Recurrent Nonsquamous Nonsquamous Non-small Cell Lung Cancer Research Articles

Association of thyroid transcription factor-1 (TTF-1) expression with efficacy of PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in advanced non-squamous non-small cell lung cancer.

Thyroid transcription factor-1 (TTF-1) expression in advanced non-squamous non-small cell lung cancer (NSCLC) has been associated with the efficacy of pemetrexed plus platinum chemotherapy. However, the relation between TTF-1 expression and efficacy of the combination of programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors plus pemetrexed and platinum chemotherapy, a standard first-line treatment regimen for advanced non-squamous NSCLC, has remained unclear. We retrospectively evaluated TTF-1 expression in tumor tissue of patients with advanced or recurrent non-squamous NSCLC treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting. Clinical characteristics and pathological data for each patient were assessed, and progression-free survival (PFS) was evaluated. Bias due to patient background was minimized by application of inverse probability of treatment weighting (IPTW) analysis. A total of 122 patients, 75 (61.5%) of whom were positive for TTF-1 immunostaining in tumor specimens, was included in this multicenter study. At the time of analysis, 89 (73.0%) patients had experienced progression events and 44 (36.1%) had died [median follow-up 14.6 months (range, 0.53-29.5 months)]. PFS was longer for TTF-1-positive patients than for TTF-1-negative patients [median, 12.2 vs. 6.0 months; hazard ratio (HR) =0.63 (95% CI: 0.37-1.06); log-rank P=0.028]. IPTW-adjusted PFS was significantly longer for TTF-1-positive than for TTF-1-negative patients [HR =0.62 (95% CI: 0.46-0.83); log-rank P=0.024]. TTF-1 expression in advanced non-squamous NSCLC can serve as a basis for prediction of PFS in patients treated with PD-1/PD-L1 inhibitors plus pemetrexed and platinum chemotherapy in the first-line setting.

Cost-Effectiveness of Bevacizumab Biosimilar LY01008 Combined With Chemotherapy as First-Line Treatment for Chinese Patients With Advanced or Recurrent Nonsquamous Non-Small Cell Lung Cancer.

Objective: To investigate whether LY01008, a locally developed bevacizumab biosimilar agent, is appropriate for widespread use among Chinese advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC) patients, our current study was designed to evaluate the cost-effectiveness of first-line LY01008 combined with platinum-doublet chemotherapy versus chemotherapy alone from the perspective of the Chinese healthcare system. Material and Methods: This economic evaluation designed a Markov model to compare the healthcare cost and quality-adjusted life-year (QALY) of first-line LY01008 combined with chemotherapy versus first-line chemotherapy. Transition probabilities, including disease progression, survival, and adverse event (AE)-related discontinuation of first-line treatment, were estimated using data from the clinical trials. Costs and health utilities were derived from local databases, hospitals, and published literature. Our base case analysis and scenario analysis focused on the cost-effectiveness of chemotherapy combined with a clinical trial dosage (15 mg/kg every 3-week cycle) and a real-world dosage (7.5 mg/kg every 3-week cycle) of LY01008, respectively. Results: In the base case analysis, first-line LY01008 combined with chemotherapy was associated with an increase of 0.48 QALYs in effectiveness and an increase of CNY 189,988 (US$ 26,240) in healthcare costs compared with first-line chemotherapy, resulting an incremental cost-effectiveness ratio (ICER) of CNY 375,425 (US$ 54,430)/QALY. In the scenario analysis, first-line LY01008 combined with chemotherapy was associated with a mean healthcare cost of CNY 265,060 (US$ 38,429), resulting an ICER of CNY 221,579 (US$ 32,125/QALY) between first-line LY01008 combined with chemotherapy versus first-line chemotherapy. The parameters that determine the cost of LY01008 have the greatest impact on the cost-effectiveness results. Conclusion: From the perspective of the Chinese healthcare system, first-line LY01008 at a real-world dosage combined with chemotherapy is likely to represent a cost-effective strategy compared with first-line chemotherapy alone for Chinese advanced or recurrent nonsquamous NSCLC patients.

Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer

This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous non-small-cell lung cancer (NSCLC). Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC). Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively. The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC.

Open-label, multicenter, randomized phase II study on docetaxel plus bevacizumab or pemetrexed plus bevacizumab for treatment of elderly (aged ≥75 years) patients with previously untreated advanced non-squamous non-small cell lung cancer: TORG1323.

BackgroundThe effectiveness of bevacizumab monotherapy in elderly patients with non-squamous non-small cell lung cancer (NSCLC) is unclear. The efficacy of the combinations for elderly patients was explored.MethodsUntreated patients (≥75 years; performance status 0–1) with stage IIIB, IV, or recurrent non-squamous NSCLC were included. Patients with epidermal growth factor receptor (EGFR) mutation or anaplastic lymphoma kinase (ALK) gene rearrangements were eligible even if they received tyrosine kinase inhibitors. Patients were randomized 1:1 to receive docetaxel (50 mg/m2) (DB) or pemetrexed (500 mg/m2) (PB) with bevacizumab (15 m/kg). The primary endpoint was progression-free survival (PFS). Treatment was administered every 3 weeks until disease progression or unacceptable toxicity.ResultsOverall, 103 patients (DB: n=51; PB: n=52) were enrolled. In the DB and PB arms, median ages [range] were 78 [75–88] and 79 [75–94] years, respectively; median PFS were 6.1 and 4.6 months, respectively [hazard ratio (HR), 1.03; 95% confidence interval (CI), 0.66–1.61]; and response rates were 43%, and 40%, respectively (P=0.840). Grade ≥3 leukopenia, neutropenia, and fatigue incidences were significantly higher in the DB arm. Febrile neutropenia incidence did not differ significantly (16% vs. 12%, P=0.578). One patient in the PB arm died from a ruptured abdominal aortic aneurysm. Quality of life (QoL) analysis revealed less deterioration in the PB arm.ConclusionsIn previously untreated elderly patients with non-squamous NSCLC, PB shows feasibility, better QoL, and promising efficacy in terms of PFS, and an objective response rate for further analysis (UMIN000012786).

