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Introduction: We characterized the safety of first-line nivolumab plus ipilimumab (NIVO+IPI) in a large patient population with metastatic NSCLC and efficacy outcomes after NIVO+IPI discontinuation owing to treatment-related adverse events (TRAEs)., Methods: We pooled data from three first-line NIVO+IPI studies (NIVO, 3 mg/kg or 240 mg every 2 wk; IPI, 1 mg/kg every 6 wk) in metastatic NSCLC (CheckMate 227 part 1, CheckMate 817 cohort A, CheckMate 568 part 1). Safety end points included TRAEs and immune-mediated adverse events (IMAEs) in the pooled population and patients aged 75 years or older., Results: In the pooled population (N = 1255), any-grade TRAEs occurred in 78% of the patients, grade 3 or 4 TRAEs in 34%, and discontinuation of any regimen component owing to TRAEs in 21%. The most frequent TRAE and IMAE were diarrhea (20%; grade 3 or 4, 2%) and rash (17%; grade 3 or 4, 3%), respectively. The most common grade 3 or 4 IMAEs were hepatitis (5%) and diarrhea/colitis and pneumonitis (4% each). Pneumonitis was the most common cause of treatment-related death (5 of 16). Safety in patients aged 75 years or older (n = 174) was generally similar to the overall population, but discontinuation of any regimen component owing to TRAEs was more common (29%). In patients discontinuing NIVO+IPI owing to TRAEs (n = 225), 3-year overall survival was 50% (95% confidence interval: 42.6-56.0), and 42% (31.2-52.4) of 130 responders remained in response 2 years after discontinuation., Conclusions: First-line NIVO+IPI was well tolerated in this large population with metastatic NSCLC and in patients aged 75 years or older. Discontinuation owing to TRAEs did not reduce long-term survival., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: IMpower110 previously revealed significant overall survival (OS) benefit with atezolizumab versus chemotherapy in patients with treatment-naive EGFR- and ALK-negative (wild type [WT]) metastatic NSCLC with high programmed death-ligand 1 (PD-L1) expression (≥50% on tumor cells [TCs] or ≥10% on tumor-infiltrating immune cells [ICs], per SP142 immunohistochemistry assay; p = 0.0106). We present primary OS analyses in lower PD-L1 expression groups and an updated, exploratory analysis in the high PD-L1 expression group., Methods: This open-label, phase 3 trial randomized patients with PD-L1 expression on greater than or equal to 1% of TC or IC to receive atezolizumab or platinum-based chemotherapy. The primary end point was OS, hierarchically tested in PD-L1 expression WT subgroups: first the high PD-L1 expression subgroup, then the high-or-intermediate PD-L1 expression subgroup (≥5% on TC or IC), and then the any PD-L1 expression subgroup (≥1% on TC or IC)., Results: The any PD-L1 expression WT population included 554 patients (excluded 18 EGFR- or ALK-positive patients). With 17 months' additional follow-up, OS improvement in the atezolizumab versus chemotherapy arm was not statistically significant in high-or-intermediate PD-L1 expression WT patients (n = 328; hazard ratio = 0.87, 95% confidence interval: 0.66-1.14, p = 0.3091; median = 19.9 versus 16.1 mo), precluding formal OS testing in any PD-L1 expression WT patients. Exploratory analysis in high PD-L1 expression WT patients (n = 205) revealed maintained OS benefit in the atezolizumab arm (hazard ratio = 0.76, 95% confidence interval: 0.54-1.09; median = 20.2 versus 14.7 mo). Updated safety data continued to favor atezolizumab., Conclusions: Statistical significance for OS was not revealed in the high-or-intermediate expression WT group, and, as a result, OS in the any PD-L1 expression WT group was not formally tested. No new safety signals were found. This updated analysis of IMpower110 supports using atezolizumab in treatment-naive, metastatic WT NSCLC with high PD-L1 expression., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: In the JAVELIN Lung 200 trial, avelumab (anti-programmed death-ligand 1 [PD-L1] antibody) did not significantly prolong overall survival (OS) versus docetaxel in patients with platinum-treated PD-L1+ NSCLC. We report greater than 2-year follow-up data., Methods: Patients with stage IIIB or IV or recurrent NSCLC with disease progression after platinum-doublet chemotherapy were randomized 1:1 to avelumab 10 mg/kg every 2 weeks or docetaxel 75 mg/m 2 every 3 weeks. The primary end point was OS in patients with PD-L1+ tumors (greater than or equal to 1% tumor cell expression; IHC 73-10 pharmDx assay)., Results: Of 792 patients, 529 had PD-L1+ tumors (264 versus 265 in the avelumab versus docetaxel arms, respectively). As of March 4, 2019, median duration of follow-up for OS in the PD-L1+ population was 35.4 months in the avelumab arm and 34.7 months in the docetaxel arm; study treatment was ongoing in 25 (9.5%) versus 0 patients, respectively. In the PD-L1+ population, 2-year OS rates (95% confidence interval [CI]) with avelumab versus docetaxel were 29.9% (24.5%-35.5%) versus 20.5% (15.6%-25.8%); in greater than or equal to 50% PD-L1+ subgroups, 2-year OS rates were 36.4% (29.1%-43.7%) versus 17.7% (11.8%-24.7%) and in the greater than or equal to 80% subgroup were 40.2% (31.3%-49.0%) versus 20.3% (12.9%-28.8%), respectively. Median duration of response (investigator assessed) was 19.1 months (95% CI: 10.8-34.8) versus 5.7 months (95% CI: 4.1-8.3). Safety profiles for both arms were consistent with the primary analysis., Conclusions: Although the JAVELIN Lung 200 primary analysis (reported previously) revealed that avelumab did not significantly prolong OS versus docetaxel in patients with platinum-treated PD-L1+ NSCLC, posthoc analyses at 2 years of follow-up revealed that 2-year OS rates were doubled with avelumab in subgroups with higher PD-L1 expression (greater than or equal to 50% and greater than or equal to 80%)., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: In the Phase 3, placebo-controlled PACIFIC trial of patients with unresectable, stage III NSCLC without disease progression after concurrent chemoradiotherapy, consolidative durvalumab was associated with significant improvements in the primary end points of overall survival (OS) (hazard ratio [HR] = 0.68; 95% confidence interval [CI]: 0.53-0.87; p = 0.00251; data cutoff, March 22, 2018) and progression-free survival (PFS) (blinded independent central review; Response Evaluation Criteria in Solid Tumors version 1.1) (HR = 0.52; 95% CI: 0.42-65; p < 0.0001; February 13, 2017) with manageable safety. Here, we report updated analyses of OS and PFS, approximately 4 years after the last patient was randomized., Methods: Patients with WHO performance status of 0 or 1 (and any tumor programmed death-ligand 1 status) were randomized (2:1) to intravenous durvalumab (10 mg/kg) or placebo, administered every 2 weeks (≤12 months), stratified by age, sex, and smoking history. OS and PFS were analyzed using a stratified log-rank test in the intent-to-treat population. Medians and 4-year OS and PFS rates were estimated by the Kaplan-Meier method., Results: Overall, 709 of 713 randomized patients received durvalumab (n/N=473/476) or placebo (n/N=236/237). As of March 20, 2020 (median follow-up = 34.2 months; range: 0.2-64.9), updated OS (HR = 0.71; 95% CI: 0.57-0.88) and PFS (HR = 0.55; 95% CI: 0.44-0.67) remained consistent with the primary analyses. The median OS for durvalumab was reached (47.5 mo; placebo, 29.1 months). Estimated 4-year OS rates were 49.6% versus 36.3% for durvalumab versus placebo, and 4-year PFS rates were 35.3% versus 19.5% respectively., Conclusion: These updated exploratory analyses demonstrate durable PFS and sustained OS benefit with durvalumab after chemoradiotherapy. An estimated 49.6% of patients randomized to durvalumab remain alive at 4 years (placebo, 36.3%), and 35.3% remain alive and progression-free (placebo, 19.5%)., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Checkpoint inhibitors (CPIs) have been approved to treat metastatic NSCLC. Pegilodecakin + CPI suggested promising efficacy in phase 1 IVY, providing rationale for randomized phase 2 trials CYPRESS 1 and CYPRESS 2., Methods: CYPRESS 1 (N = 101) and CYPRESS 2 (N = 52) included Eastern Cooperative Oncology Group performance status of 0 to 1 and first-line/second-line metastatic NSCLC, respectively, without known EGFR/ALK mutations. Patients were randomized 1:1; control arms received pembrolizumab (CYPRESS 1) or nivolumab (CYPRESS 2); experimental arms received pegilodecakin + CPI. Patients had programmed death-ligand 1 tumor proportion score of greater than or equal to 50% (CYPRESS 1) or 0% to 49% (CYPRESS 2). Primary end point was objective response rate (ORR) per investigator. Secondary end points included progression-free survival (PFS), overall survival (OS), and safety. Exploratory end points included immune activation biomarkers., Results: Median follow-up for CYPRESS 1 and CYPRESS 2 was 10.0 and 11.6 months, respectively. Results for pegilodecakin + pembrolizumab versus pembrolizumab were as follows: ORR per investigator 47% versus 44% (OR = 1.1, 95% confidence interval [CI]: 0.5-2.5); median PFS 6.3 versus 6.1 months (hazard ratio [HR] = 0.937, 95% CI: 0.54-1.625); and median OS 16.3 months versus not reached (HR = 1.507, 95% CI: 0.708-3.209). Results per blinded independent central review were consistent. Treatment discontinuation rate owing to adverse events (AEs) doubled in the experimental arm (32% versus 15%). AEs with grade greater than or equal to 3 treatment-related AEs (62% versus 19%) included anemia (20% versus 0%) and thrombocytopenia (12% versus 2%). Results for pegilodecakin + nivolumab versus nivolumab were as follows: ORR per investigator 15% versus 12% (OR = 1.2, 95% CI: 0.3-5.9); median PFS 1.9 versus 1.9 months (HR = 1.006, 95% CI: 0.519-1.951); and median OS 6.7 versus 10.7 months (HR = 1.871, 95% CI: 0.772-4.532). AEs with grade greater than or equal to 3 treatment-related AEs (70.4% versus 16.7%) included anemia (40.7% versus 0%), fatigue (18% versus 0%), and thrombocytopenia (14.8% versus 0%). Biomarker data suggested activation of immunostimulatory signals of interleukin-10R pathway in pegilodecakin-containing arms., Conclusions: Despite evidence of biological effect in peripheral blood, adding pegilodecakin to CPI did not improve ORR, PFS, or OS, in first-line/second-line NSCLC. Pegilodecakin + CPI has been found to have overall higher toxicity compared with CPI alone, leading to doubling of treatment discontinuation rate owing to AEs., (Copyright © 2020. Published by Elsevier Inc.)

