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Purpose Abemaciclib in combination with endocrine therapy (ET) has demonstrated significant efficacy benefits in HR+ , HER2− advanced breast cancer patients in the Phase 3 studies MONARCH 2 (fulvestrant as ET) and MONARCH 3 (letrozole or anastrozole as ET). Here, we report age-specific safety and efficacy outcomes. Methods Exploratory analyses of MONARCH 2 and 3 were performed for 3 age groups ( Results Pooled safety data were available for 1152 patients. Clinically relevant diarrhea (Grade 2/3) was higher in older patients receiving abemaciclib + ET (p-value, 0.695; MONARCH 3: interaction p-value, 0.634). Estimated hazard ratios ranged from 0.523–0.633 (MONARCH 2) and 0.480–0.635 (MONARCH 3). Conclusions While higher rates of adverse events were reported in older patients, they were manageable with dose adjustments and concomitant medication. Importantly, a consistent efficacy benefit was observed across all age groups. Clinical trial registration ClinicalTrials.gov: NCT02107703 (first posted April 8, 2014) and NCT02246621 (first posted September 23, 2014).

Objective: To analyze patient-reported swallowing difficulties, healthcare resource utilization and associated costs during the PROCLAIM study. Methods: Patients with stage III non-squamous non-small cell lung cancer received pemetrexed-cisplatin (PemCis) combined with concurrent thoracic radiotherapy followed by consolidation pemetrexed, or concurrent chemoradiotherapy with etoposide-cisplatin (EtoCis) followed by standard consolidation chemotherapy. Patient - reported swallowing function was measured using diaries. Resource utilization (hospitalizations, transfusions, concomitant medications) was compared between treatment arms using Fisher’s exact test and independent t-test. Medical resource use costs were analyzed using nonparametric Wilcoxon rank sum test. Results: Patient-reported difficulty in swallowing function (diary score ≥4) was 33.8% in the PemCis arm and 29% in the EtoCis arm. Overall resource use, including hospitalizations, was similar between treatment arms; however, fewer patients in the PemCis arm received transfusions and selected concomitant medications. Concurrent phase analyses were consistent with the overall study. A significantly lower percentage of patients (31.1% vs. 40.8%) were hospitalized in the PemCis arm. Total costs were significantly higher in the PemCis arm. Other medical costs (excluding study treatment costs) during the concurrent phase were lower for patients in the PemCis arm, due to significantly lower hospitalization costs and lower use of concomitant medications. Subgroup analysis yielded similar results. Conclusions: Patient-reported difficulty in swallowing post-baseline and resource utilization were consistent with previously reported safety outcomes. In the overall study, higher total costs for PemCis were driven by study drug cost. When adjusting for treatment duration, other monthly medical costs were favorable to PemCis. Patients on pemetrexed remained longer on therapy, suggesting better tolerability. ClinicalTrials.gov identifier: NCT00686959.

INTRODUCTION: We investigated the potential impact of stage migration because of positron-emission tomography (PET) scan staging on survival in the locally advanced (stage IIIA/B) NSCLC setting.METHODS: In PROCLAIM, 598 patients with stage IIIA/B nonsquamous NSCLC (intent-to-treat population) were randomized to either pemetrexed plus cisplatin and concurrent thoracic radiotherapy for 3 cycles followed by 4 cycles of pemetrexed consolidation or etoposide plus cisplatin and concurrent thoracic radiotherapy for 2 cycles followed by a consolidation platinum-based doublet regimen for up to 2 cycles. Baseline PET scan (PET Yes versus No) was one of the stratification factors. Subgroup analyses (PET Yes versus No) of overall survival (OS) and progression-free survival (PFS) were conducted on the intent-to-treat population regardless of treatment, as the study did not show superior efficacy for either arm.RESULTS: Majority (491 of 598; 82.1%) of patients had a baseline PET scan staging performed. A longer median OS (PET Yes versus No: 27.2 versus 20.8; hazard ratio = 0.81, p = 0.130) and an improved median PFS (PET Yes versus No: 11.3 versus 9.2; hazard ratio = 0.73, p = 0.012) were observed for patients with PET scans compared to those with conventional staging in both treatment arms.CONCLUSIONS: Both a significantly improved PFS and a numerically longer OS in the PET Yes subgroup, compared to patients with conventional staging, are consistent with improved survival due to stage migration. The magnitude of differences in OS and PFS based on PET scan is a reminder of the potential for factors other than the therapeutic intervention to affect outcomes.