1565P - A phase III study comparing SB8, a proposed bevacizumab biosimilar, and reference bevacizumab in patients with metastatic or recurrent non-squamous NSCLC

BackgroundSB8 is a proposed biosimilar of the reference bevacizumab (BEV). This study compared the efficacy, safety, pharmacokinetics (PK), and immunogenicity of SB8 to BEV in patients with metastatic or recurrent non-squamous non-small cell lung cancer (NSCLC). MethodsIn this randomised, double-blind, multicentre study, patients were randomised (1:1) to receive SB8 or BEV with paclitaxel and carboplatin Q3W followed by SB8 or BEV maintenance therapy until disease progression, unacceptable toxicity, death, or 1 year from the randomisation of the last patient. The primary endpoint was the best overall response rate (ORR) by 24 weeks of chemotherapy; risk ratio was analyzed in the full analysis set (FAS) and risk difference was analyzed in the per-protocol set (PPS). Secondary endpoints were progression free survival (PFS), overall survival (OS), duration of response (DOR), safety, PK, and immunogenicity. ResultsA total of 763 patients (SB8, n=379; BEV, n=384) were randomized. Baseline characteristics were balanced between SB8 and BEV. In the FAS, the best ORR was 47.6% in SB8 and 42.8% in BEV; the risk ratio was 1.11 and its 90% CI was [0.975, 1.269], which was within the pre-defined equivalence margin of [0.737, 1.357]. In the PPS, the best ORR was 50.1% in SB8 and 44.8% in BEV; the risk difference was 5.3% and its 95% CI was [−2.2%, 12.9%], of which the lower margin was contained within and the upper margin was outside the pre-defined equivalence margin of [−12.5%, 12.5%]. The secondary efficacy endpoints in the FAS were comparable between SB8 vs BEV: median PFS (8.50 vs 7.90 months), median OS (14.90 vs 15.80 months), and median DOR (5.60 vs 5.85 months). The overall incidence of treatment-emergent adverse events (TEAEs) was comparable between SB8 vs BEV (92.1% vs 91.1%). The most frequently occurring TEAEs were alopecia, anaemia, and nausea. PK parameters (Ctrough and Cmax) and the incidence of overall anti-drug antibodies (16.1% vs 11.0%) were comparable between SB8 vs BEV. ConclusionsThis study demonstrated equivalence between SB8 and BEV in terms of best ORR risk ratio. Other efficacy endpoints, safety, PK, and immunogenicity were comparable between SB8 and BEV. Clinical trial identificationNCT02754882. Legal entity responsible for the studySamsung Bioepis Co., Ltd. FundingSamsung Bioepis Co., Ltd. DisclosureM. Reck: Honoraria (self), Advisory / Consultancy: Samsung Bioepis Co., Ltd.; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Amgen; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: BMS; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy: Celgene; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Merck; Honoraria (self), Advisory / Consultancy: MSD; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Pfizer; Honoraria (self), Advisory / Consultancy: Roche. J. Choi: Full / Part-time employment: Samsung Bioepis Co., Ltd. D. Shin: Full / Part-time employment: Samsung Bioepis Co., Ltd. All other authors have declared no conflicts of interest.

P2.03a-014 A Dose-Finding and Phase 2 Study of Ruxolitinib plus Pemetrexed/Cisplatin for Nonsquamous Non–Small Cell Lung Cancer (NSCLC)

