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Patients with non-small-cell lung cancer, including squamous-cell lung cancer (SqCLC), typically present at an advanced stage. The current treatment landscape, which includes chemotherapy, radiotherapy, surgery, immunotherapy, and targeted agents, is rapidly evolving, including for patients with SqCLC. Prompt molecular and immune biomarker testing can serve to guide optimal treatment choices, and immune biomarker testing is becoming more important for this patient population. In this review we provide an overview of current and emerging practices and technologies for molecular and immune biomarker testing in advanced non-small-cell lung cancer, with a focus on SqCLC. ispartof: CLINICAL LUNG CANCER vol:19 issue:4 pages:331-339 ispartof: location:United States status: published

Background We evaluated maintenance nanoparticle albumin-bound (nab) paclitaxel in the treatment of advanced squamous non–small-cell lung cancer. Patients and Methods Patients with treatment-naive squamous non–small-cell lung cancer received four 21-day cycles of nab-paclitaxel 100 mg/m2 on days 1, 8, 15 plus carboplatin area under the curve 6 on day 1 as induction therapy. Patients without disease progression after induction were randomized 2:1 to maintenance nab-paclitaxel 100 mg/m2 (days 1 and 8 every 21 days) plus best supportive care (BSC) or BSC alone. The primary endpoint was progression-free survival (PFS). Secondary endpoints included safety and overall survival (OS). Results Overall, 420 patients had received induction therapy; 202 (nab-paclitaxel plus BSC, 136; BSC, 66) had received maintenance therapy. Enrollment was discontinued after a preplanned interim futility analysis (patients could remain in the study at the investigator’s discretion). The median PFS was 3.12 months for nab-paclitaxel plus BSC and 2.60 months for BSC; the difference was not statistically significant (hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.61-1.19; P = .36). The median OS (median follow-up, 24.2 months) was 17.18 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.70; 95% CI, 0.48-1.02; nominal P = .07). An updated analysis (median follow-up, 28.4 months) revealed a median OS of 17.61 months for nab-paclitaxel plus BSC and 12.16 months for BSC (HR, 0.68; 95% CI, 0.47-0.98; nominal P = .037). The most frequent grade 3 and 4 treatment-emergent adverse events for the entire study were neutropenia (53.1% [nab-paclitaxel plus BSC] vs. 50.0% [BSC]) and anemia (33.1% [nab-paclitaxel plus BSC] vs. 32.3% [BSC]). Only peripheral neuropathy had occurred in ≥ 5% of patients during maintenance therapy (13.1%; nab-paclitaxel plus BSC). Conclusions The results of the ABOUND.sqm did not meet the primary endpoint of PFS. An updated OS analysis revealed a trend favoring nab-paclitaxel plus BSC.

Background Bavituximab is a phosphatidylserine-targeting antibody with a selective tumor, vascular-directed immune response. In this phase II trial the efficacy and safety of bavituximab combined with docetaxel for previously treated, advanced nonsquamous non–small-cell lung cancer were evaluated. Patients and Methods Patients were randomized 1:1:1 to receive docetaxel 75 mg/m 2 every 21 days for up to 6 cycles combined with weekly, blinded infusions of placebo, bavituximab 1 mg/kg, or bavituximab 3 mg/kg until disease progression or unacceptable toxicity. The primary end point was overall response rate (ORR), with a predefined end point of 26% in the bavituximab arms. After study unblinding, vial-coding discrepancies were discovered in the placebo and bavituximab 1 mg/kg groups. In exploratory analyses, data from these groups were pooled to form the control group and compared with the 3 mg/kg group. Results Efficacy end points in the bavituximab 3 mg/kg group (n = 41) and in the placebo/bavituximab 1 mg/kg group (n = 80), respectively, were as follows: ORR, 17.1% (95% confidence interval [CI], 5.6%-28.6%) and ORR, 11.3% (95% CI, 4.3%-18.2%); median progression-free survival 4.5 and 3.3 months (hazard ratio [HR], 0.74 [95% CI, 0.45-1.21]; P = .24); median overall survival 11.7 and 7.3 months (HR, 0.66 [95% CI, 0.40-1.10]; P = .11). Toxicities were manageable and similar between arms. Conclusion The combination of bavituximab and docetaxel is well tolerated. Although no firm efficacy conclusions can be drawn and the trial did not meet the predefined primary end point, exploratory analyses suggest trends favoring the combination of bavituximab 3 mg/kg with docetaxel. This regimen is being evaluated in the ongoing, global, phase III SUNRISE trial.