International audience; OBJECTIVES:To assess the effect of long-term pemetrexed maintenance therapy on patients' renal function.METHODS:In the PARAMOUNT phase III trial (NCT 00789373), pemetrexed was compared with placebo as maintenance treatment in advanced nonsquamous non-small-cell lung cancer patients who completed 4 cycles of pemetrexed plus cisplatin induction therapy. To evaluate changes in renal function during pemetrexed continuation maintenance treatment, we retrospectively analyzed changes in serum creatinine (sCr), treatment-emergent adverse events, dose delays and treatment discontinuations associated with impaired renal function.RESULTS:Creatinine clearance ≥45 mL/min was required before the start of any cycle. Patients on pemetrexed maintenance had a significantly higher percentage maximum increase in sCr over baseline versus placebo for the range of ≥10% to ≥90% increase (p

PURPOSE: Chemoradiation therapy trials of different tumors, including lung cancer, have shown a correlation between protocol deviations and adverse outcomes. Radiation therapy quality assurance (RTQA) was mandated for all patients treated in the PROCLAIM trial evaluating 2 different chemoradiation therapy regimens. The RTQA results were evaluated from the PROCLAIM study, and the impact of irradiation deviations on efficacy outcomes was investigated.METHODS AND MATERIALS: The study was conducted from 2008 to 2014. Review of the irradiation plan was mandated for all patients. Real-time review was performed prior to irradiation start for the first enrolled patient at each site and randomly in 20% of additional patients, with non-real-time review in the remainder. The RTQA criteria evaluated included planning target volume coverage, dose homogeneity, volume of lung receiving ≥20 Gy, and maximum point dose to spinal cord.RESULTS: Major RTQA violations occurred in 40 of 554 patients, treated at 28 sites. Seven sites treated ≥2 patients with major violations. Stage IIIB disease and larger planning target volume were observed more frequently in patients with major violations. Major violations were more prevalent in sites treating either 15 patients. Patients treated at sites enrolling ≥2 patients with major violations (n = 86) had lower median overall survival (21.1 months vs 29.8 months; hazard ratio, 1.442) and progression-free survival (7.3 months vs 11.3 months; hazard ratio, 1.345) than patients treated at sites without major violations. These findings remained significant for overall survival on multivariate analysis.CONCLUSIONS: Major violations in treatment plans were uncommon in the PROCLAIM study, possibly reflecting mandatory RTQA. The RTQA violations were more frequent in patients requiring more complex chemoradiation therapy plans. Poorer observed outcomes at centers with multiple major violations are hypothesis generating.

Concurrent chemoradiotherapy (CT+RT) is a standard of care for good-performance patients with unresectable stage IIIA/IIIB non-small cell lung cancer (NSCLC).1 2 In a phase II study, treatment with two cycles of pemetrexed-cisplatin (Pem-Cis) induction, followed by full-dose Pem-Cis plus concurrent RT was well tolerated and effective in 90 patients with stage IIIA/IIIB unresectable, non-squamous NSCLC.3 Here, we report by-age subgroup data for 17 elderly (aged >70 years) and 73 non-elderly patients (aged ≤70 years). The Eastern Cooperative Oncology Group performance status 0–1, no prior systemic therapy, adequate pulmonary function (FEV1 >50% and carbon monoxide diffusing capacity (DLCO) >40% of predicted normal value) and a total lung volume to receive at least 20 Gy (V20) of ≤35% were required (patient characteristics: see online supplementary material). Patients received two 3-week cycles of Pem 500 mg/m2 and Cis 75 mg/m2 as per PEM label (vitamin supplementation). Patients with complete response (CR), partial response or stable disease were then eligible for concurrent CT+RT, which included two additional cycles of …

Introduction:The PARAMOUNT Phase III trial showed that maintenance pemetrexed after pemetrexed plus cisplatin induction was well tolerated and effective for patients with advanced nonsquamous non–small-cell lung cancer. Approximately 17% of patients receiving maintenance therapy in this study were 70 years of age or older. Here we report efficacy and safety results from the PARAMOUNT study for elderly (≥70 years) and non-elderly (

Purpose In the phase III PARAMOUNT trial, pemetrexed continuation maintenance therapy reduced the risk of disease progression versus placebo (hazard ratio [HR], 0.62; 95% CI, 0.49 to 0.79; P < .001). Here we report final overall survival (OS) and updated safety data. Patients and Methods In all, 939 patients with advanced nonsquamous non–small-cell lung cancer (NSCLC) received four cycles of pemetrexed-cisplatin induction therapy; then, 539 patients with no disease progression and Eastern Cooperative Oncology Group performance status 0 or 1 were randomly assigned (2:1) to maintenance pemetrexed (500 mg/m2 on day 1 of 21-day cycles; n = 359) or placebo (n = 180). Log-rank test compared OS between arms as measured from random assignment (α = .0498). Results The mean number of maintenance cycles was 7.9 (range, one to 44) for pemetrexed and 5.0 (range, one to 38) for placebo. After 397 deaths (pemetrexed, 71%; placebo, 78%) and a median follow-up of 24.3 months for alive patients (95% CI, 23.2 to 25.1 months), pemetrexed therapy resulted in a statistically significant 22% reduction in the risk of death (HR, 0.78; 95% CI, 0.64 to 0.96; P = .0195; median OS: pemetrexed, 13.9 months; placebo, 11.0 months). Survival on pemetrexed was consistently improved for all patient subgroups, including induction response: complete/partial responders (n = 234) OS HR, 0.81; 95% CI, 0.59 to 1.11 and stable disease (n = 285) OS HR, 0.76; 95% CI, 0.57 to 1.01). Postdiscontinuation therapy use was similar: pemetrexed, 64%; placebo, 72%. No new safety findings emerged. Drug-related grade 3 to 4 anemia, fatigue, and neutropenia were significantly higher in pemetrexed-treated patients. Conclusion Pemetrexed continuation maintenance therapy is well-tolerated and offers superior OS compared with placebo, further demonstrating that it is an efficacious treatment strategy for patients with advanced nonsquamous NSCLC and good performance status who did not progress during pemetrexed-cisplatin induction therapy.

