: 62 pts enrolled and were evaluable for efficacy and adverse events. The 6-month OS was 59% in the platinum sensitive stratum and 54% in the platinum refractory stratum. Overall response rate: sensitive stratum 21.6% (1.6% CR + 16.4% PR) and refractory stratum 12.5% (all PR). Disease control (SD+PR+CR) was 68% in platinum sensitive and 56% in refractory patients. Progression free survival and OS were 3.6 months (95% CI 2.6 - 4.6) and 6.9 months (95% CI 4.3 - 12.3) in the sensitive stratum, and 3.3 months (95% CI 1.8 – 3.9) and 6.8 months (95% CI 4.1-11) in the refractory stratum. Twenty-nine pts (47%) experienced at least one grade 3 AE and 8 subjects had grade 4 toxicities: decreased neutrophils, leukocytes, and lymphocytes, diarrhea, vomiting, sepsis, hypokalemia, hypocalcemia, and dehydration. There were three treatment related deaths: myocardial infarction (possible), lung infection (possible), sepsis (probable). Conclusions: In previously treated pts with relapsed SCLC, irinotecan and carfilzomib was effective in platinum-sensitive and, notably, platinum-refractory pts with similar toxicity profile. This combination is a viable option in relapsed SCLC, can be considered following progression on immunotherapy (IO) or in subjects who cannot receive IO, and should be further explored in a randomized phase III trial. Clinical trial information: NCT01941316.

Delayed nausea and vomiting following administration of carboplatin containing chemotherapy regimen remains a clinically significant problem for patients with cancer despite administration of standard antiemetic prophylaxis comprising of a 5-HT3 antagonist and dexamethasone. We performed a prospective study to define the incidence and risk factors for delayed chemotherapy-induced nausea and vomiting (CINV).Previously untreated patients with newly diagnosed cancer scheduled to receive carboplatin containing chemotherapy (AUC 5 or above), but no prophylactic aprepitant were enrolled in the study. The primary endpoint was the incidence of delayed CINV after Cycle 1 of chemotherapy. Secondary endpoints included the incidence of CINV with the third chemotherapy cycle and gender differences in incidence of CINV. Patients completed the Functional Living Index Emesis (FLIE) questionnaires 24, 48, 72 and 96 hours after receiving chemotherapy. Telephone interviews were conducted 24-48 hours following chemotherapy to assess the severity and need for breakthrough medications for CINV.Between December 2006 and July 2009, 105 patients were enrolled onto this study. Delayed emesis following Cycle 1 of carboplatin was observed in 30% of patients. Of these, 14.1%, 22.4% and 23.5% of patients described CINV at 48, 72, and 96 hours, respectively. The incidence of delayed CINV following Cycle 3 dropped to 12.8%, 14.6% and 16% of patients at 48, 72 and 96 hours, respectively. No differences were observed in the incidence of CINV between men and women. A total of 20% of patients required use of breakthrough antiemetics with Cycle 1.Without prophylactic aprepitant administration, 30% of patients receiving carboplatin containing regimen had moderate to severe delayed CINV.

Background: Pemetrexed is an antifolate chemotherapeutic agent approved for use in non-small cell lung cancer (NSCLC). The mammalian target of rapamycin (mTOR) pathway is implicated in lung cancer development and inhibited by temsirolimus. Methods: We performed a phase I study evaluating the combination of pemetrexed and temsirolimus in advanced non-squamous NSCLC. Results: Eight patients were enrolled in this study. The dose-limiting toxicities included grade 4 thrombocytopenia, grade 3 leukopenia and grade 3 neutropenia. The maximum tolerated dose was determined to be pemetrexed 375 mg/m2 intravenously on day 1 and temsirolimus 25 mg intravenously on days 1, 8 and 15. No objective responses were noted and 3 patients had stable disease as the best response. Conclusion: The combination of pemetrexed and temsirolimus is feasible and well tolerated. This combination may be further evaluated in patients with mTOR pathway activation, particularly in those with TSC1 or STK11 mutations.