Introduction African Americans have a greater incidence of lung cancer than whites and have been underrepresented in clinical trials. In the PointBreak trial (pemetrexed-carboplatin-bevacizumab and maintenance pemetrexed-bevacizumab [PemCBev] vs. paclitaxel-carboplatin-bevacizumab and maintenance bevacizumab [PacCBev]), 10% of the patients were African American. PointBreak had negative findings; PemCBev did not demonstrate superior overall survival (OS). Materials and Methods PointBreak subgroup efficacy and safety data were retrospectively analyzed: African Americans versus whites for PemCBev; PemCBev versus PacCBev in African Americans; and academic versus community settings for African Americans. Hazard ratios (HRs) and P values were derived from a multivariate Cox proportional hazards model after adjusting for covariates. Results Of 939 intent-to-treat (ITT) patients, 94 were African American and 805 were white. African-American enrollment was uniform across the study sites (median, 1 African American per site). In the PemCBev arm, OS (HR, 1.125; P = .525), progression-free survival (PFS) (HR, 1.229; P = .251), response ( P = .607), and toxicity profiles were similar in African Americans versus whites. For African Americans, OS (HR, 1.375; P = .209), PFS (HR, 0.902; P = .670), response ( P = 1.000), and toxicity profiles were similar in the PemCBev versus PacCBev arm. For African Americans, no significant differences were seen in OS (HR, 0.661; P = .191) or PFS (HR, 0.969; P = .915) in academic versus community practice settings. Conclusion In the PemCBev arm, this exploratory analysis showed no significant differences between African Americans and whites for the efficacy outcomes or toxicity profiles. Consistent with the ITT population negative trial result, for African Americans, the median OS was not superior for either arm. For African Americans, PFS and OS were similar in the academic and community settings. Additional outcomes data for African Americans should be collected in lung cancer studies.

The availability of targeted drugs has made the assessment of the EGFR mutation and ALK rearrangement critical in choosing the optimal treatment for patients with advanced non-small-cell lung cancer (NSCLC). In May 2013, the Italian Association of Thoracic Oncology (AIOT) organized an International Experts Panel Meeting to review strengths and limitations of the available evidence for the diagnosis and treatment of advanced NSCLC with EGFR or anaplastic lymphoma kinase (ALK) alterations and to discuss implications for clinical practice and future clinical research. All patients with advanced NSCLC, with the exclusion of pure squamous cell carcinoma in former or current smokers, should be tested for EGFR mutations and ALK rearrangements before decisions are made on first-line treatment. First-line treatment of EGFR-mutated cases should be with an EGFR tyrosine kinase inhibitor (TKI). Any available agent (gefitinib, erlotinib, or afatinib) can be used, until further data from comparative studies may better guide TKI selection. As general rule, and when clinically feasible, results of EGFR mutational status should be awaited before starting first-line treatment. Panelists agreed that the use of crizotinib is justified in any line of treatment. Although solid evidence supporting the continuation of EGFR TKIs or crizotinib beyond progression is lacking, in some cases (minimal, asymptomatic progression, or oligoprogression manageable by local therapy), treatment continuation beyond progression could be justified. Experimental strategies to target tumor heterogeneity and to treat patients after failure of EGFR TKIs or crizotinib are considered high-priority areas of research. A number of relevant research priorities were identified to optimize available treatment options.