Purpose The phase III PROCLAIM study evaluated overall survival (OS) of concurrent pemetrexed-cisplatin and thoracic radiation therapy (TRT) followed by consolidation pemetrexed, versus etoposide-cisplatin and TRT followed by nonpemetrexed doublet consolidation therapy. Patients and Methods Patients with stage IIIA/B unresectable nonsquamous non–small-cell lung cancer randomly received (1:1) pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 intravenously every 3 weeks for three cycles plus concurrent TRT (60 to 66 Gy) followed by pemetrexed consolidation every 3 weeks for four cycles (arm A), or standard therapy with etoposide 50 mg/m2 and cisplatin 50 mg/m2 intravenously, every 4 weeks for two cycles plus concurrent TRT (60 to 66 Gy) followed by two cycles of consolidation platinum-based doublet chemotherapy (arm B). The primary objective was OS. The study was designed as a superiority trial with 80% power to detect an OS hazard ratio of 0.74 with a type 1 error of .05. Results Enrollment was stopped early because of futility. Five hundred ninety-eight patients were randomly assigned (301 to arm A, 297 to arm B) and 555 patients (283 in arm A, 272 in arm B) were treated. Arm A was not superior to arm B in terms of OS (hazard ratio, 0.98; 95% CI, 0.79 to 1.20; median, 26.8 v 25.0 months; P = .831). Arm A had a significantly lower incidence of any drug-related grade 3 to 4 adverse events (64.0% v 76.8%; P = .001), including neutropenia (24.4% v 44.5%; P < .001), during the overall treatment period. Conclusion Pemetrexed-cisplatin combined with TRT followed by consolidation pemetrexed was not superior to standard chemoradiotherapy for stage III unresectable nonsquamous non–small-cell lung cancer.

Introduction Necitumumab, a second-generation, recombinant human immunoglobulin G1 epidermal growth factor receptor antibody in the phase 3 SQUIRE trial (NCT00981058), increased survival benefit for patients randomized to receive necitumumab plus gemcitabine-cisplatin compared with those who received gemcitabine-cisplatin. Here we characterize health-related quality of life (HRQoL) and tolerability results. Methods A total of 1093 patients with stage IV squamous non–small cell lung cancer were randomized 1:1 to receive necitumumab (800 mg absolute dose intravenously [IV]) plus gemcitabine-cisplatin (gemcitabine = 1250 mg/m 2 IV on days 1 and 8; cisplatin = 75 mg/m 2 IV on day 1) or gemcitabine-cisplatin alone (every 21 days) for up to six cycles. Patients receiving necitumumab plus gemcitabine-cisplatin without disease progression continued necitumumab until progression. HRQoL was measured by Eastern Cooperative Oncology Group performance status, the Lung Cancer Symptom Scale (LCSS), and the European Quality of Life Five-Dimensions questionnaire. Efficacy and LCSS outcomes were analyzed using the baseline maximum severity score of the LCSS. Tolerability was measured in terms of exposure to the study treatment and adverse events. Hospitalization rates were collected. Results Most patients in both study arms similarly maintained Eastern Cooperative Oncology Group performance status and comparable LCSS and European Quality of Life Five-Dimensions questionnaire assessments. Patients with a higher baseline LCSS had a greater survival benefit on the necitumumab arm. Chemotherapy exposure was similar in both treatment arms; 51% of patients on the necitumumab plus gemcitabine-cisplatin arm continued on single-agent necitumumab. The most frequent grade 4 adverse events were neutropenia (6.1% versus 7.9%) and thrombocytopenia (3.2% versus 4.3%) in the necitumumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin arms, respectively. Hospitalizations were slightly higher with necitumumab plus gemcitabine-cisplatin (36.4%) than with gemcitabine-cisplatin (34.0%). Conclusions The addition of necitumumab to gemcitabine-cisplatin was well tolerated, did not negatively affect HRQoL or toxicity, and particularly benefited patients with more severe baseline symptoms or lower HRQoL.