Dysregulation of the JAK/STAT pathway contributes to abnormal inflammatory responses, oncogenesis, treatment resistance, and poor prognosis in NSCLC. This phase 2 clinical trial evaluated the JAK1/JAK2 inhibitor ruxolitinib+pemetrexed/cisplatin as first-line treatment for patients with stage IIIB/IV or recurrent nonsquamous NSCLC and systemic inflammation (per modified Glasgow Prognostic Score [mGPS]). Key inclusion criteria were mGPS of 1/2 and ECOG performance status ≤1. Part 1, an open-label, 21-day safety run-in, assessed ruxolitinib (15 mg BID [chosen dose for Part 2]) plus pemetrexed (500 mg/m2 IV on Day 1) and cisplatin (75 mg/m2 IV on Day 1). Ruxolitinib dose selection for Part 2 required <3 dose-limiting toxicities (DLTs) for 9 evaluable patients. Part 2 randomized patients to ruxolitinib+pemetrexed/cisplatin or placebo+pemetrexed/cisplatin. The trial was terminated early for lack of efficacy in other solid tumor programs in patients with high systemic inflammation. All 15 patients enrolled in Part 1 received ruxolitinib 15 mg BID plus pemetrexed/cisplatin. Median age was 64 years; male, 80%; mGPS 1, 80%. Median treatment duration was 140 days. The Table reports Part 1 safety data. Four patients were inevaluable for DLTs (<80% compliance, n=2; disease progression, n=2). No DLTs occurred in 11 evaluable patients. The Part 1 overall response rate (ORR) was 53% (8/15; all partial responses). At study termination, 39 and 37 patients were randomized in Part 2 to ruxolitinib and placebo, respectively. Median treatment duration was 43 days. ORR was 31% (12/39) with ruxolitinib+pemetrexed/cisplatin versus 35% (13/37) with placebo+pemetrexed/cisplatin (all partial responses). The short follow-up duration may limit interpretation of Part 2 efficacy. The Part 2 safety profile was consistent with Part 1 (data to be presented).TableThe Most Common Treatment-Emergent Adverse Events in Part 1Event, n (%)Ruxolitinib+Pemetrexed/Cisplatin (N=15)All-GradeGrade 3/4Nonhematologic*Nausea11(73)1(7)Fatigue8(53)3(20)Vomiting8(53)1(7)Constipation7(47)0Diarrhea7(47)0Dizziness7(47)0Peripheral edema7(47)0Decreased appetite6(40)0Pyrexia6(40)0Dyspnea5(33)1(7)Pneumonia4(27)3(20)Pulmonary embolism2(13)2(13)Sepsis2(13)2(13)New/worsening hematologic laboratory abnormalitiesAnemia13(87)5(33)Lymphopenia11(73)2(13)Leukopenia9(60)1(7)Neutropenia9(60)5(33)Thrombocytopenia9(60)1(7)*Common all-grade (≥30%) or grade 3/4 (≥10%) events. Open table in a new tab *Common all-grade (≥30%) or grade 3/4 (≥10%) events. Ruxolitinib 15 mg BID had an acceptable safety profile in combination with pemetrexed/cisplatin as first-line treatment of patients with stage IIIB/IV or recurrent nonsquamous NSCLC.

Patients' Attitudes and Physicians' Perceptions Toward Maintenance Therapy for Advanced Non–Small-cell Lung Cancer: A Multicenter Italian Survey

IntroductionPemetrexed maintenance therapy (MT) after induction with platinum-based chemotherapy has recently become a common treatment strategy for advanced nonsquamous non–small-cell lung cancer (NSCLC). However, the benefits of MT should be weighed with consideration of the patients' perceptions and preferences. The aim of the present study was to evaluate patients' attitudes toward MT and to describe physicians' awareness of their patients' inclinations. Materials and MethodsWe administered a 12-question anonymous survey and the Distress Thermometer Questionnaire to patients with advanced or recurrent nonsquamous NSCLC. The survey was also distributed to the referring physicians. ResultsFrom December 2014 to July 2015, 92 patients and 37 physicians were enrolled. All 92 patients completed the questionnaire at T0 (before starting chemotherapy) and 56.5% also did so at T1 (after completion of induction). The physicians completed the survey only at T0. Most patients had a positive attitude toward MT at both T0 (78.9%) and T1 (86.5%), and 100% of the physicians thought their patients would be in favor of MT. The physicians believed that their patients' attitudes toward MT would decrease proportionally with the reduction in the magnitude of the overall survival increase and expected benefits. The decrease expected by the physicians was much greater than that reported by the patients. This was especially true for an overall survival increase as small as 1 month (51.9% of patients accepting MT vs. 13.5% supposed by physicians) or when the only treatment benefit was radiologic tumor stabilization (69.3% of patients accepting MT vs. 37.8% supposed by physicians). ConclusionNSCLC patients have a generally positive attitude toward MT, which is not directly proportional to the expected benefits and greater than the attitude expected by physicians.

Nintedanib plus pemetrexed versus placebo plus pemetrexed in patients with relapsed or refractory, advanced non-small cell lung cancer (LUME-Lung 2): A randomized, double-blind, phase III trial

ObjectivesLUME-Lung 2 investigated the efficacy/safety of nintedanib plus pemetrexed in patients with pretreated non-squamous non-small cell lung cancer (NSCLC). Materials and methodsPatients with stage IIIB/IV or recurrent non-squamous NSCLC who had received one prior chemotherapy regimen were randomized (1:1 stratified by histology [adenocarcinoma/non-adenocarcinoma], prior bevacizumab, Eastern Cooperative Oncology Group performance status and presence of brain metastases) to receive intravenous pemetrexed 500mg/m2 on Day 1 plus nintedanib 200mg orally twice daily or matching placebo on Days 2–21, every 3 weeks until progression/unacceptable toxicity. Progression-free survival (PFS) by independent central review was the primary endpoint. Overall survival (OS) was the key secondary endpoint. ResultsBased on the pre-planned futility analysis of investigator-assessed PFS, conducted by an independent data monitoring committee, recruitment was halted on 18 June 2011 after 713 (n=353 nintedanib/pemetrexed; n=360 placebo/pemetrexed)/1300 planned patients had enrolled. There were no safety concerns. Subsequent analysis demonstrated a significant improvement in PFS favoring nintedanib/pemetrexed over placebo/pemetrexed (median 4.4 months vs 3.6 months; hazard ratio [HR]=0.83, 95% confidence interval [CI] 0.70–0.99, p=0.0435). There was no significant difference in OS (median 12.0 months vs 12.7 months; HR=1.01, 95% CI 0.85–1.21, p=0.8940) after 514 deaths. Nintedanib/pemetrexed resulted in a higher incidence of grade ≥3 elevated alanine aminotransferase (23.3% vs 7.3%), elevated aspartate aminotransferase (12.1% vs 1.7%) and diarrhea (3.5% vs 1.1%) compared with placebo/pemetrexed, but no difference in hypertension, bleeding or thrombosis. ConclusionAlthough recruitment stopped prematurely, combining nintedanib with pemetrexed significantly prolonged PFS in patients with advanced non-squamous NSCLC after first-line chemotherapy, with a manageable safety profile.