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/m 2 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/m 2 (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., (Copyright © 2020. Published by Elsevier Inc.)

Introduction: The phase II, single-arm ASCEND-3 study assessed the efficacy and safety of ceritinib in anaplastic lymphoma kinase (ALK) inhibitor (ALKi)-naive patients with ALK-rearranged NSCLC who had received at least three previous lines of chemotherapy. Here, we report the final efficacy and safety results., Methods: Eligible patients (including those with asymptomatic or neurologically stable brain metastases) received oral ceritinib (750 mg/day, fasted). The primary end point was investigator-assessed overall response rate (ORR). Secondary end points were Blinded Independent Review Committee-assessed ORR; investigator- and Blinded Independent Review Committee-assessed overall intracranial response rate, duration of response, time to response, disease control rate, and progression-free survival (PFS); overall survival (OS); and safety. Exploratory end points included patient-reported outcomes., Results: Of the 124 patients enrolled, 122 (98.4%) had received previous antineoplastic medications (31 patients [25.0%] received at least three regimens), and 49 (39.5%) had baseline brain metastases. The median follow-up time (data cutoff: January 22, 2018) was 52.1 (range, 48.4-60.1) months. The investigator-assessed ORR was 67.7% (95% confidence interval [CI]: 58.8-75.9), and the median PFS was 16.6 months (95% CI: 11.0-23.2). The median OS was 51.3 months (95% CI: 42.7-55.3). Most common adverse events (all grades, ≥60% of patients, all-causality) were diarrhea (85.5%), nausea (78.2%), and vomiting (71.8%). Overall, 18 patients (14.5%) had an adverse event leading to treatment discontinuation. Health-related quality of life was maintained during ceritinib treatment., Conclusions: Ceritinib exhibited prolonged and clinically meaningful OS, PFS, and duration of response in chemotherapy-pretreated (at least three lines), ALKi-naive patients with ALK+ NSCLC. The safety profile was consistent with that reported in previous studies., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: Nivolumab monotherapy is approved in the United States for third-line or later metastatic small cell lung cancer based on pooled data from nonrandomized and randomized cohorts of the multicenter, open-label, phase 1/2 trial of nivolumab ± ipilimumab (CheckMate 032; NCT01928394). We report updated results, including long-term overall survival (OS), from the randomized cohort., Methods: Patients with small cell lung cancer and disease progression after one to two prior chemotherapy regimens were randomized 3:2 to nivolumab 3 mg/kg every 2 weeks or nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks for four cycles followed by nivolumab 3 mg/kg every 2 weeks. Patients were stratified by number of prior chemotherapy regimens and treated until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) by blinded independent central review., Results: Overall, 147 patients received nivolumab and 96 nivolumab plus ipilimumab. Minimum follow-up for ORR/progression-free survival/safety was 11.9 months (nivolumab) and 11.2 months (nivolumab plus ipilimumab). ORR increased with nivolumab plus ipilimumab (21.9% versus 11.6% with nivolumab; odds ratio: 2.12; 95% confidence interval: 1.06-4.26; p = 0.03). For long-term OS, minimum follow-up was 29.0 months (nivolumab) versus 28.4 months (nivolumab plus ipilimumab); median (95% confidence interval) OS was 5.7 (3.8-7.6) versus 4.7 months (3.1-8.3). Twenty-four-month OS rates were 17.9% (nivolumab) and 16.9% (nivolumab plus ipilimumab). Grade 3 to 4 treatment-related adverse event rates were 12.9% (nivolumab) versus 37.5% (nivolumab plus ipilimumab), and treatment-related deaths were n =1 versus n = 3, respectively., Conclusions: Whereas ORR (primary endpoint) was higher with nivolumab plus ipilimumab versus nivolumab, OS was similar between groups. In each group, OS remained encouraging with long-term follow-up. Toxicities were more common with combination therapy versus nivolumab monotherapy., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: In the phase 3 PACIFIC study of patients with unresectable stage III NSCLC without progression after chemoradiotherapy, durvalumab demonstrated significant improvements versus placebo in the primary end points of progression-free survival (hazard ratio [HR] = 0.52, 95% confidence interval [CI]: 0.42-65, p < 0.0001) and overall survival (OS) (HR = 0.68, 95% CI: 0.53-0.87, p = 0.00251), with manageable safety and no detrimental effect on patient-reported outcomes. Here, we report 3-year OS rates for all patients randomized in the PACIFIC study., Methods: Patients, stratified by age, sex, and smoking history, were randomized (2:1) to receive durvalumab, 10 mg/kg intravenously every 2 weeks, or placebo for up to 12 months. OS was analyzed by using a stratified log-rank test in the intention-to-treat population. Medians and rates at 12, 24, and 36 months were estimated by the Kaplan-Meier method., Results: As of January 31, 2019, 48.2% of patients had died (44.1% and 56.5% in the durvalumab and placebo groups, respectively). The median duration of follow-up was 33.3 months. The updated OS remained consistent with that previously reported (stratified HR = 0.69 [95% CI: 0.55-0.86]); the median OS was not reached with durvalumab but was 29.1 months with placebo. The 12-, 24- and 36-month OS rates with durvalumab and placebo were 83.1% versus 74.6%, 66.3% versus 55.3%, and 57.0% versus 43.5%, respectively. All secondary outcomes examined showed improvements consistent with previous analyses., Conclusions: Updated OS data from PACIFIC, including 3-year survival rates, demonstrate the long-term clinical benefit with durvalumab after chemoradiotherapy and further establish the PACIFIC regimen as the standard of care in this population., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: We assessed the Aurora A kinase inhibitor, alisertib, plus paclitaxel (henceforth referred to as alisertib/paclitaxel) as second-line treatment for SCLC., Methods: In this double-blind study, patients with relapsed or refractory SCLC were stratified by relapse type (sensitive versus resistant or refractory) and brain metastases and randomized 1:1 to alisertib/paclitaxel or placebo plus paclitaxel (henceforth referred to as placebo/paclitaxel) in 28-day cycles. The primary end point was progression-free survival (PFS). Associations of c-Myc expression in tumor tissue (prespecified) and genetic alterations in circulating tumor DNA (retrospective) with clinical outcome were evaluated., Results: A total of 178 patients were enrolled (89 in each arm). The median PFS was 3.32 months with alisertib/paclitaxel versus 2.17 months with placebo/paclitaxel (hazard ratio [HR] = 0.77, 95% confidence limit [CI]: 0.557-1.067, p = 0.113 in the intent-to-treat population versus HR = 0.71, 95% CI: 0.509-0.985, p = 0.038 with corrected analysis applied). Among 140 patients with genetic alternations, patients with cell cycle regulator mutations (cyclin-dependent kinase 6 gene [CDK6], retinoblastoma-like 1 gene [RBL1], retinoblastoma-like 2 gene [RBL2], and retinoblastoma 1 gene [RB1]) had significantly improved PFS with alisertib/paclitaxel versus with placebo/paclitaxel (3.68 versus 1.80 months, respectively [HR = 0.395, 95% CI: 0.239-0.654, p = 0.0003]), and overall survival (7.20 versus 4.47 months, respectively [HR = 0.427, 95% CI: 0.259-0.704, p = 0.00085]). A subset of patients with c-Myc expression showed significantly improved PFS with alisertib/paclitaxel. The incidence of grade 3 or higher drug-related adverse events was 67% (58 patients) with alisertib/paclitaxel versus 22% (25 patients) with placebo/paclitaxel. Twelve patients (14%) versus 11 (12%) died on study, including four versus zero treatment-related deaths., Conclusions: Efficacy signals were seen with alisertib/paclitaxel in relapsed or refractory SCLC. c-Myc expression and mutations in cell cycle regulators may be potential predictive biomarkers of alisertib efficacy; further prospective validations are warranted., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: CheckMate 153 (NCT02066636) is a phase 3B/4 study assessing nivolumab in previously treated patients with advanced NSCLC. Eligibility criteria allowed enrollment of patients with poor prognostic features of advanced age or diminished Eastern Cooperative Oncology Group performance status (ECOG PS), which are typically underrepresented in or excluded from randomized controlled trials., Methods: Patients with stage IIIB or IV NSCLC and an ECOG PS of 0 to 2 with disease progression after at least one systemic therapy received nivolumab (3 mg/kg every 2 weeks) until progression, unacceptable toxicity, or consent withdrawal. The primary end point was the incidence of grade 3 to 5 select treatment-related adverse events (TRAEs)., Results: Among 1426 treated patients, 556 (39%) were aged 70 years or older and 128 (9%) had an ECOG PS of 2. The median treatment duration was 3.2 months. Across subgroups and the overall population, the incidences of select grade 3 to 5 TRAEs (6%-9%) and grade 3 or 4 TRAEs (12%-14%) were similar. One grade 5 TRAE was documented. The median overall survival time was comparable in the overall population (9.1 months) and patients aged 70 years or older (10.3 months) but shorter in patients with an ECOG PS of 2 (4.0 months). Patient-reported outcomes generally improved., Conclusions: Data from this large predominantly community-based study, which included patients aged 70 years or older and with an ECOG PS of 2, are consistent with registrational studies. As expected, the median overall survival for patients with an ECOG PS of 2 was lower than for the overall population but comparable with historical data., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: For patients with recurrent SCLC, topotecan remains the only approved second-line treatment, and the outcomes are poor. CheckMate 032 is a phase 1/2, multicenter, open-label study of nivolumab or nivolumab plus ipilimumab in SCLC or other advanced/metastatic solid tumors previously treated with one or more platinum-based chemotherapies. We report results of third- or later-line nivolumab monotherapy treatment in SCLC., Methods: In this analysis, patients with limited-stage or extensive-stage SCLC and disease progression after two or more chemotherapy regimens received nivolumab monotherapy, 3 mg/kg every 2 weeks, until disease progression or unacceptable toxicity. The primary end point was objective response rate. Secondary end points included duration of response, progression-free survival, overall survival, and safety., Results: Between December 4, 2013, and November 30, 2016, 109 patients began receiving third- or later-line nivolumab monotherapy. At a median follow-up of 28.3 months (from first dose to database lock), the objective response rate was 11.9% (95% confidence interval: 6.5-19.5) with a median duration of response of 17.9 months (range 3.0-42.1). At 6 months, 17.2% of patients were progression-free. The 12-month and 18-month overall survival rates were 28.3% and 20.0%, respectively. Grade 3 to 4 treatment-related adverse events occurred in 11.9% of patients. Three patients (2.8%) discontinued because of treatment-related adverse events., Conclusions: Nivolumab monotherapy provided durable responses and was well tolerated as a third- or later-line treatment for recurrent SCLC. These results suggest that nivolumab monotherapy is an effective third- or later-line treatment for this patient population., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Introduction: The FIR phase II study (NCT01846416) evaluated the efficacy and safety of anti-programmed death-ligand 1 (PD-L1) atezolizumab in advanced NSCLC selected by tumor cell (TC) or tumor-infiltrating immune cell (IC) PD-L1 expression., Methods: Patients with PD-L1 TC2/3 (PD-L1 staining on ≥5% of TC) or IC2/3 tumors (PD-L1 staining on ≥5% of IC; determined by SP142 PD-L1 immunohistochemistry assay) with paired fresh and archival histology samples were recruited into cohort 1 (chemotherapy-naive/>6 months between adjuvant chemotherapy and recurrence), cohort 2 (≥ second-line without brain metastases), or cohort 3 (≥ second-line with treated brain metastases). Patients received 1200 mg atezolizumab on day 1 (21-day cycles). Primary endpoint was investigator-assessed modified Response Evaluation Criteria in Solid Tumors, objective response rate (Response Evaluation Criteria in Solid Tumors v1.1). Secondary endpoints were overall survival, progression-free survival, duration of response, and safety., Results: Patients (N = 138) were enrolled (137 evaluable for response: cohort 1, n = 31; cohort 2, n = 93; and cohort 3, n = 13). Investigator-assessed objective response rate was 32%, 21%, and 23% for cohorts 1, 2, and 3, respectively. Treatment-related adverse events were reported in 81%, 67%, and 69% of patients, respectively, including grade 3-4 treatment-related adverse events in 16%, 19%, and 15%, respectively. Moreover, 88.6% (86 of 97) paired baseline tumor samples had <5% change in TC/IC PD-L1 expression over time., Conclusions: Atezolizumab monotherapy showed clinical activity in patients with NSCLC, including those with brain metastases; safety was consistent with previous trials. Atezolizumab has completed phase III monotherapy studies in second-line. Front-line trials are ongoing, confirming these favorable results., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Crizotinib, an anaplastic lymphoma kinase (ALK) inhibitor, is a first-line treatment for ALK translocation-positive advanced non-small cell lung cancer (NSCLC); however, patients eventually progress. Immunotherapies, including the programmed death-1 inhibitor nivolumab, have resulted in durable responses and long-term overall survival in patients with NSCLC. We hypothesized that combining targeted therapy with immunotherapy could result in more patients with responses and/or more durable responses. Herein we report data from a study assessing nivolumab plus crizotinib in patients with previously untreated advanced ALK translocation-positive NSCLC., Methods: Group E in CheckMate 370 was a single-arm cohort designed to evaluate the safety of first-line nivolumab (240 mg every 2 weeks) plus crizotinib (250 mg twice daily) in patients with ALK translocation-positive NSCLC. The primary endpoint of safety would be met if ≤20% of patients discontinued treatment due to treatment-related adverse events by week 17. Objective response rate was a secondary endpoint. A planned safety review occurred in November 2016; the data cutoff was May 26, 2017., Results: Of the first 13 patients treated with nivolumab plus crizotinib, 5 (38%) developed severe hepatic toxicities leading to the discontinuation of the combination. Of these, two patients died and the presence of severe hepatic toxicities may have contributed to death. Enrollment was closed and combination treatment discontinued due to observed grade ≥3 hepatic toxicities. Five patients (38%) had a partial response., Conclusions: These findings do not support further evaluation of nivolumab 240 mg every 2 weeks plus crizotinib 250 mg twice daily., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Squamous cell lung cancer (SqCLC) is a distinct histologic subtype of NSCLC that is challenging to treat because of specific clinicopathologic characteristics, which include older age, advanced disease at diagnosis, comorbid diseases, and the central location of tumors. These characteristics have a bearing on treatment outcomes in advanced SqCLC, resulting in a median survival approximately 30% shorter than for patients with other NSCLC subtypes. In the context of the specific features of SqCLC, we review challenges of treating SqCLC and the current guideline-recommended treatments for advanced (metastatic) SqCLC in different patient subpopulations. We also evaluate recently approved treatment options, including necitumumab, afatinib, nivolumab, pembrolizumab, and atezolizumab; discuss the survival benefits associated with each agent in the advanced SqCLC population; and propose a treatment algorithm incorporating these agents for this challenging-to-treat disease. Lastly, we review the preliminary clinical evidence for immunotherapy agents in development for advanced NSCLC., (Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