Background The combination of necitumumab with gemcitabine-cisplatin significantly improved overall survival (OS) in patients with stage IV squamous non–small-cell lung cancer (NSCLC), in the phase III SQUamous NSCLC treatment with the Inhibitor of EGF REceptor (SQUIRE) trial. Paclitaxel-carboplatin was selected as an alternative standard of care in the current phase II study. Patients and Methods Patients were randomized (stratified according to Eastern Cooperative Oncology Group performance status and sex) 2:1 to ≤ six 3-week cycles (Q3W) of paclitaxel and carboplatin with or without necitumumab. Chemotherapy was paclitaxel 200 mg/m 2 on day 1 Q3W and carboplatin area under the curve 6 on day 1 Q3W. Necitumumab 800 mg, on days 1 and 8, was continued until disease progression or intolerable toxicity occurred. The primary end point was objective response rate (ORR) on the basis of Response Evaluation Criteria In Solid Tumors version 1.1. Results One hundred sixty-seven patients were randomized to the necitumumab-containing arm (n = 110) or the chemotherapy-only arm (n = 57). The combination of necitumumab with chemotherapy resulted in an ORR of 48.9% versus 40.0%. Median progression-free survival and OS were 5.4 versus 5.6 months (hazard ratio [HR], 1.0) and 13.2 versus 11.2 months (HR, 0.83; P = .379) in each treatment arm, respectively. Disease control rate was 87.2% versus 84.0%. Grade ≥ 3 adverse events typically associated with epidermal growth factor receptor (EGFR) monoclonal antibodies showing a > 2% increase were hypomagnesemia (5.7% vs. 0) and rash (2.8% vs. 0). Any Grade thromboembolic events occurred in Conclusion The results of our study support previously reported results that the combination of necitumumab with chemotherapy improves survival in patients with advanced squamous NSCLC and shows a safety profile consistent with that of EGFR monoclonal antibodies.

We present the treatment rationale and study design of the MetLung phase III study. This study will investigate onartuzumab (MetMAb) in combination with erlotinib compared with erlotinib alone, as second- or third-line treatment, in patients with advanced non-small-cell lung cancer (NSCLC) who are Met-positive by immunohistochemistry. Approximately 490 patients (245 per treatment arm) will receive erlotinib (150 mg oral daily) plus onartuzumab or placebo (15 mg/kg intravenous every 3 weeks) until disease progression, unacceptable toxicity, patient or physician decision to discontinue, or death. The efficacy objectives of this study are to compare overall survival (OS) (primary endpoint), progression-free survival, and response rates between the 2 treatment arms. In addition, safety, quality of life, pharmacokinetics, and translational research will be investigated across treatment arms. If the primary objective (OS) is achieved, this study will provide robust results toward an alternative treatment option for patients with Met-positive second- or third-line NSCLC.

Five-day topotecan is approved by the US Federal Drug Administration (FDA) for sensitive relapsed small-cell lung cancer (SCLC). We previously found that 4 mg/m(2) intravenous (I.V.) weekly dosing resulted in low-grade 3/4 toxicity but an overall response rate (ORR)10%. We hypothesized that higher topotecan dosing could improve ORR without significantly increasing toxicity.This multicenter phase II trial sought a 25% ORR (α = 0.04; β = 0.20). Eligible patients (sensitive or refractory relapsed SCLC; Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0-1; measurable disease) received weekly topotecan (6 mg/m(2) I.V. for 6 weeks) and were restaged every 8 weeks.Baseline characteristics were N = 38, enrolled 5/2006-10/2007; median age 64 years (range, 35-82), 47% female, 74% ECOG PS 1, 50% refractory relapsed SCLC. The median follow-up was 15 months (range, 12-24 months). No patients received all planned therapy; only 1 patient was able to receive all planned treatment in cycle 1 because of hematologic toxicity and progressive disease (PD). Among all patients, ORR was 8% (95% confidence interval [CI], 2%-21%), 24% had stable disease, and disease in 47% progressed. Among sensitive relapsed patients ORR was 16% (95% CI, 3%-40%) with no complete responses; median response duration was 3.3 months. Five (26%) patients had stable disease; 8 (42%) patients had PD. Among sensitive relapsed patients, the median time to progression (TTP) and overall survival (OS) was 2.5 months and 8.6 months, respectively. Among refractory relapsed patients there were no ORRs, and median TTP and OS were 1.5 months and 3.7 months, respectively. Grade 3/4 toxicities (10%) included neutropenia (53%), leukopenia (42%), thrombocytopenia (37%), anemia (13%), fatigue (13%), and pain (13%). There were no treatment-related deaths.Weekly topotecan (6 mg/m(2) I.V.) is not feasible because of hematologic toxicity and does not improve efficacy in patients with relapsed SCLC.