Feasibility study of first-line chemotherapy using Pemetrexed and Bevacizumab for advanced or recurrent nonsquamous non-small cell lung cancer in elderly patients: TORG1015.

BackgroundThe addition of bevacizumab to cytotoxic agents prolongs survival in patients with nonsquamous non-small cell lung cancer (NSCLC). To date, there is no evidence to suggest that treatment with a cytotoxic agent plus bevacizumab is more effective than a cytotoxic agent alone for nonsquamous NSCLC in elderly patients. We conducted a feasibility study of pemetrexed plus bevacizumab as a first-line treatment for advanced or recurrent nonsquamous NSCLC in elderly patients.MethodsMajor eligibility and exclusion criteria included: chemotherapy-naive status; non-fitness for bolus combination chemotherapy; stage III/IV or relapsed nonsquamous NSCLC; age ≥70; performance status 0–1; absence of brain metastasis; and no history of hemoptysis and thoracic irradiation. Pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) were administered intravenously on day 1, and repeated every 3 weeks thereafter. The primary endpoint was safety, and the secondary endpoints were objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and the percentage of patients who completed ≥3 cycles.ResultsFrom October 2010 to April 2012, a total of 12 patients were enrolled. No dose-limiting toxicity or treatment-related deaths were observed. Three patients achieved PR, and the ORR was 25 %. The median PFS and OS were 5.4 months (95 % CI 1.1–8.8 months) and 13.6 months (95 % CI 5.3–15.6 months), respectively. Seven of 12 patients (58 %) received ≥3 cycles.ConclusionsPemetrexed plus bevacizumab in the treatment of elderly patients with nonsquamous NSCLC was well tolerated and shows promise as first-line treatment.Trial registrationUMIN Clinical Trial Registry; UMIN000004263. Registered on 25 September, 2010.

1218 - Prospective, Single-Arm, Post-Marketing Clinical Study of Pemetrexed (PEM) and Carboplatin Combination Followed by Maintenance Pem in Chemo-Naïve Japanese Patients with Non-Squamous Non-Small Cell Lung Cancer (NSCLC): 24 Month Follow-Up OS Results

ABSTRACT Background Platinum doublet chemotherapy is standard first-line treatment for advanced NSCLC, however, further studies are required to establish the effectiveness of maintenance therapy. The aim of this study was to evaluate the efficacy and safety of Pem/Carboplatin (Cb) followed by Pem in Japanese patients (pts) with advanced non-squamous NSCLC. This study is sponsored by Eli Lilly Japan K.K. (ClinicalTrials.gov: NCT01020786). Patients and methods Pts were chemo-naive with unresectable stage IIIB, IV or postoperative recurrent non-squamous NSCLC, and a PS (ECOG) of 0-1. Pts received Cb AUC 6 and Pem 500 mg/m2 on Day 1 of each 21-day cycle for 4 cycles as induction therapy. Pts who achieved non-PD at the end of the 4-cycle induction therapy could continue Pem as maintenance therapy until PD. The primary endpoint was PFS, and it was assumed that the threshold and the expected values for the median PFS were 5 and 7 months, respectively. Results A total of 111 pts were enrolled. Of the 109 treated pts, 75 pts (69%) completed induction therapy and 60 pts (55%) entered maintenance therapy; 15 pts (14%) discontinued in the 4th cycle due to PD (8 pts), AE (4 pts), and investigator or subject decision (3 pts). Pts (n = 109): median age 63 years, stage IV/others (66%/34%), PS 0/1 (34%/66%), EGFR-mutant/wild-type/unknown (22%/58%/20%). Among the 109 pts, 38 pts (35%) achieved PR, 41 pts (38%) SD, and 21 pts (19%) PD. Median PFS and MST from enrollment was 5.6 months (95% CI: 4.3, 7.2) and 20.2 months (95% CI: 16.7, incalculable), respectively. The MST for EGFR (-) pts was 19.4 months; MST could not be calculated for EGER ( + ) pts (17 pts [71%] censored). The most common Gr 3/4 toxicities in the induction and maintenance phases were neutropenia (57%), thrombocytopenia (41%), anemia (31%), whereas Gr 3 febrile neutropenia occurred in 1 pt without any regimen-related deaths. Conclusions PFS as the primary endpoint was not better than expected, but other endpoints seemed favorable. Hematologic toxicities were frequently observed. Updated data including MST will be presented at the congress. Disclosure S. Enatsu: An employee of Eli Lilly Japan K.K. R. Sekiguchi: An employee of Eli Lilly Japan K.K. All other authors have declared no conflicts of interest.