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 < 4% of patients in either arm., 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., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Lung cancer care is rapidly changing with advances in genomic testing, the development of next-generation targeted kinase inhibitors, and the continued broad study of immunotherapy in new settings and potential combinations. The International Association for the Study of Lung Cancer and the Journal of Thoracic Oncology publish this annual update to help readers keep pace with these important developments. Experts in thoracic cancer and care provide focused updates across multiple areas, including prevention and early detection, molecular diagnostics, pathology and staging, surgery, adjuvant therapy, radiotherapy, molecular targeted therapy, and immunotherapy for NSCLC, SCLC, and mesothelioma. Quality and value of care and perspectives on the future of lung cancer research and treatment have also been included in this concise review., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objective: This phase I clinical study (NCT01415297) evaluated the safety, tolerability, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of IT-139 (formerly NKP-1339) monotherapy in patients with advanced solid tumours. IT-139, sodium trans-(tetrachlorobis(1H-indazole)ruthenate(III)), is a novel small molecule that suppresses the stress induction of GRP78 in tumour cells. GRP78 is a key regulator of misfolded protein processing, and its upregulation in tumours is associated with intrinsic and drug-induced resistance., Methods: Forty-six patients with advanced solid tumours refractory to treatment received intravenous infusions of IT-139 on days 1, 8 and 15 for every 28 days, and doses were evaluated across nine cohorts at 20, 40, 80, 160, 320, 420, 500, 625 and 780 mg/m 2 ., Results: Overall, IT-139 was well tolerated. The treatment-emergent adverse events (AEs) occurring in ≥20% of patients were nausea, fatigue, vomiting, anaemia and dehydration. The majority of patients had AEs that were ≤grade 2, regardless of relationship with the study drug. Of the total 38 efficacy-evaluable patients, one patient with a carcinoid tumour achieved a durable partial response. Nine additional patients achieved stable disease . The MTD was determined to be 625 mg/m 2 . IT-139 exhibited first-order linear pharmacokinetics., Conclusions: IT-139 demonstrated a manageable safety profile at the MTD and modest anti-tumour activity in this study of patients with solid tumours refractory to treatment. The lack of dose-limiting haematological toxicity and the absence of neurotoxicity position IT-139 well for use in combination with a broad spectrum of anticancer drugs., Trial Registration Number: NCT01415297.