IntroductionIn a phase III, randomized, double-blind study (PARAMOUNT), maintenance pemetrexed demonstrated significant benefit in advanced non–small-cell lung cancer (NSCLC). We present safety, resource use, and quality of life (QoL) results.MethodsAfter four 21-day cycles of pemetrexed-cisplatin (N = 939), patients with advanced nonsquamous NSCLC, whose disease had not progressed and who had a performance status of 0/1, were randomized 2:1 (N = 539) to maintenance pemetrexed 500 mg/m2 plus best supportive care or placebo plus best supportive care every 21 days until disease progression or unacceptable toxicity. QoL was measured using the EuroQol 5-dimensional questionnaire (EQ-5D).ResultsFrequently reported grade 3 to 4 drug-related toxicities with maintenance pemetrexed versus placebo were anemia (4.5% versus 0.6%; p = 0.016), fatigue (4.2% versus 0.6%; p = 0.016), and neutropenia (3.6% versus 0.0%; p < 0.006). No significant differences in drug-related grade 3 to 5 toxicities were observed with long-term pemetrexed exposure (>6 cycles), except grade 3 to 4 neutropenia, which did not result in increased infections. Patients on maintenance pemetrexed required more transfusions (13.4% versus 5.0%; p = 0.003), granulocyte colony- or granulocyte-macrophage colony-stimulating factors (5.3% versus 0.0%; p

Objectives: Enzastaurin is a serine/threonine kinase inhibitor that targets protein kinase C and AKT pathways. Enzastaurin and pemetrexed demonstrated synergy in preclinical studies. This trial was designed to evaluate the safety and efficacy of first-line enzastaurin plus cisplatin-pemetrexed in advanced non-small cell lung cancer (NSCLC). Methods: A safety lead-in phase (n = 13) of enzastaurin 125 or 250 mg twice daily was added to cisplatin-pemetrexed. A subsequent randomized, placebo-controlled phase II study (n = 22) of the combination was conducted to evaluate efficacy. Results: The combination was well tolerated and showed activity, with 7 (53.8%, 95% CI 26.7–80.9) confirmed partial responses and 2 stable diseases in 13 treated patients in the lead-in phase. However, the study was terminated early based on interim results from two phase II NSCLC studies of enzastaurin plus cytotoxic chemotherapy, which indicated no efficacy improvement. Conclusions: Enzastaurin and cisplatin-pemetrexed is tolerable with preliminary activity in patients with advanced NSCLC, but because of a lack of efficacy improvement in other phase II NSCLC studies, the study was terminated early.

Introduction We examined the efficacy of enzastaurin plus pemetrexed as second-line therapy in patients with advanced (stage IIIA/B or IV) non-small cell lung cancer in a double-blinded, randomized, phase II study. Methods Patients received pemetrexed 500 mg/m 2 intravenously on day 1 of 21-day cycles (day 8 in cycle 1) plus oral enzastaurin (250 mg two times per day; combination arm) or placebo (pemetrexed arm). Both arms received supplementation with vitamin B 12 , folic acid, and dexamethasone. An interim analysis was conducted to determine whether efficacy would warrant a phase III study. Results The interim analysis showed no evidence of improved progression-free survival with enzastaurin. At final analysis (N = 160, 80 in each arm), baseline characteristics were well balanced. There was no significant difference in progression-free survival (3.0 months, p = 0.544) or overall survival (9.6 months in combination arm and 7.4 months in pemetrexed arm, p = 0.171). Drug-related serious adverse events included cerebrovascular accident, palpitations, and renal failure (n = 1, each) in combination arm and neutropenic sepsis, thrombocytopenia, and panniculitis (n = 1, each) in pemetrexed arm. Nonhematologic drug-related grade 3/4 toxicities were similar in both arms. Grade 3/4 hematologic toxicities were higher with the combination, specifically leukopenia (6.3% versus 0%), neutropenia (15.2% versus 5.0%), and thrombocytopenia (8.9% versus 1.3%). Of the 26 deaths reported on-study or within 30 days of discontinuation (10 in combination arm and 16 in pemetrexed arm), none were drug related. Conclusion The combination regimen of enzastaurin and pemetrexed is well tolerated but does not improve efficacy over pemetrexed and placebo as second-line treatment of unselected patients with advanced non-small cell lung cancer.