Background Patients with locally advanced or organ confined, high risk, prostate cancer are at significant risk of having disease recurrence despite definitive local therapy. We evaluated the 2-year progression-free survival of subjects treated with chemotherapy administered prior to definitive therapy with surgery or radiation. Patients and methods Patients ( n = 24) with locally advanced and high risk localized prostate cancer were treated with neoadjuvant docetaxel 36 mg/m2 i.v. weekly for 3 weeks and estramustine 140 mg orally 3 times daily for 3 consecutive days every 28 days prior to definitive treatment with prostatectomy or radiation. Results All evaluable patients, except 1, completed the proposed cycles of neoadjuvant chemotherapy with minimal dose reductions or delays. Of the 22 evaluable patients, 12 underwent radical prostatectomy and 10 underwent external beam radiation therapy. Twenty-one of 22 patients achieved a prostate-specific antigen (PSA) reduction > 25%. There were no pathologic complete responses. With a median follow-up of 24 months, the 2-year progression-free survival was 45%. Conclusions Our findings support the safety, tolerability, and efficacy of neoadjuvant chemotherapy in patients with men with high risk, locally advanced prostate adenocarcinoma, although the relative contributions of androgen deprivation therapy and docetaxel cannot be determined. The effectiveness of neoadjuvant chemotherapy in preventing prostate cancer relapses should be studied in a randomized trial.

Introduction S-1 is a rationally designed oral agent that combines the 5-fluorouracil prodrug tegafur with gimeracil and oteracil, which inhibit 5-fluorouracil degradation by dihydropyrimidine dehydronase and phosphorylation within the gastrointestinal tract, respectively, to increase antineoplastic activity while reducing gastrointestinal toxicity. We investigated the activity and toxicity of S-1 in combination with cisplatin in patients with unresectable non-small cell lung cancer (NSCLC). Methods Cisplatin, 75 mg/m 2 , was administered intravenously on day 1, with S-1, 25 mg/m 2 PO two times a day, days 1 to 14, every 21 days for a maximum of six cycles. Primary end point was overall response. Results A total of 58 patients received at least one cycle of protocol-specified therapy. The best overall response rate was 23.2% (95% confidence interval: 13.0–36.4), and the disease control rate was 67.9%. The median progression-free survival was 4.0 months (95% confidence interval: 3.3–5.5). There did not appear to be any relationship between response to therapy and tumor histology. The most frequently reported adverse events of G3 or more (≥10%) were neutropenia (28%), hyponatremia (19%), diarrhea (17%), hypokalemia (12%), fatigue (10%), dehydration (10%), and deep vein thrombosis (10%). Conclusions Although the S-1 + cisplatin regimen used in this study appeared to have a similar level of antitumor activity and toxicity to that of established cisplatin-based doublets in NSCLC, the protocol-specified criteria of sufficient efficacy to warrant further study with an objective response rate ≥30% was not achieved. Therefore, while S-1 appears to be a promising agent in NSCLC, further evaluation should be conducted to determine the optimal S-1-based regimen to take forward for additional study.

The promising results of crizotinib in molecularly selected patients with advanced non-small cell lung cancer (NSCLC) whose tumor cells had a novel fusion protein involving anaplastic lymphoma kinase presented at the 2010 American Society of Clinical Oncology reinforce once again the importance of understanding molecular heterogeneity of lung cancer and careful patient selection. Several other important issues were the subject of presentations related to lung cancer at the recently concluded American Society of Clinical Oncology annual meeting. The articles covered a wide variety of topics including optimal staging techniques to detect mediastinal nodal involvement, the role of platinum-based doublet chemotherapy in the management of elderly patients with advanced NSCLC, use of maintenance therapy with gemcitabine, and the impact of early introduction of organized palliative care in improving the quality of life of patients with advanced NSCLC. This report provides a brief overview of the presentations related to lung cancer that are relevant to clinical practice and future research.