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., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Squamous cell lung cancer (sqCLC) is an aggressive form of cancer that poses many therapeutic challenges. Patients tend to be older, present at a later stage, and have a high incidence of comorbidities, which can compromise treatment delivery and exacerbate toxicity. In addition, certain agents routinely available for nonsquamous cell histologic subtypes, such as bevacizumab and pemetrexed, are contraindicated or lack efficacy in sqCLC. Therapeutic progress has been much slower for advanced sqCLC, with median survival times of approximately 9 to 11 months in most studies. Herein, we discuss the current therapeutic landscape for patients with sqCLC versus with nonsquamous NSCLC. Current evidence indicates that new targeted treatments, notably monoclonal antibodies such as ramucirumab and necitumumab, and immunotherapies such as nivolumab and pembrolizumab can provide survival prolongation, although the benefits are still relatively modest. These incremental improvements, all realized since 2012, in aggregate, will very likely have a clinically meaningful impact for patients with sqCLC. We also discuss recent genomic studies of sqCLC that have identified potentially actionable molecular targets, as well as the relevant targeted agents in clinical development. Finally, we discuss the magnitude of survival benefit and the risk-to-benefit ratio that would prove clinically meaningful in this underserved patient population with unmet needs., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Lung cancer remains the leading cause of cancer-related death worldwide. NSCLC accounts for more than 85% of all lung cancers, and the prognosis for advanced-stage disease is typically poor. In recent years, the importance of histologic subtypes of NSCLC has been recognized, and the distinction between squamous and other NSCLC histologic subtypes is now critical to patient management. Squamous cell lung cancer (sqCLC) represents approximately 25% to 30% of NSCLC. The prognosis for patients with advanced NSCLC is poorer for those with sqCLC than for those with adenocarcinoma. This is partly due to a number of clinical characteristics that distinguish sqCLC from other NSCLC histologic subtypes, such as smoking history, comorbid diseases, age, and molecular profile. Together, these factors make sqCLC an especially challenging disease to manage. Herein, we review some of the key clinicopathologic features of sqCLC. Understanding these features to optimally address many of the unique therapeutic challenges of this disease is likely to be central to ultimately improving outcomes for patients with squamous NSCLC., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2016 Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Treatment impact on quality of life (QoL) informs treatment management decisions in advanced nonsquamous non-small-cell lung cancer (NS NSCLC). QoL outcomes from the phase III PointBreak trial are reported., Methods: Chemonaive patients (n = 939) with stage IIIB/IV nonsquamous non-small-cell lung cancer and Eastern Cooperative Oncology Group performance status 0 to 1 were randomized (1:1) to pemetrexed-carboplatin-bevacizumab (pemetrexed arm) or paclitaxel-carboplatin-bevacizumab (paclitaxel arm). Patients without progressive disease received maintenance pemetrexed-bevacizumab (pemetrexed arm) or bevacizumab (paclitaxel arm). QoL was assessed using Functional Assessment of Cancer Therapy (FACT)-General (FACT-G), FACT-Lung (FACT-L), and FACT/Gynecologic Oncology Group-Neurotoxicity (FACT-Ntx) instruments. Subscale scores, total scores, and trial outcome indices were analyzed using linear mixed-effects models. Post hoc analyses examined the association between baseline FACT scores and overall survival (OS)., Results: Mean score differences in change from baseline significantly favored the pemetrexed arm for the neurotoxicity subscale score, FACT-Ntx total scores, and FACT-Ntx trial outcome index. They occurred at cycle 2 (p < 0.001) and persisted through induction cycles 2 to 4 and six maintenance cycles. Investigator-assessed, qualitative, drug-related differences in grade 2 (1.6% versus 10.6%) and grade 3 (0.0% versus 4.1%) sensory neuropathy and grade 3/4 fatigue (10.9% versus 5.0%, p = 0.0012) were observed between the pemetrexed and paclitaxel arms. Baseline FACT-G, FACT-L, and FACT-Ntx scores were significant prognostic factors for OS (p < 0.001)., Conclusions: Randomized patients reported similar changes in QoL, except for less change from baseline in neurotoxicity on the pemetrexed arm; investigators reported greater neurotoxicity on the paclitaxel arm and greater fatigue on the pemetrexed arm. Higher baseline FACT scores were favorable prognostic factors for OS.

There have been significant advances in the understanding of the biology and treatment of non-small-cell lung cancer (NSCLC) during the past few years. A number of molecularly targeted agents are in the clinic or in development for patients with advanced NSCLC. We are beginning to understand the mechanisms of acquired resistance after exposure to tyrosine kinase inhibitors in patients with oncogene addicted NSCLC. The advent of next-generation sequencing has enabled to study comprehensively genomic alterations in lung cancer. Finally, early results from immune checkpoint inhibitors are very encouraging. This review summarizes recent advances in the area of cancer genomics, targeted therapies, and immunotherapy.

Introduction: PRONOUNCE compared the efficacy and safety of pemetrexed+carboplatin followed by pemetrexed (Pem+Cb) with paclitaxel+carboplatin+bevacizumab followed by bevacizumab (Pac+Cb+Bev) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC)., Methods: Patients ≥18 years of age with stage IV nonsquamous NSCLC (American Joint Committee on Cancer v7.0), and Eastern Cooperative Oncology Group performance status 0/1 were randomized (1:1) to four cycles of induction Pem+Cb (pemetrexed, 500 mg/m, carboplatin, area under the curve = 6) followed by Pem maintenance or Pac+Cb+Bev (paclitaxel, 200 mg/m, carboplatin, area under the curve = 6, and bevacizumab, 15 mg/kg) followed by Bev maintenance in the absence of progressive disease or discontinuation. The primary objective was progression-free survival (PFS) without grade 4 toxicity (G4PFS). Secondary end points were PFS, overall survival (OS), overall response rate (ORR), disease control rate (DCR), and safety. Resource utilization was also assessed., Results: Baseline characteristics of the patients randomized to Pem+Cb (N = 182) and Pac+Cb+Bev (N = 179) were well balanced between the arms. Median (months) G4PFS was 3.91 for Pem+Cb and 2.86 for Pac+Cb+Bev (hazard ratio = 0.85, 90% confidence interval, 0.7-1.04; p = 0.176); PFS, OS, ORR, or DCR did not differ significantly between the arms. Significantly more drug-related grade 3/4 anemia (18.7% versus 5.4%) and thrombocytopenia (24.0% versus 9.6%) were reported for Pem+Cb. Significantly more grade 3/4 neutropenia (48.8% versus 24.6%), grade 1/2 alopecia (28.3% versus 8.2%), and grade 1/2 sensory neuropathy were reported for Pac+Cb+Bev. Number of hospitalizations and overall length of stay did not differ significantly between the arms., Conclusions: Pem+Cb did not produce significantly better G4PFS compared with Pac+Cb+Bev. Pem+Cb was not superior in PFS, OS, ORR, or DCR compared with Pac+Cb+Bev. Both regimens were well tolerated, although, toxicity profiles differed.