Objectives Two phase III trials of advanced NSCLC patients were compared to examine relative efficacy and safety of differing treatment regimens. The JMDB trial investigated first-line pemetrexed–cisplatin (pemetrexed 500 mg/m 2 plus cisplatin 75 mg/m 2 every 21 days; maximum: 6 cycles). The PARAMOUNT phase III trial compared maintenance pemetrexed versus placebo after patients with nonsquamous NSCLC completed 4 cycles of first-line pemetrexed–cisplatin without disease progression. Methods Overall survival (OS) and progression-free survival (PFS), analyzed by Kaplan–Meier and Cox methods, and toxicity rates were compared between the PARAMOUNT arms and a selected homogeneous population from JMDB: 346 patients with disease and prior treatment characteristics matching the PARAMOUNT population. Results Outcomes for the PARAMOUNT placebo arm were similar to the JMDB homogeneous group (median PFS: 5.6 versus 6.2 months, p = 0.117, HR = 1.16; median OS: 14.0 versus 14.2 months, p = 0.979, HR = 1.00). The PARAMOUNT maintenance pemetrexed group had statistically superior efficacy compared with the JMDB homogeneous group (median PFS: 7.5 versus 6.2 months, p p = 0.003, HR = 0.75). Patients who received pemetrexed maintenance (median 4 cycles, range 1–44) following 4 cycles of pemetrexed–cisplatin exhibited a higher incidence of drug-related serious adverse events compared with JMDB patients (median 6 cycles of pemetrexed–cisplatin) (10.6% versus 2.9%); grade 3/4 fatigue and renal toxicity were also higher in the pemetrexed arm of PARAMOUNT. Conclusions The across-trial comparison of a relevant JMDB study population with the two arms of the PARAMOUNT study supported the efficacy of the pemetrexed continuation maintenance strategy and suggested the results are not influenced by limiting the pemetrexed–cisplatin induction treatment to four cycles. Although longer exposure to pemetrexed–cisplatin or maintenance pemetrexed increased some toxicities, the overall incidence remained low, underscoring the relative safety of these treatment regimens.

IntroductionIn the PARAMOUNT (“A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed plus Best Supportive Care vs. Best Supportive Care Immediately Following Induction Treatment with Pemetrexed Plus Cisplatin for Advanced Non-Squamous Non–Small-Cell Lung Cancer”) trial, patients with advanced nonsquamous non–small-cell lung cancer (NS-NSCLC) benefited from pemetrexed maintenance therapy after induction therapy with pemetrexed and cisplatin by extending survival, delaying disease progression, and maintaining quality of life (QoL). However, low-grade 1 or 2 toxicities during long-term maintenance treatment may become burdensome and impact QoL.Materials and MethodsPatients in this double-blind study (n = 539), who had completed 4 induction cycles (pemetrexed with cisplatin) without progressive disease (PD) and had an ECOG performance status of 0/1, were randomized 2:1 to pemetrexed maintenance (500 mg/m2, day 1) plus best supportive care (BSC) or placebo plus BSC until PD. Adverse events (by maximum Common Terminology Criteria for Adverse Events [CTCAE] grade) and QoL (EuroQol 5-dimensional [EQ-5D] scale) were assessed.ResultsA median of 4 maintenance cycles was administered (range, pemetrexed 1-44; mean ± SD 7.9 ± 8.3; placebo 1-38; mean ± SD 5.0 ± 5.2), with 28% of pemetrexed and 12% of placebo patients receiving ≥ 10 maintenance cycles. The pemetrexed dose intensity was 94%. More patients receiving pemetrexed (12%) than placebo discontinued because of possible drug-related CTCAEs (4%; P = .005). Overall, pemetrexed was associated with significantly more (P < .05) low-grade events (grade 1/2 nausea, grade 2 anemia, edema, and neutropenia) than placebo. Overall, the incidence of low-grade fatigue, anemia, and neutropenia decreased with long-term pemetrexed exposure; however, renal events increased across treatment arms. EQ-5D analyses demonstrated no treatment-by-time interaction or overall treatment differences between the 2 arms.ConclusionPARAMOUNT demonstrated a low incidence of low-grade toxicities with long-term pemetrexed exposure without compromising QoL in patients with NS-NSCLC.

To determine the feasibility of the paclitaxel, oxaliplatin, cisplatin combination in advanced ovarian cancer (AOC), 15 patients with AOC (8 chemonaive, and 7 second-line, disease-free interval > or = 12 months) received paclitaxel 135 mg/m2 at day 1, with oxaliplatin 100 mg/m2 and cisplatin 75 mg/m2 at day 2, every 3 weeks for 6 cycles. Pretreated patients received prophylactic granulocyte colony-stimulating factor (5 microg/kg/d, days 6-13). Seventy cycles were administered; median 5 (range: 2-6 cycles) in chemonaive, and 4 (range: 2-6) in pretreated patients. There were grades III to IV neutropenia in 77%, febrile neutropenia in 24%, and grades III to IV thrombocytopenia in 4% of the cycles. Besides neutropenia, cumulative neurosensory toxicity was also limiting although reversible, with National Cancer Institute Common Toxicity Criteria grades II to III observed in 13 patients. Three of the pretreated patients had complete responses (43%), three had partial responses, and one had disease stabilization. Six of the 8 chemonaive patients had complete responses (75%), 1 had disease stabilization, and 1 had disease progression. The median follow-up is 17 months (range: 9-20 months) in chemonaive and 41 months (range: 13-58 months) in pretreated patients, and time to progression has been consistently more than 12 months, with 6 patients (5 chemonaive) still progression free (range: 15+ to 22+ months). This active combination shows acceptable hematologic toxicity, and reversible cumulative neurosensory toxicity. Further clinical exploration of the present combination appears warranted.