Background/Aims. Topotecan and docetaxel are active agents in the treatment of various malignant diseases. Both drugs cause dose-limiting hematologic toxicity. This study defines the maximum tolerated dose (MTD) and dose-limiting toxicity of weekly topotecan when administered in combination with docetaxel 25 mg/m2 given day 1, 8,15 every 28 days. Methods. Thirteen patients were enrolled. Median age was 62 years. Majority of the patients had lung cancer. Results. The maximum tolerated dose was docetaxel 25 mg/m2 and topotecan 3 mg/m2 administered weekly. Dose-limiting toxicity was febrile neutropenia. Eight patients developed at least grade 3 neutropenia in all cycles. Non-hematologic toxicities were mild. No objective responses were noted. Two patients with non-small cell lung cancer had stable disease as a best response. Conclusion. Combination docetaxel and topotecan given weekly is tolerable. The recommended phase II dose is docetaxel 25 mg/m2 and topotecan 3 mg/m2 day 1, 8, 15 every 28 days.

Purpose To evaluate the efficacy of maintenance sunitinib after chemotherapy for small-cell lung cancer (SCLC). Patients and Methods The Cancer and Leukemia Group B 30504 trial was a randomized, placebo-controlled, phase II study that enrolled patients before chemotherapy (cisplatin 80 mg/m2 or carboplatin area under the curve of 5 on day 1 plus etoposide 100 mg/m2 per day on days 1 to 3 every 21 days for four to six cycles). Patients without progression were randomly assigned 1:1 to placebo or sunitinib 37.5 mg per day until progression. Cross-over after progression was allowed. The primary end point was progression-free survival (PFS) from random assignment for maintenance placebo versus sunitinib using a one-sided log-rank test with α = .15; 80 randomly assigned patients provided 89% power to detect a hazard ratio (HR) of 1.67. Results One hundred forty-four patients were enrolled; 138 patients received chemotherapy. Ninety-five patients were randomly assigned; 10 patients did not receive maintenance therapy (five on each arm). Eighty-five patients received maintenance therapy (placebo, n = 41; sunitinib, n = 44). Grade 3 adverse events with more than 5% incidence were fatigue (19%), decreased neutrophils (14%), decreased leukocytes (7%), and decreased platelets (7%) for sunitinib and fatigue (10%) for placebo; grade 4 adverse events were GI hemorrhage (n = 1) and pancreatitis, hypocalcemia, and elevated lipase (n = 1; all in same patient) for sunitinib and thrombocytopenia (n = 1) and hypernatremia (n = 1) for placebo. Median PFS on maintenance was 2.1 months for placebo and 3.7 months for sunitinib (HR, 1.62; 70% CI, 1.27 to 2.08; 95% CI, 1.02 to 2.60; one-sided P = .02). Median overall survival from random assignment was 6.9 months for placebo and 9.0 months for sunitinib (HR, 1.28; 95% CI, 0.79 to 2.10; one-sided P = .16). Three sunitinib and no placebo patients achieved complete response during maintenance. Ten (77%) of 13 patients evaluable after cross-over had stable disease on sunitinib (6 to 27 weeks). Conclusion Maintenance sunitinib was safe and improved PFS in extensive-stage SCLC.

Purpose To investigate the impact of modern postoperative radiotherapy (PORT) on overall survival (OS) for patients with N2 non–small-cell lung cancer (NSCLC) treated nationally with surgery and adjuvant chemotherapy. Patients and Methods Patients with pathologic N2 NSCLC who underwent complete resection and adjuvant chemotherapy from 2006 to 2010 were identified from the National Cancer Data Base and stratified by use of PORT (≥ 45 Gy). A total of 4,483 patients were identified (PORT, n = 1,850; no PORT, n = 2,633). The impact of patient and treatment variables on OS was explored using Cox regression. Results Median follow-up time was 22 months. On univariable analysis, improved OS correlated with younger age, treatment at an academic facility, female sex, urban population, higher income, lower Charlson comorbidity score, smaller tumor size, multiagent chemotherapy, resection with at least a lobectomy, and PORT. On multivariable analysis, improved OS remained independently predicted by younger age, female sex, urban population, lower Charlson score, smaller tumor size, multiagent chemotherapy, resection with at least a lobectomy, and PORT (hazard ratio, 0.886; 95% CI, 0.798 to 0.988). Use of PORT was associated with an increase in median and 5-year OS compared with no PORT (median OS, 45.2 v 40.7 months, respectively; 5-year OS, 39.3% [95% CI, 35.4% to 43.5%] v 34.8% [95% CI, 31.6% to 38.3%], respectively; P = .014). Conclusion For patients with N2 NSCLC after complete resection and adjuvant chemotherapy, modern PORT seems to confer an additional OS advantage beyond that achieved with adjuvant chemotherapy alone.