Background Targeting 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 Methods Eligibility 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/m 2 I.V. days 1 and 8; gemcitabine 1000 mg/m 2 I.V. days 1 and 8; and cetuximab 400 mg/m 2 I.V. day 1, then 250 mg/m 2 I.V. weekly. Patients received up to 6 cycles with restaging every 6 weeks. The primary endpoint was an overall response rate (ORR) ≥ 25%. Results Sixty-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. Conclusion Cetuximab/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.

PURPOSE This prospective randomized study compared overall survival (OS) in patients with previously untreated advanced non–small-cell lung cancer (NSCLC) when treated with the platinum agent–based triple drug combination of paclitaxel/carboplatin/gemcitabine (PCG) versus the nonplatinum agent–based doublet drug combination of gemcitabine/vinorelbine. PATIENTS AND METHODS Advanced (stages IIIB, IV, and recurrent) chemotherapynaive patients with NSCLC and performance status 0-2 were randomly assigned to the PCG arm (paclitaxel 200 mg/m 2 on day 1, carboplatin area under the concentration-time curve of 5 on day 1, and gemcitabine 1000 mg/ m 2 on days 1 and 8, every 21 days) or to the gemcitabine/vinorelbine arm (gemcitabine 1000 mg/m 2 on days 1, 8, and 15 and vinorelbine 25 mg/m 2 on days 1, 8, and 15, every 28 days). RESULTS A total of 337 patients were randomly assigned to the 2 arms. The median time to progression was 6 months for PCG and 3.9 months for gemcitabine/vinorelbine with 1- and 2-year progression-free survival rates of 13% and 2% versus 14% and 4% ( P = .324 log rank). Median OS for PCG was 10.3 months versus 10.7 months for gemcitabine/vinorelbine with 1-, 2-, and 3-year OS rates of 38%, 12%, and 2% versus 45%, 12%, and 6%, respectively ( P = 0.269 log rank). Grade 3/4 thrombocytopenia, nausea/vomiting, myalgia/arthralgia, and neuropathy were significantly greater in the PCG arm. CONCLUSION There was no difference in OS or progression-free survival when comparing PCG and gemcitabine/vinorelbine, and gemcitabine/vinorelbine was significantly less toxic. Gemcitabine/vinorelbine is a reasonable nonplatinum agent–based doublet therapy for patients with advanced NSCLC.

Lorvotuzumab mertansine (LM, IMGN901) is a CD56-targeting antibody-drug conjugate developed for tumor-selective delivery of the cytotoxic maytansinoid DM1. This phase 1/2 study evaluated the combination of LM with first-line carboplatin/etoposide chemotherapy in patients with extensive-disease small-cell lung cancer. Overall, modest improvements in patient tumor responses did not outweigh the increased safety risks of the triplet combination. Introduction: This trial assessed the safety and efficacy of LM in combination with carboplatin/etoposide therapy compared to carboplatin/etoposide treatment alone in patients with previously untreated extensive-disease small-cell lung cancer (ED-SCLC). Patients and Methods: A run-in phase 1 stage was used to determine the recommended phase 2 dose and characterize the dose-limiting toxicities of LM in combination with carboplatin/etoposide followed by LM alone in patients with CD56-positive solid tumors. In phase 2, chemotherapy-naive ED-SCLC patients were randomized 2:1 to carboplatin AUC (area under the plasma concentration vs. time curve) of 5 day 1 + etoposide 100 mg/m(2) days 1 to 3 plus LM (arm 1) or alone (arm 2). Results: In the phase 1 study (n = 33), a dose of LM at 112 mg/m(2) with carboplatin/etoposide was identified as the recommended phase 2 dose. However, because of an increased incidence of peripheral neuropathy events during early phase 2, this dose was reduced to 90 mg/m(2). In phase 2, a total of 94 and 47 evaluable patients were assigned to arms 1 and 2, respectively. No difference in median progression-free survival was observed between arms 1 and 2 (6.2 vs. 6.7 months). The most common treatment-emergent adverse event leading to discontinuation was peripheral neuropathy (29%). A total of 21 patients had a treatment-emergent adverse event leading to death (18 in arm 1 and 3 in arm 2); for 10 individuals, this was an infection (pneumonia or sepsis) deemed to be related to the study drug. Conclusion: The combination of LM plus carboplatin/etoposide did not improve efficacy over standard carboplatin/etoposide doublet therapy in ED-SCLC patients and showed increased toxicity, including a higher incidence of serious infections with fatal outcomes. (C) 2016 The Authors. Published by Elsevier Inc.