Introduction: Bevacizumab, a recombinant humanized monoclonal antibody against vascular endothelial growth factor, was approved by the US Food and Drug Administration for the treatment of advanced non-small-cell lung cancer (NSCLC) in combination with carboplatin and paclitaxel. ARIES (Avastin Regimens: Investigation of Effectiveness and Safety), a prospective observational cohort study, evaluated outcomes in a large, community-based population of patients with first-line NSCLC., Methods: From 2006 to 2009, ARIES enrolled patients with locally advanced or metastatic NSCLC who were eligible for bevacizumab, excluding those with predominantly squamous histology. Patients were required to provide informed consent and to have initiated bevacizumab with chemotherapy within 4 months before enrollment. There were no protocol-defined treatments or assessments. The dosing of bevacizumab and chemotherapy, and the choice of chemotherapy regimen, was at the discretion of the treating physician., Results: ARIES enrolled 1967 patients with first-line NSCLC. At study closure, median follow-up was 12.5 months (range, 0.2-65.5). Median age was 65 years (range, 31-93), and 252 patients (12.8%) identified as never smokers. Median progression-free survival was 6.6 months (95% confidence interval, 6.3-6.9), and median overall survival was 13.0 months (95% confidence interval, 12.2-13.8) with first-line bevacizumab plus chemotherapy. Incidences of bevacizumab-associated adverse events (19.7% overall) were consistent with those in randomized controlled trials of bevacizumab in NSCLC., Conclusion: Results from ARIES demonstrate similar outcomes to randomized controlled trials of bevacizumab when added to standard chemotherapy in a real-world patient population with advanced NSCLC.

Introduction: The phase 3 MONET1 study evaluated motesanib (a small-molecule inhibitor of vascular endothelial growth factor receptors) plus carboplatin/paclitaxel versus placebo plus carboplatin/paclitaxel as first-line therapy for advanced non-small-cell lung cancer (NSCLC). Treatment and enrollment of patients with squamous histology were permanently discontinued following higher early mortality and gross hemoptysis in those with squamous NSCLC who received motesanib. Enrollment of patients with nonsquamous histology was temporarily halted, but resumed following a protocol amendment (Scagliotti et al. J Clin Oncol. 2012;30:2829-2836). Herein, we report data from the squamous cohort., Methods: Patients with stage IIIB/IV or recurrent squamous NSCLC (without prior systemic therapy for advanced disease) received up to six 3-week cycles of chemotherapy (carboplatin, area under the curve 6 mg/mL•min/paclitaxel, 200 mg/m) and were randomized 1:1 to receive motesanib 125 mg (Arm A) or placebo (Arm B) once daily. The primary end point was overall survival., Results: Three-hundred and sixty patients with squamous NSCLC were randomized (Arm A, n = 182; Arm B, n = 178) between July 2007 and November 2008. Twenty-three patients (13%) in Arm A and 10 (6%) in Arm B had fatal adverse events within the first 60 days of treatment. Among these, six patients in Arm A, but none in Arm B, had fatal bleeding events. At final analysis, serious adverse events had occurred in 47% of patients in Arm A and 29% of patients in Arm B. Median overall survival was similar in Arms A and B (11.1 versus 10.7 months)., Conclusions: Motesanib plus carboplatin/paclitaxel had unacceptable toxicity compared with carboplatin/paclitaxel alone in patients with advanced squamous NSCLC.

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

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., (Copyright © 2013. Published by Elsevier Inc.)

Introduction: Small cell lung cancer (SCLC) is an aggressive malignancy that although initially sensitive to chemo- and radiation therapy, inevitably relapses resulting in poor survival. Increasing evidence suggests that immune responses against SCLC cells make immunotherapy a viable therapeutic approach. Furthermore, preclinical data have shown that certain chemotherapeutic regimens may augment the immunotherapeutic response in SCLC. This review discusses current evidence supporting immunotherapy for SCLC, progress made, and ongoing clinical trials., Methods: We searched PubMed and abstracts presented at recent oncology congresses for publications on the clinical benefit of immunotherapy/checkpoint blockade for treatment of SCLC., Results: Preliminary data from ongoing clinical trials in SCLC have shown that some antiangiogenic agents, vaccines, and immunomodulators, including interferon-α and immune checkpoint blockers (i.e., anticytotoxic T-lymphocyte-associated antigen-4 [CTLA-4] antibodies) may be efficacious as single agents and in combination with standard-of-care regimens. Notably, in a phase II trial, ipilimumab--a fully human anti-CTLA-4 monoclonal antibody recently approved for treatment of unresectable or metastatic melanoma-demonstrated encouraging results when used as part of a chemoimmunotherapeutic regimen in patients with SCLC. Ipilimumab is undergoing further investigation in this population., Conclusions: Treatment options for SCLC are limited and prognosis poor, emphasizing the need for novel treatments. Although current strategies successfully induce a response, the response is not durable. Evidence of an immune response in SCLC and a better understanding of the immunosuppressive tumor environment support the combinatorial use of immunomodulators, such as ipilimumab, with traditional chemotherapy regimens to improve patient outcomes and potentially sustain the effect from chemotherapeutic induction.

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., (Copyright © 2012. Published by Elsevier Inc.)

Background and Purpose: We wanted to evaluate the efficacy, defined as 2-year disease-free survival (DFS), and safety of bevacizumab/chemoradiation in preoperative and adjuvant settings for patients with stage II/III rectal cancer., Patients and Methods: Eligible patients had stage II/III rectal adenocarcinoma, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, and adequate organ function, and received preoperative (cohort A) or adjuvant (cohort B) treatment at physician discretion. Patients received 5-fluorouracil (5-FU) as an intravenous infusion (IVCI) 225 mg/m(2)/d on days 1-42, bevacizumab 5 mg/kg intravenously (I.V.) on days 1 and 15 (cohort A), or every 2 weeks (cohort B), with radiation therapy to 50.4 Gy. After surgery (cohort A) or chemoradiation (cohort B), FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin) and bevacizumab were administered for 4 months and then bevacizumab was given alone for up to 1 year., Results: Sixty-six patients (cohort A = 35; cohort B = 31) were enrolled from August 2006-April 2009: median age was 57 years; male patients, 62%; ECOG PS 0, 75%; stage II/III, 31%/69%. In cohort A, the complete pathologic response (pCR) rate was 29% (11% microscopic residual disease, 49% gross disease). Four patients did not undergo surgery (toxicity, 2 patients; progressive disease, 1 patient; patient decision, 1 patient). One- and 2-year DFS for cohorts A/B were 85%/not reached and 97%/89%, respectively (median survival not reached for either cohort). Frequent grade 3/4 toxicity included diarrhea (A cohort, 14%; B cohort, 29%), neutropenia (A cohort, 14%, B cohort, 23%), mucositis (A cohort, 23%, B cohort, 0%), and fatigue (A cohort, 6%, B cohort, 10%). Other serious toxicity included bowel perforation and pelvic infection (cohort A, 1 patient each), bowel perforation (2 patients), anal wound dehiscence (1 patient), perianal infection (2 patients), and rectovaginal fistula (1 patient) (cohort B), without treatment-related death in either cohort., Conclusions: Bevacizumab can be added to standard preoperative and adjuvant chemoradiation in most patients with expected and manageable toxicity and may increase treatment efficacy., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: To assess time to progression (TTP) in elderly patients with previously untreated nonsquamous non-small cell lung cancer treated with pemetrexed/gemcitabine/bevacizumab or pemetrexed/carboplatin/bevacizumab., Methods: Eligible patients were aged 70 years or older with newly diagnosed stage IIIB/IV nonsquamous non-small cell lung cancer; Eastern Cooperative Oncology Group performance status 0 to 1; adequate organ function; and no active central nervous system metastasis. Patients were randomized 1:1 to cohort A (pemetrexed 500 mg/m2 IV, gemcitabine 1500 mg/m2 IV, and bevacizumab 10 mg/kg IV; days 1 and 15 of 28-day cycles) or cohort B (pemetrexed 500 mg/m2 IV, carboplatin area under the concentration-time curve =5 IV, and bevacizumab 15 mg/kg IV; day 1 of 21-day cycles). After six cycles, stable/responding patients continued bevacizumab until disease progression., Results: Between March 2007 and December 2009, 110 patients (median age, 76 years; 88% stage IV) were treated for medians of 2.5 cycles (cohort A) and 6 cycles (cohort B). Overall response rate was 35% in both cohorts, with stable disease rates of 33% (A) and 45% (B). TTP by cohort was 4.7 and 10.2 months with median OS 7.5 and 14.8 months, respectively. Severe toxicities included the following: neutropenia (A, 51% and B, 45%), fatigue (A, 36% and B, 18%), anemia (A, 22% and B, 7%), infection (A, 25% and B, 7%), thrombocytopenia (A, 11% and B, 31%), and thromboembolism (A, 7% and B, 7%). Three potential treatment-related deaths occurred in cohort A (sepsis, thrombocytopenia, and myocardial infarction) and two in B (sepsis and pulmonary hemorrhage)., Conclusions: Treatment with pemetrexed/carboplatin/bevacizumab was associated with improved TTP and OS in this elderly population and should be further evaluated. Treatment-related toxicities were expected and usually manageable, although deaths occurred with both regimens.