2553 Background: MLN8237 is a potent Aurora A kinase inhibitor which synergizes with paclitaxel in preclinical studies for various solid malignancies. Methods: We conducted a two-part, phase 1 study combining MLN8237 with nab-paclitaxel in patient with advanced, refractory solid malignancies (NCT01677559). The part 1, dose-escalation phase utilizes a standard a 3+3 design for determination of maximum tolerated dose (MTD) and dose limiting toxicities (DLTs), starting from nab-Paclitaxel 100mg/m2/week 3 out of a 4-week cycle, and MLN8237 20mg BID D1-3/week (denoted nP/M 100/20). In the part 2, dose-expansion cohort, patients with advanced pancreatic ductal adenocarcinoma (PDAC) or high grade neuroendocrine tumor (pNET) who progressed on standard chemotherapy were enrolled. Results: Totally 33 patients (17 in part 1 and 16 in part 2) with a median age of 61 were enrolled. In part 1, the most frequent treatment-related toxicities (all Grade/Grade 3-4) were: nausea (65%/6%), neutropenia (61%/18%), fatigue (47%/6%), anorexia (47%/0%), oral mucositis (53%/6%) and anemia (35%/18%). Two of 3 patients experienced a DLT at dose nP/M 100/50 (Grade 4 neutropenia; febrile neutropenia). No treatment-related mortality occurred. MTD was set at nP/M 100/40 for part 2. At data cutoff, totally 20 patients from the entire study were evaluable for treatment response. One patient with small cell lung cancer achieved partial response and is in cycle 29. Nine other patients (9/20, 45%) with the following tumor histology achieved stable disease after two cycles: 1 small cell lung cancer, 1 lung neuroendocrine carcinoma, 1 lung squamous cell carcinoma, 1 PDAC and 5 high grade pNET (range: 3 and ongoing ~ 18 cycles). Conclusions: MLN8237 plus nab-paclitaxel has manageable side effect profile with very promising activity in tumors with high grade neuroendocrine features, warranting further testing. Exploratory studies on pharmacodynamic markers are ongoing. Clinical trial information: NCT01677559.

This study aimed to determine the maximum-tolerated dose and dose-limiting toxicities of pegylated liposomal doxorubicin (PLD) in combination with temsirolimus (T) in patients with refractory solid tumors. Using a standard “3+3” dose escalation design, 23 patients were enrolled in three dosing cohorts in this phase I study. The starting dose level was PLD at 30 mg/m2 every 4 weeks and T at 20 mg weekly. Pharmacokinetics (PK) of doxorubicin were evaluated for patients in the expansion cohort. The most common treatment-related adverse events of all grades were mucositis/stomatitis (69.6 %), anorexia (52.2 %), thrombocytopenia (52.2 %), and fatigue (47.8 %). The recommended doses of this combination for phase II studies are 25 mg/m2 PLD and 25 mg T. PK analyses suggested increased exposure of doxorubicin in this combination regimen compared to doxorubicin administered as a single agent, possibly due to PK drug interactions. Out of 18 patients evaluable for a treatment response, two had partial responses (PR) (breast cancer and hepatocellular carcinoma) and six had stable disease (SD). Two patients remained on treatment for more than 1 year. The combination of PLD and T is tolerable, and the treatment resulted in clinical benefit. The combination regimen should be further explored in appropriate tumor types. Electronic supplementary material The online version of this article (doi:10.1007/s00280-014-2493-x) contains supplementary material, which is available to authorized users.