Background This phase II study examined the efficacy of mapatumumab in combination with paclitaxel and carboplatin in patients with non–small-cell lung cancer (NSCLC). Patients and Methods Patients with stage IIIB or stage IV advanced primary NSCLC were randomly assigned (1:1:1) to receive up to 6 courses of standard-dose paclitaxel and carboplatin or a combination of paclitaxel, carboplatin, and mapatumumab (10 mg/kg or 30 mg/kg). Primary efficacy end points were overall response rate and median progression-free survival (PFS). Secondary efficacy end points included disease control rate, overall survival (OS), time to response, and duration of response. Exploratory studies included evaluation of historical biopsy materials for TRAIL-R1 expression by immunohistochemical analysis and serum levels of M30, a marker of apoptosis, before and after the first 2 doses of mapatumumab. Safety parameters, including adverse events (AEs), laboratory tests, and immunogenicity, were assessed. Results The majority of patients had stage IV disease (79%) and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 (58%); baseline characteristics were similar across treatment arms. No improvements in response or disease control rates, PFS, or OS were gained from the addition of mapatumumab. Adverse events in the mapatumumab arms were generally consistent with toxicities seen in the carboplatin and paclitaxel control arm. Levels of M30 were highly variable, and consistent patterns were not seen across treatment arms. Conclusion This study showed no clinical benefit from adding mapatumumab to carboplatin and paclitaxel in unselected patients with NSCLC. The combination was generally well tolerated. The possibility of subgroups sensitive to mapatumumab is discussed.

Background Topotecan is currently the only US Federal Drug Administration (FDA)-approved drug for second-line treatment of relapsed small-cell lung cancer (SCLC). We investigated the efficacy and safety of a novel topotecan-bevacizumab combination in treating relapsed SCLC. Patients and Methods Each 21-day treatment cycle consisted of bevacizumab (15 mg/kg) administration on day 1 and oral topotecan (2.3 mg/m 2 /d) administration on days 1 to 5. Treatment was continued for 8 cycles or until disease progression/toxicity. The primary objective was evaluation of 3-month progression-free survival (PFS). Overall response rate (ORR), duration of response, time to response (TTR), and overall survival (OS) were secondary objectives. Results The study enrolled 50 patients between July 2008 and May 2010. The 3-month PFS was 65% (95% confidence interval [CI], 49.3%-76.9%), which was promising compared with the historical control of 50% ( P = .017) but did not meet the predefined criteria for clinically meaningful improvement. Median PFS was 6.24 months for the sensitive subgroup (progression time from end of previous chemotherapy > 90 days; n=27) and 2.91 months for the resistant subgroup (progression time ≤ 90 days; n=23). No patient achieved complete response (CR), and the ORR was 16%. Twenty (40%) patients had stable disease (SD) and 13 (26%) had progressive disease (PD). Median OS, TTR, and duration of response were 7.4, 1.3, and 4.7 months, respectively. The worst reported adverse events (AEs) were grade 1/2 in 11 (22%) patients and grade 3/4/5 in 39 (78%) patients. Conclusion Improvement in the 3-month PFS after treatment with topotecan-bevacizumab was promising compared with the historical control and justifies additional studies with this regimen.