First-Line Bevacizumab-Based Therapy in Advanced Non-Squamous Non-Small-Cell Lung Cancer

First-line bevacizumab-based therapy has been shown to improve outcomes in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). The recent international phase IV SAiL study (a Study of Avastin [bevacizumab] in combination with platinum-containing chemotherapy in patients with advanced or recurrent non-squamous cell Lung cancer) evaluated the safety and efficacy of bevacizumab combined with standard chemotherapy regimens in routine clinical practice. Here we report the results of a subanalysis of baseline characteristics and efficacy data for Italian patients enrolled in SAiL. In the SAiL study, patients with untreated locally advanced, metastatic or recurrent non-squamous NSCLC received bevacizumab (7.5 or 15 mg/kg) every 3 weeks plus chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. Efficacy was assessed in terms of time to disease progression (TTP) and overall survival (OS). The Italian intent-to-treat population comprised 215 patients from a SAiL population of 2212 patients. At baseline, Italian patients tended to have less advanced disease than the overall population. Thus, the proportion of patients at enrollment with tumour stage IIIb and IV was 23.7 and 76.3 %, respectively, for the Italian population versus 19.7 and 80.3 % for the whole SAiL population. In addition, a higher proportion of Italian patients had an Eastern Cooperative Oncology Group performance status of 0 (72.6 vs. 37.2 %) and the prevalence of co-morbid conditions was lower in Italian patients (59.5 % of Italian patients reported a co-morbid condition and 60.0 % were receiving non-oncological treatment compared with 73.3 and 73.4 %, respectively, of SAiL patients overall). The mean exposures to bevacizumab and to chemotherapy were comparable between the Italian patient group and overall patient population, although cisplatin doublets were more commonly employed in Italian patients whereas carboplatin doublets were more commonly employed in the overall SAiL population. The median TTP and OS times for Italian and SAiL populations were comparable (TTP, 7.8 months vs. 7.8 months; OS, 14.8 months vs. 14.6 months). The results of this subanalysis of the SAiL study of bevacizumab treatment in routine clinical practice suggest that Italian oncologists tend to prescribe bevacizumab to a selected population of patients with less advanced disease than is the case in the overall population. Nevertheless, the first-line use of bevacizumab in combination with chemotherapy offers clinical benefits to Italian patients with advanced or recurrent non-squamous NSCLC.

International, Randomized, Placebo-Controlled, Double-Blind Phase III Study of Motesanib Plus Carboplatin/Paclitaxel in Patients With Advanced Nonsquamous Non–Small-Cell Lung Cancer: MONET1

We evaluated whether motesanib (a selective oral inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit) combined with carboplatin/paclitaxel improved overall survival (OS) versus chemotherapy alone in patients with nonsquamous non-small-cell lung cancer (NSCLC) and in the subset of patients with adenocarcinoma. Patients with stage IIIB/IV or recurrent nonsquamous NSCLC (no prior systemic therapy for advanced disease) were randomly assigned 1:1 to carboplatin (area under the curve, 6 mg/ml · min) and paclitaxel (200 mg/m(2)) intravenously for up to six 3-week cycles plus either motesanib 125 mg (arm A) or placebo (arm B) once daily orally. OS was the primary end point. Secondary end points included progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), and association between placental growth factor (PLGF) change and OS. A total of 1,090 patients with nonsquamous NSCLC were randomly assigned (arms A/B, n = 541 of 549); of those, 890 had adenocarcinoma (n = 448 of 442). Median OS in arms A and B was 13.0 and 11.0 months, respectively (hazard ratio [HR], 0.90; 95% CI, 0.78 to 1.04; P = .14); median OS for the adenocarcinoma subset was 13.5 and 11.0 months, respectively (HR, 0.88; 95% CI, 0.75 to 1.03; P = .11). In descriptive analyses (arms A v B), median PFS was 5.6 months versus 5.4 months (P = < .001); ORR was 40% versus 26% (P < .001). There was no association between PLGF change and OS in arm A. The incidence of grade ≥ 3 AEs (arms A and B, 73% and 59%, respectively) and grade 5 AEs (14% and 9%, respectively) was higher with motesanib treatment. Motesanib plus carboplatin/paclitaxel did not significantly improve OS over carboplatin/paclitaxel alone in patients with advanced nonsquamous NSCLC or in the adenocarcinoma subset.

Phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC): Asian subgroup analysis.