BACKGROUND The aim of this study was to evaluate the toxicity and efficacy of the combination of 5-fluorouracil, bleomycin, epirubicin, and cisplatin (FBEC) in the treatment of patients with undifferentiated carcinoma of nasopharyngeal type (UCNT). The study included patients with metastatic or recurrent disease (Group A) and previously untreated patients with locally advanced nonmetastatic disease (T ≥ 3 or any T, N ≥ 2, M0, according to 1987 criteria of the International Union Against Cancer and the American Joint Committee on Cancer (Group B). METHODS From January 1992 to November 1996, 49 patients with histologically proven UCNT were treated with intravenous (i.v.) 5-fluorouracil (700 mg/m2/day by continuous infusion for 4 days), epirubicin (70 mg/m2 i.v. on Day 1), Bleomycin (10 mg i.v. bolus on Day 1 followed by 12 mg/m2/day by continuous infusion for 4 days), and cisplatin (100 mg/m2 on Day 5); this regimen was repeated every 21 days. Six cycles were given to Group A (26 patients), with bleomycin omitted during the last 3 cycles. In Group B (23 patients), only 3 cycles were given, followed by conventional radiotherapy (70 gray for 7 weeks). RESULTS Of the 26 patients entered in Group A, 23 were evaluable for response. Nine complete responses (CRs) and 9 partial responses (PRs) were assessed, for a 78% objective response rate (ORR) (95% CI: 56–92). Three patients are alive with no evidence of disease after 43, 61, and 73 months, respectively. These patients achieved a CR with chemotherapy followed by consolidating radiotherapy to their target lesions. In Group B, the ORR was 91.5%, with 5 CRs (22%) and 16 PRs (69.5%) assessed in the 23 patients. Three months after the end of radiotherapy, the ORR was 87% (20 patients). After a median follow-up of 51 months (range, 24–67months), 15 patients (65%) are alive without evidence of disease. Forty percent of cycles (51% in Group A, 25% in Group B) resulted in Grade 4 neutropenia, with fever and/or sepsis in 9.5%. Mucositis was seen in 42% of pretreated patients. There were 3 treatment-related deaths (2 from complications of infection and 1 bleomycin fibrosis at a total dose of 160mg/m2), all of them in Group A. CONCLUSIONS The FBEC regimen has good activity, with durable responses in patients with locally advanced, metastatic, or recurrent UCNT. This regimen is safe for patients with locally advanced disease, but close follow-up and supportive measures are needed when it is used to treat those with metastatic or recurrent disease. Cancer 1999;86:1101–8. © 1999 American Cancer Society.

Objectives: The aim of this study was to evaluate the efficacy and tolerability of the combination of cisplatin–gemcitabine with concurrent thoracic radiotherapy for locally advanced non-small cell lung cancer (LA-NSCLC). Methods: This was a phase II, multicenter, open-label, single-arm trial in treatment-naïve patients with stage IIIA and IIIB LA-NSCLC. After three induction cycles with gemcitabine 1250 mg/m2 plus cisplatin 80 mg/m2, two concurrent chemoradiotherapy cycles with gemcitabine 300 mg/m2, cisplatin 80 mg/m2, and radiotherapy (63 Gy) were administered. The primary endpoint was response rate after induction chemotherapy followed by concurrent chemoradiotherapy. Secondary endpoints included time to progressive disease (TtPD), overall survival (OS), and safety. Results: Overall, 49 patients (median age 63.4 years; 73.5% male; Karnofsky performance status scores of 80, 85, 90, and 100 [16.3%, 2.0%, 49.0%, and 32.7%, respectively]; disease stage IIIA or IIIB 28.6% and 71.4%, respectively) were enrolled and treated. Response rate was 38.8% (95% confidence interval [CI] 25.2–53.8%). Median TtPD was 11.4 months (95% CI 9.4–12.9). Median OS was 21.8 months (95% CI 17.5–26.0), with 1- and 2-year survival rates of 70.8% and 43.7%, respectively. Overall, six patients discontinued from study treatment due to adverse events (AEs), of which two were serious AEs. The most relevant grade 3/4 AEs were neutropenia and thrombocytopenia in induction chemotherapy and chemoradiotherapy, and grade 3 events related to radiation in acute chemoradiotherapy, e.g. dysphagia, radiation pneumonitis, and radiation esophagitis. Conclusions: Induction chemotherapy followed by concurrent chemoradiotherapy with gemcitabine (300 mg/m2) and cisplatin was associated with acceptable toxicity. The observed median OS time was 21.8 months. Response evaluation was difficult as in many cases it was not possible to differentiate tumor progression from local radiofibrosis.