The taxanes are among the most active cytotoxic agents in oncology and are widely used in adjuvant and advanced treatment settings in multiple tumor types. Paclitaxel and docetaxel are standard therapies in advanced non–small-cell lung cancer (NSCLC) and are increasingly used in earlier treatment settings. The taxanes are generally well tolerated but can be associated with severe, irreversible (and rarely life-threatening) toxicity. Premedication and special infusion sets are necessary to reduce the risk of hypersensitivity reactions. Newer taxanes are in development designed to improve the therapeutic index and ease of administration. Several agents have completed phase I/II clinical trials and are in phase III testing. Many other novel taxanes are at earlier stages of development and appear promising as single agents and in combination regimens. Safer and more effective taxanes could replace paclitaxel and docetaxel as standard treatments in NSCLC.

BACKGROUND This randomized phase II trial evaluated the efficacy and toxicity of oral topotecan compared with intravenous docetaxel in the second-line treatment of patients with non–small-cell lung cancer (NSCLC). PATIENTS AND METHODS Eighty patients were randomized to receive topotecan (2 mg per day or 2.5 mg per day fixed dose for 5 of 7 days for 2 weeks) or docetaxel (75 mg/m 2 ) every 21 days. Thirty-nine patients received 138 cycles of topotecan. RESULTS The overall response rate (RR; ORR) was 8%, median time to progression (TTP) was 1.6 months, median survival was 8.4 months, and the 1- and 2-year survival rates were 36% and 13%, respectively, for patients receiving topotecan. Forty-one patients were randomized, but only 38 patients were actually treated with 136 cycles of docetaxel. The ORR was 8% (7% intent to treat RR), median TTP was 1.4 months, median survival was 7.6 months, and the 1- and 2-year survival rates were 29% and 13%, respectively, for patients receiving docetaxel. CONCLUSION Oral topotecan appears to be active and well tolerated when administered as a fixed dose daily for 5 of every 7 days for 2 weeks every 21 days and might provide another treatment alternative for patients with advanced-stage NSCLC.

BACKGROUND: Patients with advanced non–small-cell lung cancer (NSCLC) and poor performance status (PS) are often excluded from trials. Gefitinib is a safe oral agent that may benefit these patients. PATIENTS AND METHODS: Seventy-two patients with poor PS and advanced NSCLC were enrolled onto this study of gefitinib 250 mg per day given orally until disease progression, with evaluation at 8 weeks. Eligible patients had no previous chemotherapy, an Eastern Cooperative Oncology Group PS of 2/3, and stage IIIB/IV NSCLC. Quality of life (QOL) and symptom response (SR) scores were calculated using the Functional Assessment of Cancer–Lung questionnaire. Patient characteristics included a median age of 75 years; PS of 2/3; and bronchoalveolar (n = 3), adenocarcinoma (n = 29), squamous cell (n = 21), large-cell (n = 11), and unspecified histology (n = 6). Mean treatment duration was 4 months (range, 3 days to 18 months), and median duration of follow-up was 12 months. Grade 3/4 toxicities included rash and diarrhea. RESULTS: Among 70 patients assessed for response, there were 3 partial responses (4%), 32 patients with stable disease (46%), and 18 with progressive disease (26%). Median progression-free survival (PFS) and overall survival (OS) were 3.7 months and 6.3 months, respectively. Six-month and 1-year PFS and OS rates were 35% and 21% and 50% and 24%, respectively. Eighty-two percent and 48% of patients reported improvements or no change in QOL and SR, respectively. CONCLUSION: Gefitinib demonstrates modest efficacy and is well tolerated as initial therapy in advanced NSCLC for patients with poor PS.