Introduction: Despite recent advances in treatment, lung cancer remains the leading cause of cancer-related mortality in the United States. Therefore, there is a strong need for developing clinical trials in lung cancer therapeutics. Only a small fraction of patients with lung cancer are enrolled in clinical trials. It is critical to understand the barriers to participation in lung cancer clinical trials. Methods: We reviewed the outpatient charts of consecutive patients with non-small cell lung cancer who presented for initial evaluation or consultation for further therapeutic management to the thoracic medical oncology group at the Alvin J. Siteman Cancer Center between January 1, 2006, and December 31, 2006. Available and appropriate clinical trials specific to the histologic subtype and stage were presented to the patients routinely, and reasons for nonenrollment were documented. We collected information on age, gender, ethnicity, histology, stage, performance status (PS), and insurance status. Results: During the study period, 263 patients with non-small cell lung cancer were identified for the study. After initial screening, 183 patients had clinical trials available, which were appropriate for their diagnosis and stage of disease. One hundred one patients (55.2%) were ineligible for enrollment in a clinical trial. The most common reasons for ineligibility were poor PS (18%), need for emergent radiation (12%), lack of adequate staging information (6%), and comorbid conditions (4.9%). Despite being eligible for participation, 57 patients (31.1%) did not enroll in a clinical trial. Patient refusal accounted for 8.7%. The problems with transportation and distance from the medical center were reasons given for nonparticipation by 7.1%. Eleven patients (6%) did not participate in a clinical trial because of insurance issues. Ultimately, 25 patients (13.7%) were enrolled in a clinical trial. Conclusions: Poor PS, the need for emergent radiation, and patient refusal were the most common reasons for not participating in a clinical trial.

BackgroundThe median age of patients with newly diagnosed non-small cell lung cancer (NSCLC) at presentation is 71 years. We conducted an analysis of Surveillance, Epidemiology, and End Results data to assess whether the presentation and outcomes of NSCLC in younger patients (age ≤40 years) are different from that in older patients (age >40 years).MethodsWe obtained the demographic, clinical, and outcomes data for all patients diagnosed with NSCLC from 1988 to 2003 in the Surveillance, Epidemiology, and End Results registry. Patients were grouped by age at diagnosis into younger than or equal to 40 years (younger cohort) or older than 40 years (older cohort).ResultsDuring the period analyzed, we identified 2775 patients with NSCLC in the younger cohort and 236,313 patients in the older cohort. Compared with the older group, the younger group had greater proportion of African Americans (19.2% versus 10.9%; p < 0.0001), Asian or Pacific Islander (10.3% versus 5.9%; p < 0.0001), women (48.7% versus 41.9%; p < 0.0001), and patients with stage IV disease (57.4% versus 43.0%; p < 0.0001). Adenocarcinoma was more common in younger patients than in the older patients (57.5% versus 45.2%; p < 0.0001). Squamous cell carcinoma was less prevalent in the younger cohort than in older cohort (12.5% versus 26.4%; p < 0.0001). Five-year overall survival and cancer specific survival were significantly better for younger patients than for older patients across all stages.ConclusionsThere is a greater representation of African Americans, Asians or Pacific Islanders, women, and adenocarcinoma histology in the younger cohort of patients with NSCLC compared with the older cohort. Despite presenting with stage IV disease more often, the overall and cancer-specific survivals are better in younger cohort than in the older cohort.