8529Background: Standard of care for inoperable stage III NSCLC is concurrent chemoradiotherapy. Safety and resource utilization are important for treatment decisions. Methods: Resource utilization...

The synergistic activity of pemetrexed with platinum agents in non-small cell lung cancer (NSCLC) and the renal safety of carboplatin suggest a balanced benefit/risk profile for this combination in elderly patients. This multicenter, single-arm, phase II study included 62 patients (≥70 years) with chemonaive advanced NSCLC, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1, and assigned to receive 6 cycles of 3-weekly pemetrexed 500 mg/m(2) and carboplatin AUC 5. The primary endpoint was objective tumor response rate (ORR). Sixty-two patients received at least one dose of chemotherapy. Median age was 76.4 years [70.2-86] and all patients had PS 0 (16.1%) or PS 1 (83.9%). Stage IIIb disease in 21% patients and stage IV in 79% patients. Non-squamous cell carcinoma in 66.1% patients (adenocarcinoma 51.6%, large cell carcinoma 8.1%, other 6.5%) and squamous cell carcinoma in 33.9% patients. ORR was 28.6% (95% confidence interval [CI], 16.58-43.26), all were partial responses. Stable disease rate was 42.9%. Grade 3/4 toxicities related to study drugs were: asthenia 16.1%, anorexia 4.8%, diarrhea 3.2%, neutropenia 51.6%, leucopenia 30.7%, thrombocytopenia 29%, anemia 19.4%. One related fatal septic shock occurred. In advanced NSCLC, pemetrexed use is restricted to non-squamous histology. The combination pemetrexed-carboplatin could be a valuable treatment option in elderly patients. Neutropenia was the most common toxicity. The ORR is within the range of data reported for pemetrexed-carboplatin in the general NSCLC population (24-31%).

Purpose This is a phase I, escalating-dose trial targeting exclusively patients with non-small cell lung cancer (NSCLC), investigating pemetrexed and fixed-dose cisplatin concurrently administered with high-dose radiotherapy (RT) after induction chemotherapy (CT). Primary objective was to determine the maximum tolerated dose and recommended phase II dose of pemetrexed. Patients and Materials Patients with unresected stage III NSCLC, planned V20 ≤ 35%, and FEV ≥ 1.3 L, were treated every 21 days for 2 cycles (pemetrexed 500 mg/m 2 ; cisplatin 75 mg/m 2 ), followed by 2 cycles of concurrent CT-RT: pemetrexed starting dose was 400 mg/m 2 , escalated up to 800 mg/m 2 per 100 mg/m 2 dose level (DL), cisplatin at 75 mg/m 2 and RT at fixed dose of 66 Gy/33 fractions. Results Nine of 10 enrolled patients (age range 46–68 years; 6 men; ECOG PS 0 [6 patients], PS 1 [4] ; stage IIIA [1] , IIIB [9] ; 6 adenocarcinomas, 3 squamous cell carcinomas, 1 large cell carcinoma) were entered on 3 DLs. Dose escalation of pemetrexed was conducted up to 600 mg/m 2 based on the independent safety monitoring board recommendation. One dose-limiting toxicity occurred at DL3: Grade 4 septic shock. Grade 3 related toxicities: 2 neutropenia at DL3, 2 lymphopenia per DL (3 recurrent), 2 leukopenia (1 recurrent) at DL3, 1 gastric pain (DL3), 1 nausea and 1 recurrent vomiting (DL2). No Grade 3/4 radiation-related toxicities were observed. No toxic death was observed. Disease control rate was 77.7% (1 CR, 4 PR, 2 SD). One-year survival rate was 90%. Conclusions This phase I report of pemetrexed is dedicated to NSCLC with induction therapy and fixed high-dose RT. Pemetrexed at 500 mg/m 2 , concurrently given with cisplatin and RT was well tolerated and appears to be the only third-generation agent that can likely be recommended safely at full dose in future trials with concurrent RT.