Background We previously reported the development of tracheoesophageal (TE) fistulae in patients with small-cell lung cancer (SCLC) treated with chemoradiation and concurrent and sequential bevacizumab (J Clin Oncol 2008; 26(15 suppl):410s [Abstract 7554]). In this phase II trial, we evaluated concurrent chemoradiation and bevacizumab in patients with unresectable stage III non—small-cell lung cancer (NSCLC) and observed similar fistula development. Patients and Methods This was a phase II trial designed to enroll 50 patients, with a primary aim of achieving a 40% improvement in historical 10-month median time to progression (α, .05; β, .20). Patients with newly diagnosed unresectable nonsquamous stage III NSCLC, measurable disease, Eastern Cooperative Oncology Group performance status 0/1, signed informed consent, and no pleural or pericardial effusions were eligible. Hemoptysis or need for anticoagulation were exclusion factors. Treatment was composed of induction, consolidation, and maintenance phases. Induction treatment included carboplatin area under the curve (AUC) = 5 intravenous (I.V.), pemetrexed 500 mg/m2 I.V., and bevacizumab 15 mg/kg I.V. weeks 1 and 4. Radiation was administered concurrently 1.8 Gy per day to 61.2 Gy. After a break in therapy from weeks 8 to 16, consolidative therapy commenced and included carboplatin AUC = 6 I.V., pemetrexed 500 mg/m2 I.V., and bevacizumab 15 mg/kg I.V. weeks 16, 19, and 22. Maintenance therapy was composed of bevacizumab 15 mg/kg every 3 weeks for 9 cycles. Patients were restaged after induction and consolidation phases (per Response Evaluation Criteria in Solid Tumors). Results Enrollment was staggered in groups of 5 for safety monitoring beginning in February 2007. Among the first 5 patients, 2 patients developed TE fistulae. Patient 1 developed a TE fistula 34 weeks into therapy (during the fourth maintenance bevacizumab and 26 weeks after chemoradiation). Patient 2 developed a TE fistula 40 weeks into therapy (during the sixth maintenance bevacizumab and 32 weeks after chemoradiation). Both patients experienced antecedent severe esophagitis. Both patients were managed with stents and are alive. The other 3 patients have not developed TE fistulae to date and are alive. The trial was subsequently closed for safety in December 2007. Conclusion TE fistula development has occurred in both SCLC and NSCLC trials where chemotherapy, bevacizumab, and radiation were administered. Strategies to safely incorporate novel therapies into standard chemoradiation lung cancer regimens are needed.

Background Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, provides benefit in advanced non—smallcell lung cancer (NSCLC), prolonging progression-free and overall survival. Observational cohort studies such as ARIES (“Avastin® Regimens: Investigation of Treatment Effects and Safety”) provide valuable safety and effectiveness data for a broader patient population than controlled trials, such as Eastern Cooperative Oncology Group (ECOG) 4599, which have strict eligibility criteria required for study participation. The ARIES study objective is to further delineate clinical outcomes associated with bevacizumab use in a real-world setting in patients with advanced NSCLC. Patients and Methods Patients with locally advanced/metastatic nonsquamous NSCLC, whose first therapy includes bevacizumab, may enroll. There are no protocol-specified treatments or assessments. Data are collected at baseline, then quarterly, including targeted safety events, until death, consent withdrawal, loss to follow-up, or study closure. ARIES is conducted at 276 US sites. Planned NSCLC accrual is 2000 patients. Results As of February 14, 2008, 996 evaluable patients with NSCLC have been enrolled. Median follow-up is 6.1 months; 84% of patients have ≥ 1 quarterly update. Key demographics are shown in Table 1. Targeted serious adverse events (SAEs) to date include venous thromboembolic events and other events, 2%; grade 3/4 bleeding and arterial thromboembolic events, 1% each; gastrointestinal perforation, reversible posterior leukoencephalopathy syndrome, pulmonary hemorrhage, hypertension, and wound complications, Conclusion Low rates of targeted SAEs were preliminarily observed despite the inclusion of patients underrepresented in E4599, including those with ECOG performance status ≥ 2, brain metastasis, therapeutic anticoagulation at baseline, and older age. Updated safety data, treatment patterns (with bevacizumab dose and duration), and demographics will be provided at the meeting, based on > 1300 patients.