Background: Preclinical studies have shown synergism between topoisomerase I and II inhibitors. Methods: We conducted a phase I study evaluating the combination of pegylated liposomal doxorubicin and irinotecan in patients with previously treated solid tumors. Results: Twelve patients were enrolled. The median age was 62 years (range 19–72). The most common grade 3/4 toxicities were neutropenia (dose-limiting toxicity), diarrhea and nausea/vomiting. The maximal tolerated dose and recommended schedule were pegylated liposomal doxorubicin 20 mg/m2 over 60 min on day 1, followed by irinotecan 100 mg/m2 over 90 min on days 1 and 8 of a 21-day cycle. There were no objective clinical responses, but 5 patients achieved stable disease lasting a median of 11 weeks duration (range 2–35). Conclusions: This regimen should be further studied in patients with tumors known to have a sensitivity to both topoisomerase I and II inhibitors such as ovarian and small cell carcinoma.

Purpose To estimate the efficacy of third-generation (3G) chemotherapy agents (paclitaxel, docetaxel, gemcitabine, vinorelbine, and irinotecan) on response and survival in stage IIIB/IV non-small cell lung cancer (NSCLC). Methods A meta-analysis was performed using trials identified through MEDLINE. Results on tumor response and survival were collected from randomized trials comparing 3G monotherapy versus best supportive care (BSC), 3G monotherapy versus second-generation (2G) platinum-based regimens, and 3G platinum-based regimens versus 2G platinum-based regimens. Results Of the 2480 citations screened, 20 randomized controlled trials fulfilled the inclusion and exclusion criteria, and 19 trials were used in the analyses. The data from two, three-arm trials were used in two different comparisons. Five trials ( n = 1029 patients) compared 3G monotherapy with BSC. The summary risk difference (RD) for 1-year survival favored 3G agents by 7% (95% confidence interval [CI]: 2%, 12%). Four trials ( n = 871 patients) compared treatment with 3G monotherapy versus 2G platinum-based regimens. The response RD was −6% (95% CI: −11%, 0%), and the 1-year survival rate RD was 3% (95% CI: −3%, 10%), suggesting that despite a slightly higher response rate for 2G platinum-based regimens relative to 3G monotherapy, there is equivalency in survival. Twelve trials ( n = 3995) compared 3G versus 2G platinum-based regimens. The RD for response was 12% (95% CI: 10%, 15%). A RD for 1-year was not calculated, because of heterogeneity among the trials. A subset analysis of 3G versus 2G platinum-based doublets revealed a 1-year survival-rate RD of 6% (95% CI: 2%, 10%), favoring 3G platinum-based regimens without evidence of heterogeneity. Conclusions 3G agents have been a significant advance in the treatment of NSCLC.

To the EditorSeveral randomized trials utilizing platinum baseddoublet regimens have shown a survival benefit foradjuvant chemotherapy for non-small cell lungcancer (NSCLC) [1 5]. Adjuvant chemotherapy isincreasingly used in the USA following the publica-tions of the above mentioned studies. To our knowl-edge, there have been no reports on delivery andtoxicity of adjuvant chemotherapy for NSCLC out-side the clinical trial setting. We performed an auditof all patients with NSCLC who underwent surgicalresection and received adjuvant chemotherapy atWashington University School of Medicine betweenJanuary 2003 and December 2005. A total of 40patients were identified to have received adjuvantchemotherapy for NSCLC. The median age in thisgroup was 57 years (range 40 73). The majority ofpatients (68%) were Caucasian with African Amer-icans representing 27% of the population. Men andwomen were represented in equal proportions. Over90% of the patients had a favorable (0 1) Adultcomorbidity evaluation score-27 (ACE-27) at thetime of surgery. The median time from surgery tothe start of cycle 1 of chemotherapy was 49 (range16 118) days. Cisplatin with docetaxel was the mostfrequently used (43%) adjuvant chemotherapy regi-men during the study period followed by carboplatinand paclitaxel (17%), carboplatin and docetaxel(17%), and carboplatin and gemcitabine (15%).Of the 40 patients, 16 (40%) had received theintended dose (all the scheduled cycles without anydose modifications or delays). Seven patients (18%)did not receive the planned cycles of chemotherapywhile 21 (53%) patients had dose reductions and3 (8%) had dose delays (Table I). Adjuvant therapywas discontinued without completion of the sched-uled number of cycles due to toxicities in 6 (15%).Seventeen patients (42%) reported grade 3/4 toxi-cities, most commonly neutropenia and fatigue.Neutropenic fever occurred in two patients. Therewere no deaths resulting from adjuvant chemo-therapy.Most of the current data regarding delivery andtolerability of adjuvant chemotherapy for NSCLCare obtained from prospective studies [4,6 9] cis-platin and docetaxel, 11 (65%) received full doses ofchemotherapy without dose reduction, delays oromission. Grade 3/4 neutropenia in our studyoccurred in 25% of the patients as opposed to 36%in the CALGB 9633 trial, 17.5% (grade 4 alone) inthe IALT trial and 85% in the ANITA trial [2,4,7].This report provides the first ‘‘real life’’ experienceregarding the chemotherapy delivery and toxicity inpatients with resected non-small cell lung canceroutside the context of clinical trials.