7549 Background: MONET1 evaluated overall survival (OS) in patients (pts) with nonsquamous NSCLC receiving motesanib (an oral VEGFR 1, 2 and 3, PDGFR and Kit inhibitor) plus C/P compared with pts receiving placebo plus C/P. Analysis of the total population (N=1090) showed that motesanib + C/P did not significantly improve OS vs C/P alone (primary endpoint). Here we present results of a subgroup analysis of Asian pts. Methods: Asian pts (Japan, S. Korea, Philippines, Hong Kong, Taiwan, Singapore) with stage IIIB/IV or recurrent nonsquamous NSCLC and no prior systemic therapy for advanced NSCLC were analysed. Pts were randomized to up to six 3-wk cycles of C (AUC 6 mg/mL·min) and P (200 mg/m2) with either motesanib 125 mg QD (Arm A) or placebo QD (Arm B) orally continuously. Results: 227 Asian pts (incl. 106 Japanese pts) with nonsquamous NSCLC were randomized (Arm A/B, n=110/117); 198 had adenocarcinoma (n=97/101). Median age was 60 y (range 30–78); 80% had stage IV disease. At the time of analysis, 139 pts had died (118 pts with adenocarcinoma). Pts received a median of 164 days of motesanib vs 125 days of placebo (vs 106 and 126 days in non-Asian pts). Median follow-up was 63 wks. Efficacy results are shown in the table. Motesanib/placebo-related AEs were seen in 94/74% of pts respectively; Gr ≥3 related AEs in 48/22%. Most common emergent AEs were (Arm A/B) alopecia (78/76%), diarrhea (63/33%), and nausea (55/43%); gallbladder disorders (Gr 1–2) were seen in 9/2% of pts. Gr ≥3 AEs more frequent in Arm A vs B included neutropenia (36/22%) and hypertension (13/3%). Emergent Gr 5 events were seen in (Arm A/B) 5/4% vs 16/11% in non-Asian pts. Conclusions: In contrast to non-Asian pts, in the subgroup of Asian pts with advanced nonsquamous NSCLC, motesanib plus C/P treatment was associated with increased OS, PFS, and objective response rates (ORR) compared with C/P alone, with no excess of treatment-related mortality. [Table: see text]

A randomized phase II study of axitinib in combination with pemetrexed/cisplatin (pem/cis) as first-line therapy for nonsquamous non-small cell lung cancer (NSCLC).

7551 Background: Axitinib is a potent and selective second-generation inhibitor of VEGF receptors 1, 2, and 3 that has promising single-agent activity in advanced NSCLC. Efficacy and safety of axitinib (in 2 dosing schedules) combined with pem/ciswere evaluatedfor non-squamous NSCLC. Methods: Patients with confirmed stage IIIB, IV, or recurrent non-squamous NSCLC and ECOG performance status (PS) 0 or 1 were stratified by gender and PS, and randomized 1:1:1 to receive six 21-day cycles of axitinib continuously plus pem/cis (arm I); axitinib on Days 2 through 19 followed by a 3-day interruption plus pem/cis (arm II); or pem/cis alone (arm III). Axitinib was administered at a starting dose of 5 mg BID. Pem/cis (500/75 mg/m2) was infused on Day 1 of each cycle. Primary endpoint was progression-free survival (PFS). Results: Baseline characteristics of patients in arm I (n=55), arm II (n=58), or arm III (n=57) ranged between 59–62 yr median age; 62–65% male; 71–85% White; 73–85% current/ex-smokers; and 43–47% PS 0. There were no significant differences in PFS or overall survival (OS) between axitinib-containing arms I and II compared with pem/cis alone, but objective response rates (ORR) were higher (Table). Most common all causality grade 3 adverse events (AEs) in arm I, II, and III, respectively, were hypertension (20%, 17%, 0%); neutropenia (18%, 10%, 9%); nausea (16%, 5%, 7%); vomiting (13%, 5%, 4%); fatigue (11%,16%,16%); and anemia (7%, 14%, 9%). Grade 4 AEs observed in &gt;1 patient were asthenia and pulmonary embolism (2 patients each in arm II). Conclusions: Axitinib combined with pem/cis was generally well tolerated, but efficacy was not significantly better than pem/cis alone in non-squamous NSCLC. [Table: see text]

Bevacizumab in combination with first-line metastatic chemotherapy in patients with advanced nonsquamous non-small cell lung cancer (NSCLC): Results from the cohort study EOLE.

e18005 Background: EOLE, a large cohort of 423 patients included in 1 year (July 2010 – July 2010) with locally advanced, metastatic or recurrent non-squamous NSCLC, aimed to describe the targeted population receiving first-line bevacizumab (Bev) in addition to chemotherapy with regards to progression-free survival, overall survival, safety and quality of life in real clinical practice. Methods: Patients who received physician’s choice of 1st-line Bev-containing treatment were included in this cohort study. Results: This analysis describes the inclusion data of 417 patients consisting of adenocarcinoma (92%), large cell carcinoma (4%), undifferentiated carcinoma in predominantly non-squamous (3%), bronchoalveolar carcinoma (1%). Patient characteristics were as follow: the median age being 60 (years) [32; 84], more males than females (68%), 40% had a baseline ECOG Performance Status (PS) 0, 47% of PS 1 and 12% of PS 2, most patients had Stage IV disease (91%), 13% of patients had never smoked. Tumor location was reported as central for 17% of patents and among them 4% was in contact with the large vessels. For 3% of the lesions a cavitation was notified; and 20% of included patients had brain metastases. The main comorbidities at the inclusion were: cardiovascular (45%), arterial thromboembolic and /or venous (20%) with pulmonary embolism (3%); related to the tumor lesion - bloody sputum (4%) and hemoptysis (1%). 68% of patients have received the dose of Bev 7.5mg/kg q3w; for 49% of patients Bev was combined with cisplatin/pemetrexed, 24% with carboplatin/paclitaxel, 13% with carboplatin/pemetrexed and 7% with cisplatin/gemcitabine. The EGFR mutation analysis was carried out for about 50% of patients. Conclusions: Compared to AVAil and SAil studies, EOLE cohort included more patients classified as having: a baseline PS of 2 (p &lt;0.0001, Fisher test), a never smoked status (p&lt;0.0001, chi2 test) and an adenocarcinoma (92%) (p&lt;0.0001, chi2 test). Around a half of included patients received combination Bev - cisplatin /pemetrexed.