Background: 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., Patients and Methods: 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., Results: 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., Conclusion: 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., (Copyright © 2011. Published by Elsevier Inc.)

Introduction: Voreloxin is an anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II, causing double-strand breaks in DNA, irreversible G2 arrest, and rapid onset of apoptosis. Based on preclinical activity of voreloxin in chemoresistant tumors, early phase I clinical activity, and a mechanism of action similar to other topoisomerase II inhibitors such as the anthracyclines and etoposide, this phase II trial was undertaken as second-line treatment of small cell lung cancer (SCLC)., Methods: Patients with extensive stage SCLC previously treated with one prior chemotherapy regimen were eligible. Patients with chemotherapy-sensitive or chemotherapy-refractory disease were considered as separate cohorts. Voreloxin (48 mg/m) was administered on the first day of each 21-day cycle for up to six cycles. The primary end point was objective response rate., Results: Fifty-five patients were enrolled including 28 with refractory SCLC and 27 with sensitive SCLC; 47 were evaluable for response. Three patients with sensitive SCLC had an objective response, including one complete response and two partial responses (11% response rate based on intent to treat). No patients in the refractory cohort had a response. The primary grade 3 toxicity was neutropenia., Conclusion: Voreloxin has minimal activity in relapsed SCLC when administered at 48 mg/m in a 3-week schedule.

Introduction: Pemetrexed and gemcitabine are safe and active non-small cell lung cancer (NSCLC) therapies when administered every 3 weeks. Biweekly scheduling was studied in this phase II trial., Methods: The primary objective was to assess the overall response rate in chemotherapy-naive patients with unresectable stage III/IV NSCLC. Patients received 500 mg/m(2) of pemetrexed intravenously and 1500 mg/m(2) of gemcitabine intravenously every 2 weeks for 8 to 12 cycles with restaging every 4 cycles. Patients also received supplemental folate/B12 therapy. Entry criteria included the following: all non-small cell histologies, measurable disease, Eastern Cooperative Oncology Group 0 to 2, and informed consent., Results: Seventy-two patients were enrolled. Baseline characteristics included the following: median age: 66 years (41-85 years); male/female: 65%/35%; Eastern Cooperative Oncology Group 0/1/2: 19%/67%/14%; and histology: adenocarcinoma (36%), large cell (18%), squamous (13%), and mixed or not specified (34%). The median number of cycles was 7 (range, 1-12). The most common (> or =5%) grade 3/4 toxicities were as follows: neutropenia (47%), leukopenia (31%), fatigue (25%), dyspnea (18%), pain (11%), and anemia (8%). Complete/partial responses for all patients: 1 patient/18 patients, respectively, for an overall response rate of 26% (95% confidence interval, 17-38%). Thirty-nine percentage of patients had stable disease, and 21% had disease progression (10 patients were not evaluable). Median progression-free survival was 6.2 months. One-year overall survival was 37.5%., Conclusion: Biweekly administration of pemetrexed and gemcitabine seems to be well tolerated with activity comparable with other first-line NSCLC regimens. Further study addressing whether biweekly scheduling could be an effective strategy to shorten overall treatment duration will require a randomized design.

Background: Vinflunine is a new microtubule inhibitor with preclinical activity in small cell lung cancer (SCLC). In this phase II trial, we evaluated vinflunine in patients with relapse-sensitive and refractory SCLC., Methods: This trial aimed to achieve a 20% objective response rate (ORR) in platinum-sensitive patients. Patients with Eastern Cooperative Oncology Group performance status 0 to 2 and measurable disease received vinflunine (320 mg/m(2) IV) every 21 days (< or =6 cycles; response evaluation every 6 weeks)., Results: Patient characteristics (N = 51): median age 63 years (range, 37-85 years); male, 55%; Eastern Cooperative Oncology Group performance status 2, 16%; relapse-sensitive SCLC, 53%. The overall ORR was 19.6% (95% confidence interval [CI] 10-33%). Twelve (23.5%) patients had stable disease; 18 (35.3%) patients had progressive disease. Among relapse-sensitive patients, ORR was 22.2% (95% CI 9-42%). Among relapse-refractory patients, ORR was 16.7% (95% CI 5-37%). Median follow-up was 15 months (range, 12-18 months); median progression-free survival (PFS) was 1.6 months (95% CI 1.3-3.9 months); median overall survival (OS) was 4.9 months (95% CI 3.2- 6.5 months). Among relapse-sensitive patients, PFS and OS were 1.6 and 4.9 months, respectively. Among relapsed-refractory patients, PFS and OS were 1.4 and 4.0 months, respectively. In general, vinflunine was well tolerated, although neutropenia was a notable toxicity. Grade 3/4 toxicities (>5%): neutropenia (32%), arthralgia/myalgia (16%), fatigue (16%), hyponatremia (12%), leukopenia (12%), nausea/vomiting (12%), constipation (6%), and thrombocytopenia (6%). The rates of toxicities were relatively well balanced among relapse-sensitive and refractory patients; one patient died of sepsis that was possibly treatment related., Conclusions: Vinflunine has activity in relapsed SCLC, including refractory relapsed patients. Neutropenia was common but associated with rare febrile episodes. Additional study in relapse-refractory SCLC is indicated.