Background: Preclinical studies have shown that binding of PPAR-γ (polysome-proliferator activated receptor gamma) and retinoid-X receptor (RXR) to their ligands can slow growth and promote differentiation of malignant cells. Rosiglitazone, a PPAR-γ ligand, is approved for treatment of insulin-resistant diabetes, and bexarotene, a RXR ligand, is approved for treatment of cutaneous T-cell lymphoma. After binding to its ligand, the PPAR-γ receptor heterodimerizes with the RXR resulting in synergistic effects in preclinical models. We conducted a phase I study of bexarotene and rosiglitazone to define the MTD of rosiglitazone in this combination regimen. Methods: Patients with resistant solid tumors received bexarotene 300 mg/m2/day. The starting dose of rosiglitazone was 4 mg/day and was escalated in five cohorts by 2-mg increments up to 12 mg/day. Both drugs were continued until disease progression or toxicity was observed. Patients received atorvastatin 10 mg/day to control bexarotene-related hypertriglyceridemia. Results: Twenty-three patients were enrolled, with a median of 4 prior regimens (range 0–8). The study was closed after completing the 12 mg/day cohort without encountering dose-limiting toxicity. The most common grade 3 or 4 toxicities were hypertriglyceridemia (17%), dyspnea (9%), nausea (9%), and dehydration (9%). No objective responses were observed. Conclusions: The combination of bexarotene (300 mg/m2/day) and rosiglitazone (12 mg/day) is safe and feasible but did not result in objective responses in heavily pretreated patients with solid tumors. This combination is suitable for evaluation in other conditions such as hematologic malignancies and inflammatory diseases.

7520 Background: Adjuvant chemotherapy (CT) improves overall survival (OS) in patients with completely resected stage II and III non-small cell lung cancer (NSCLC). However, its role in patients with stage IB disease remains unclear. We therefore evaluated the role of adjuvant CT in patients with completely resected T2N0M0 NSCLC. Methods: Patients with pathologic stage T2N0M0 NSCLC who underwent complete (R0) resection from 2003 to 2010 were identified from the National Cancer Database (NCDB). Patients were grouped based on tumor size: 3-3.9 cm, 4-4.9 cm, 5-5.9 cm and 6-7 cm. Survival curves according to the CT status were estimated by the Kaplan-Meier product-limit method and compared by log-rank test. Cox proportional hazard model was used to evaluate whether adjuvant CT was an independent predictor for survival for each tumor size groups. Results: Among the 29,908 patients meeting inclusion criteria, there were 5,209 (17.4%) and 24,699 (82.6%) patients in the CT and observation groups respectively. Pat...