Randomized phase II study of first-line carboplatin-paclitaxel with or without bevacizumab in Japanese patients with advanced non-squamous non-small-cell lung cancer

PurposeThis multicenter, randomized, open-label, phase II study (JO19907) compared the efficacy and safety of first-line carboplatin-paclitaxel (CP) alone with bevacizumab-CP in Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). MethodsChemonaïve patients with stage IIIB, IV or recurrent non-squamous NSCLC were eligible for participation. Patients were randomly assigned in a 2:1 ratio to receive bevacizumab-CP or CP alone. Chemotherapy was repeated for up to 6 cycles or until disease progression or unacceptable toxicity. Bevacizumab recipients who completed ≥3 cycles of chemotherapy could continue bevacizumab as monotherapy until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). ResultsAfter confirming the tolerability of bevacizumab-CP in a small number of patients, 180 patients were recruited, of whom 121 were assigned to bevacizumab-CP and 59 to CP alone. Hazard ratio (HR) for PFS was 0.61 with bevacizumab-CP versus CP alone (p=0.0090; median 6.9 versus 5.9 months). Objective response rate was significantly higher with bevacizumab-CP than with CP alone (60.7% versus 31.0%; p=0.0013). Median overall survival was >22 months in both treatment groups (HR 0.99; p=0.9526). No new safety signals were detected. ConclusionStudy JO19907 met its primary endpoint, demonstrating that the addition of bevacizumab to first-line CP significantly improves PFS in Japanese patients with advanced non-squamous NSCLC. This prolonged PFS by bevacizumab did not translate into OS benefit with the extremely longer underlying survival compared to historical data. No new safety signals were identified in this population. (Japan Pharmaceutical Information Center [JAPIC] registration number: CTI-060338).

An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC).

LBA7512 Background: This study evaluated whether motesanib (a selective oral inhibitor of VEGFR 1, 2 and 3; PDGFR and Kit) plus C/P improved overall survival (OS) compared with placebo + C/P in patients (pts) with nonsquamous NSCLC and in a subset of pts with adenocarcinoma. Methods: Pts had stage IIIB/IV or recurrent nonsquamous NSCLC and no prior systemic therapy for advanced NSCLC. The study initially enrolled all histologies but was amended to exclude pts with squamous NSCLC owing to a high rate of hemoptysis. Pts were randomized 1:1 to receive up to six 3-wk cycles of C (AUC 6 mg/mL·min) and P (200 mg/m2) with either motesanib 125 mg QD (Arm A) or placebo QD (Arm B) orally continuously. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), adverse events (AEs), objective response rate (ORR) and association between placental growth factor (PLGF) change and OS. OS was evaluated using a stratified Cox model and 2-sided log-rank test (α=0.03 for nonsquamous pts and α=0.02 for adenocarcinoma pts). Results: 1090 pts with nonsquamous NSCLC were randomized (Arm A/B, n=541/549); 890 had adenocarcinoma (n=448/442). 61% were men; median age was 60 years (range 21–87); 83% had stage IV disease. At the time of analysis, 753 pts had died (608 pts with adenocarcinoma). Median follow-up was 10.6 mo. OS was not significantly improved in Arm A compared with Arm B (Table). In Arm A, PLGF analysis did not show an association with OS. The incidence of grade ≥3 AEs in Arms A/B was 73/59%. Grade ≥3 AEs occurring more frequently in Arm A than B included neutropenia (22/15%), diarrhea (9/1%), hypertension (7/1%) and cholecystitis (3/0%). The incidence of grade 5 AEs was 14/9% in Arms A/B. Conclusions: In pts with advanced nonsquamous NSCLC, treatment with motesanib + C/P did not significantly improve OS compared with C/P alone. [Table: see text]

Safety and efficacy of first-line bevacizumab-based therapy in advanced non-squamous non-small-cell lung cancer (SAiL, MO19390): a phase 4 study

Results of two phase 3 trials have shown first-line bevacizumab in combination with chemotherapy improves clinical outcomes in patients with advanced or recurrent non-squamous non-small-cell lung cancer (NSCLC). The SAiL (MO19390) study was undertaken to assess the safety and efficacy of first-line bevacizumab combined with standard chemotherapy regimens in clinical practice. Between August, 2006, and June, 2008, patients with untreated locally advanced, metastatic, or recurrent non-squamous NSCLC were recruited to this open-label, single group, phase 4 study from centres in 40 countries. Eligible patients had histologically or cytologically documented inoperable, locally advanced, metastatic, or recurrent disease (stage IIIB-IV); an Eastern Cooperative Oncology Group performance status of 0-2; and adequate haematological, hepatic, and renal function. Patients received bevacizumab (7.5 or 15 mg/kg every 3 weeks) plus standard chemotherapy for up to six cycles, followed by single-agent bevacizumab until disease progression. The primary endpoint was safety; analysis was by intention to treat (ITT). This study is registered with ClinicalTrials.gov, number NCT00451906. At the final data cutoff (July 24, 2009), an ITT population of 2212 patients was assessed. The incidence of clinically significant (grade > or = 3) adverse events of special interest was generally low; thromboembolism occurred in 172 (8%) patients, hypertension in 125 (6%), bleeding in 80 (4%), proteinuria in 67 (3%), and pulmonary haemorrhage in 15 (1%). 57 (3%) patients died because of these adverse events, with thromboembolism (26 patients, 1%) and bleeding (17, 1%) as the most common causes. The most common grade 3 or higher serious adverse events deemed by investigators to be associated with bevacizumab were pulmonary embolism (28 patients; 1%) and epistaxis, neutropenia, febrile neutropenia, and deep vein thrombosis (all of which occurred in 13 patients [1%]). Bevacizumab was temporarily interrupted after 28 (2%) of 1347 bleeding events and 72 (7%) of 1025 hypertension events, and permanently discontinued after 110 (8%) bleeding events and 40 (4%) hypertension events. No new safety signals were reported. Our results confirm the manageable safety profile of first-line bevacizumab in combination with various standard chemotherapy regimens for treatment of advanced non-squamous NSCLC. F Hoffmann-La Roche Ltd.