Background: Carboplatin and topotecan are commonly used in the treatment of small cell lung cancer (SCLC); however, there are no data for this combination in the first-line setting using weekly topotecan. In this multicenter, community-based phase II trial, we evaluated carboplatin and weekly topotecan in the previously untreated patients with extensive stage SCLC., Methods: This trial was designed to achieve an objective response rate (ORR) of 70% (alpha = 0.05; beta = 0.20); secondary aims were to assess time to progression, toxicity, and overall survival (OS). Patients with Eastern Cooperative Oncology Group performance status 0 to 1, measurable disease, and adequate organ function were eligible., Treatment: carboplatin area under the concentration-time curve = 5 (intravenous) on day 1 and topotecan 4 mg/m(2) (intravenous) on days 1 and 8, every 21 days for up to six cycles, with restaging every 6 weeks (per RECIST)., Results: Between June 2006 and November 2008, 61 patients were enrolled. The median follow-up is 40 weeks (range 27-109 weeks). Patient characteristics were as follows: median age 67 years (range 40-84 years); male, 53%; and Eastern Cooperative Oncology Group performance status 0, 28%. Complete responses were seen in two patients and partial responses in 33 patients; ORR was 57% (95% confidence interval [CI] 44-70). Stable disease was seen in 12 patients (20%), and progressive disease was seen in two patients (3%). The median time to progression was 5.5 months (95% CI 4.0-6.3 months). The median OS was 8.5 months (95% CI 7.2-11.4 months). One-year OS was 29%. Grade 3/4 toxicity in >5%: neutropenia (66%), thrombocytopenia (48%), leukopenia (40%), anemia (30%), fatigue (13%), dehydration (8%), infection (8%), and pain (7%)., Conclusions: The ORR achieved with carboplatin and weekly topotecan was less than the anticipated rate of 70%; however, it was comparable with historical rates seen with other platinum doublets in the first-line extensive stage SCLC setting. This regimen was generally well tolerated, with myelosuppression as its primary toxicity.

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/m2 I.V. days 1 and 8; gemcitabine 1000 mg/m2 I.V. days 1 and 8; and cetuximab 400 mg/m2 I.V. day 1, then 250 mg/m2 I.V. weekly. Patients received up to 6 cycles with restaging every 6 weeks. The primary endpoint was an overall response rate (ORR) > or = 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.

Introduction: Patients with diffuse large B-cell lymphoma (DLBCL) who are very elderly or have poor performance status are difficult to treat with a full course of R-CHOP (rituximab plus cyclophosphamide/doxorubicin/vincristine/ prednisone) therapy. In this phase II trial, we treated this group of patients with a novel regimen containing 3 courses of rituximab/chemotherapy followed by maintenance rituximab., Patients and Methods: Patients with newly diagnosed stage II-IV DLBCL were eligible if they were considered poor candidates for 6-8 cycles of R-CHOP therapy. Patients who were eligible for anthracycline therapy received 3 cycles of rituximab plus cyclophosphamide/ mitoxantrone/vincristine/prednisone (CNOP); the remainder of patients received R-CVP (rituximab plus cyclophosphamide/ vincristine/prednisone). Patients without progression after completion of 3 cycles received 4 courses of maintenance rituximab (375 mg/m2 weekly x 4, repeated every 6 months) for 24 months., Results: Between May 2003 and July 2007, 51 patients were enrolled. The median age was 78 years, and 43% of patients were > 80 years of age. Nineteen patients (37%) had Eastern Cooperative Oncology Group performance status of 2, and 72% had high-intermediate or high-risk International Prognostic Index scores. After a median follow-up of 48 months, the 2-, 3-, and 4-year progression-free survival rates are 71%, 65%, and 56%, respectively. The 2-, 3-, and 4-year overall survival rates are 72%, 67%, and 67%, respectively. Treatment was well tolerated, with few severe toxicities and no treatment-related deaths., Conclusion: This abbreviated course of rituximab/chemotherapy, followed by maintenance rituximab, was active and well tolerated in these very elderly patients. Brief-duration rituximab/chemotherapy as well as maintenance rituximab merit further evaluation in this setting.

Introduction: Bevacizumab's role in the treatment of small cell lung cancer (SCLC) is unknown. A multicenter phase II trial with bevacizumab plus chemotherapy was conducted in patients with untreated extensive-stage SCLC., Methods: Eligibility: no prior SCLC chemotherapy, no active brain metastases, no hemoptysis, and Eastern Cooperative Oncology Group performance status 0-1. Treatment consisted of irinotecan (60 mg/m2) administered intravenously (IV) on days 1, 8, 15; carboplatin area under the concentration-time curve = 4, IV, on day 1; bevacizumab (10 mg/kg, IV) on days 1 and 15 every 28 days for up to six cycles. Restaging was performed every two cycles (8 weeks). Patients with no progression received maintenance bevacizumab. Primary end point is 40% improvement in historical median time to progression (TTP) of 6 months., Results: Fifty-one patients were enrolled from February 2006 to March 2007 (22-month median follow-up). Baseline features: median age 66 years (range 46-81 years); male 57%; and Eastern Cooperative Oncology Group performance status 0-1 33/67%. Objective response rate 84% (95% CI 71-93%): 1 complete and 42 partial responses. Two patients (4%) had stable disease, and two patients had progressive disease. Four patients were unassessable because of treatment-related toxicity. Median TTP was 9.13 months (95% CI 7.36-9.46 months). Median overall survival was 12.1 months (95% CI 9.6-13.5 months); 1- and 2-year overall survivals were 51 and 14%, respectively. Grade 3/4 toxicity (> or = 10%): neutropenia (39%), thrombocytopenia (22%), dehydration (10%), diarrhea (31%), fatigue (20%), and pulmonary symptoms (10%). No significant bleeding occurred., Conclusions: In this phase II trial, irinotecan, carboplatin, and bevacizumab achieved response, TTP, and survival outcomes that compare favorably with larger randomized trials using chemotherapy alone. Randomized trials can best assess bevacizumab's impact in the first-line treatment of extensive-stage SCLC.

Purpose: We aim to compare the efficacy and toxicity of liposomal doxorubicin and weekly docetaxel as first-line treatments for patients with metastatic breast cancer (MBC)., Patients and Methods: Patients who had received no previous chemotherapy for MBC were eligible. Previous hormonal therapy, adjuvant chemotherapy, and radiation therapy were allowed. Patients were randomized to receive liposomal doxorubicin 40 mg/m(2) intravenously [I.V.] every 28 days or weekly docetaxel 36 mg/m(2) I.V. days 1, 8, and 15, repeated every 28 days. Patients with objective response or stable disease after 2 cycles continued treatment until tumor progression or unacceptable toxicity. At progression, patients were allowed to cross over to the other regimen. The trial was designed to detect a true difference of 10% in response rate with an 80% power., Results: Between March 2001 and July 2007, 102 patients were randomized. The 2 groups had similar demographics; 68% of patients had received previous adjuvant chemotherapy. Liposomal doxorubicin and weekly docetaxel produced similar objective response rates (28% vs. 31%), disease control rates (48% vs. 44%), and progression-free survival (6.5 months vs. 5.5 months). Both agents were well tolerated. Both agents produced crossover responses as second-line treatment (liposomal doxorubicin, 35%; weekly docetaxel, 14%)., Conclusion: Liposomal doxorubicin is well tolerated and has activity similar to weekly docetaxel in the first-line treatment of patients with MBC.