Background: We conducted a single-arm, dose-escalation, phase 1 clinical trial in order to define the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of bexarotene in combination with docetaxel. Methods: Patients with solid tumors and no other curative treatment options were eligible. Oral bexarotene was taken daily in combination with docetaxel 25 mg/m2 administered intravenously on days 1, 8, and 15 of a 28-day cycle. The dose of bexarotene started at 200 mg/m2 and increased by 100 mg/m2/dose level, until either a MTD or the final dose of 400 mg/m2 was reached. Results:Fifteen patients were enrolled in the study. Median age was 58 years. The majority had non-small-cell lung cancer. The study went to completion without reaching an MTD. Hematological toxicities were mild. Three patients developed grade 3 hypertriglyceridemia, all occurring during the first cycle of treatment. No objective responses were noted. Four patients had stable disease as a best response, 3 with non-small-cell lung cancer and 1 with angiosarcoma. Conclusions:Treatment was well tolerated and no DLT was seen at docetaxel 25 mg/m2 and bexarotene 400 mg/m2. Given that stable disease was durable in 4 patients, future studies with this combination may be warranted.

Background: The optimal schedule of taxane administration has been an area of active interest in several recent clinical trials. Methods: To address a pure schedule question, we randomized 161 patients with advanced stage IIIB or IV non-small-cell lung cancer (NSCLC) to either paclitaxel 225 mg/m2 every 3 weeks × 4 cycles or 75 mg/m2/week × 12 (cumulative dose on each arm = 900 mg/m2). Both arms received concurrent carboplatin AUC 6 every 3 weeks × 4 cycles. Results: The two arms were well-balanced in terms of known prognostic factors. The overall response rate and survival outcomes were similar on the two arms. There was significantly more grade 3/4 thrombocytopenia and grade 2–4 anemia on the weekly arm but less severe myalgias/arthralgias and alopecia. No difference in the rates of peripheral neuropathy was observed; however, patients on the every 3 weeks arm reported significantly more taxane therapy-related side-effects on the functional assessment of cancer therapy taxane subscale. Conclusions: This randomized trial exploring schedule-related issues with carboplatin/paclitaxel confirms the versatility of this regimen.

Advanced, metastatic non-small-cell lung cancer (NSCLC) remains a challenge to oncologists. There is little doubt that platinum-based combination chemotherapy improves survival and has a palliative effect by improved patients' symptoms and quality of life. Yet chemotherapy is not curative, is associated with toxicity, and can be costly. In most recent phase III trials, the median survival time is 8 to 10 months. Therefore, the optimal duration of therapy-one that balances survival and palliative effects against toxicity, cost, and intrusiveness on patients' lives-remains an important issue. Three recent randomized trials that addressed this in stage IIIB/IV NSCLC are reviewed. Two evaluated brief durations of first-line therapy (3 cycles in one, 4 in the other) versus longer-duration therapy (6 cycles and continuous therapy, respectively). No benefit in response rate, symptom relief, quality of life, or survival was noted for the longer-duration therapy. In addition, cumulative toxicities occurred more frequently in patients who received longer treatment durations. The third trial administered 4 cycles of first-line platinum-based therapy and then randomized responding patients to observation or 6 months of further therapy with vinorelbine. No survival benefit was noted for vinorelbine. There trials suggest that duration of first-line therapy in advanced, metastatic NSCLC should be brief (3 to 4 cycles). Prolonged therapy does not appear to improve survival and carries the risk of cumulative toxicity. Second-line therapy considered in those patients fit enough to receive it at the time of disease progression.

Switch Maintenance With Sunitinib (S) in Advanced Non-Small Cell Lung Cancer (NSCLC): An Alliance (CALGB 30607), Randomized, Placebo-Controlled Phase 3 Trial Metastatic Non-Small Cell Lung Cancer M.A. Socinski, X. Wang, M. Baggstrom, L. Gu, T. Stinchcombe, M. Edelman, S. Baker, H. Mannuel, J. Crawford, and E. Vokes; University of Pittsburgh Cancer Institute, Pittsburgh, PA, Alliance Statistics and Data Center, Durham, NC, Washington University School of Medicine, St Louis, MO, University of North Carolina, Chapel Hill, NC, University of New Mexico Cancer Center, Albuquerque, NM, Virginia Commonwealth University, Richmond, VA, University of Maryland Greenbaum Cancer Center, Baltimore, MD, Duke Cancer Institute, Durham, PA, University of Chicago Medicine and Biological Sciences, Chicago, IL