Randomized, open-label, multicenter phase II study of bevacizumab in combination with carboplatin and paclitaxel in chemotherapy-naive Japanese patients with advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC): JO19907

8036^ Background: Two phase III trials (ECOG 4599 and BO17704) demonstrated that the addition of bevacizumab (Bev) to platinum-based regimens improved overall and/or progression-free survival (PFS) in patients (pts) with advanced non-squamous NSCLC (Sandler et al. NEJM 2006; Manegold et al. ESMO2008). However, no investigation with Bev has been conducted in Japanese NSCLC pts. Methods: This randomized, open-label phase II study compared a 3-weekly regimen of 15mg/kg of Bev plus carboplatin/paclitaxel (CP) versus CP alone. The primary endpoint was PFS; secondary endpoints included overall survival (OS), response rate (RR) and safety. Eligibility criteria: histologically or cytologically documented previously untreated advanced or recurrent non-squamous NSCLC; ECOG PS 0–1; no brain metastases. A size of 180 pts was planned to be randomized to: C AUC=6 and P 200mg/m2 q3 wks for up to 6 cycles plus Bev continued to progression at 15mg/kg q3 wks, or CP alone at the randomization ratio of 2:1. The study was designed to observe a 20% reduction in the risk of a PFS event in the Bev arm compared with control. Results: Between 4/07 and 3/08, 180 pts were accrued. Three pts of them were ineligible and 3 pts were not dosed at all. PFS (as assessed by investigators) and RR were significantly improved. OS is immature due to short duration of follow up. Updated PFS results as assessed by the central review committee and OS data will be provided. No new safety signals for Bev were detected. Conclusions: This is the first study of Bev in Japanese pts with NSCLC. The addition of 15mg/kg of Bev to CP significantly improved PFS and RR. The HR of PFS seemed at least as good as previous trials outside Japan. Safety of Bev was within a range already reported. This study confirms the efficacy and safety of Bev in Japanese pts with NSCLC. [Table: see text] [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .

Final safety results of BO17704 (AVAiL): A phase III randomized study of first-line bevacizumab (Bv) and cisplatin/gemcitabine (CG) in patients (pts) with advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC)

8039 Background: AVAiL, an international placebo-controlled phase III trial, showed that Bv-based therapy significantly improved PFS and response rate in patients with advanced/recurrent NSCLC. This report summarizes overall safety findings from AVAiL. Methods: AVAiL randomized 1,043 patients with untreated locally advanced, metastatic or recurrent non-squamous NSCLC to C 80mg/m2 (d1) and G 1,250mg/m2 (d1 and d8) q3w for up to 6 cycles plus either Bv 7.5mg/kg q3w (n=331 with safety data), Bv 15mg/kg q3w (n=329) or placebo (n=326). Bv/placebo was administered until disease progression. Primary endpoint was PFS; secondary endpoints included OS, response rate, and safety. Safety was measured using NCI-CTC version 3.0 criteria for adverse events (AEs). Results: At final analysis, the median/maximum duration of Bv therapy was 4.9/28.5 mo (Bv 7.5) and 4.3/23.4 mo (Bv 15). The most common AEs overall were hematological and gastrointestinal (GI), and occurred in similar proportions of pts in the Bv and placebo arms. Grade ≥3 AEs occurred in 80%, 83%, and 77% of pts in the Bv 7.5, Bv 15 and placebo arms, respectively. The most common grade ≥3 adverse events were hematological, mainly neutropenia and thrombocytopenia. Neutropenia was reported in 43% (Bv 7.5), 40% (Bv 15) and 34% (placebo) of pts. Grade ≥3 AEs of special interest included hypertension (7%, 9% and 2%), proteinuria (2%, 3% and 0%), bleeding (4%, 5% and 2%) and hemoptysis (0.5%, 1.2% and 1.3%). The incidence of grade 5 hemoptysis was low (0.9%, 0.9% and 0% of pts, respectively). The incidence of GI perforations (&lt;1%), thromboembolic events (≤8%), CHF (≤1%) and wound healing complications (&lt;1%) was low and similar between treatment arms. The incidence of serious AEs was 39%, 45% and 36% in the Bv 7.5, Bv 15 and placebo arms, respectively. No new safety signals were reported. Conclusions: After E4599, AVAiL further demonstrated the efficacy of Bv in combination with platinum-based chemotherapy in the treatment of advanced NSCLC. Final safety data confirm the well established and manageable safety profile of Bv-based therapy in pts with advanced NSCLC. [Table: see text]