Background: Patients with advanced non-squamous non-small-cell lung cancer (NSCLC) benefit from pemetrexed maintenance therapy after induction therapy with a platinum-containing, non-pemetrexed doublet. The PARAMOUNT trial investigated whether continuation maintenance with pemetrexed improved progression-free survival after induction therapy with pemetrexed plus cisplatin. Methods: In this double-blind, multicentre, phase 3, randomised placebo-controlled trial, patients with advanced non-squamous NSCLC aged 18 years or older, with no previous systemic chemotherapy for lung cancer, with at least one measurable lesion, and an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 participated. Before randomisation, patients entered an induction phase which consisted of four cycles of induction pemetrexed (500 mg/m 2) plus cisplatin (75 mg/m 2) on day 1 of a 21-day cycle. Patients who did not progress after completion of four cycles of induction and who had an ECOG performance status of 0 or 1 were stratified according to disease stage (IIIB or IV), ECOG performance status (0 or 1), and induction response (complete or partial response, or stable disease), and randomly assigned (2:1 ratio) to receive maintenance therapy with either pemetrexed (500 mg/m 2 every 21 days) plus best supportive care or placebo plus best supportive care until disease progression. Randomisation was done with the Pocock and Simon minimisation method. Patients and investigators were masked to treatment assignment. The primary endpoint was progression-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT00789373. Findings: Of the 1022 patients enrolled, 939 participated in the induction phase. Of these, 539 patients were randomly assigned to receive continuation maintenance with pemetrexed plus best supportive care (n=359) or with placebo plus best supportive care (n=180). Among the 359 patients randomised to continuation maintenance with pemetrexed, there was a significant reduction in the risk of disease progression over the placebo group (HR 0·62, 95% CI 0·49-0·79; p

Background: The objectives were to determine the maximum tolerated dose (MTD) of pemetrexed and cisplatin with concurrent radiotherapy. Secondary objectives include incidence and nature of acute and late toxicities, tumor response and overall survival. Patients and methods: Treatment naive patients received 1 cycle of cisplatin 80 mg/m(2) in study I (stage III NSCLC), 75 mg/m(2) in study II (LD-SCLC) and pemetrexed 500 mg/m(2) before the phase I part. In study I, patients were treated in cohorts with escalating cisplatin doses (60-80 mg/m(2)), pemetrexed doses (400-500 mg/m(2)) and concurrent escalating radiotherapy doses (66 Gy in 33-27 fractions). In study II, patients were treated with cisplatin 75 mg/m(2) and escalating pemetrexed doses (400-500 mg/m(2)) with concurrent escalating radiotherapy doses (50-62 Gy). Results: The trials closed prematurely: study I because of poor accrual, study II because of sponsor decision. Thirteen patients were treated: 4 with NSCLC, 9 with LD-SCLC. No dose-limiting toxicity was observed. There was no grade 4 toxicity, grade 3 hematological toxicity was mild. One patient developed grade 3 acute esophagitis, but was able to complete radiotherapy without delay. Two patients experienced grade 2 late pulmonary toxicity, 1 complete response, 6 partial responses and 1 progressive disease were observed. Conclusions: Although the studies stopped too early to assess MTD, we have demonstrated that the combination of cisplatin and pemetrexed with concurrent radiotherapy up to 66 Gy (33 x 2 Gy) is well tolerated and this new combination shows activity in NSCLC. Pemetrexed is the first 3rd generation cytotoxic found to be tolerable at full dose with concurrent radiotherapy. (C) 2009 Elsevier Ireland Ltd. All rights reserved.

In a recent large phase III study, previously treated patients with advanced non-small cell lung cancer who received pemetrexed demonstrated a survival time similar to patients who received docetaxel (median, 8.3 months with pemetrexed versus 7.9 months with docetaxel), with a more favorable toxicity profile, and significantly fewer Common Toxicity Criteria grade 3/4 toxicities. This is a retrospective risk-benefit analysis of survival without grade 3/4 toxicity, defined as the time to the first occurrence of Common Toxicity Criteria grade 3 or 4 toxicity or death, in the prospective phase III study comparing pemetrexed with docetaxel.A total of 541 patients (of 571 randomized) received either pemetrexed (500 mg/m intravenously [IV]) supplemented with vitamin B12 injections and oral folic acid or docetaxel (75 mg/m IV) on day 1 of 21-day cycles. Survival without grade 3/4 toxicity was analyzed using Kaplan-Meier and Cox methods.Pemetrexed demonstrated a statistically significantly longer survival without grade 3/4 toxicity compared with docetaxel (hazard ratio = 0.60, 95% confidence interval: 0.50-0.72; p0.0001). A supportive analysis based on selected grade 3/4 toxicities (neutropenia lasting5 days, febrile neutropenia, infection with neutropenia, anemia, thrombocytopenia, fatigue, nausea, vomiting, diarrhea, stomatitis, and neurosensory events) also demonstrated an advantage for pemetrexed (hazard ratio = 0.53; 95% confidence interval: 0.44-0.64; p0.0001).This analysis of survival without grade 3/4 toxicity suggests a benefit-to-risk profile that favors pemetrexed over docetaxel in the second-line treatment of patients with non-small cell lung cancer.

e19023 Background: As previously reported, the SQUIRE study demonstrated that the addition of N to GC chemotherapy significantly improved survival in patients (pts) with stage IV squamous NSCLC. He...

Objectives The PARAMOUNT trial showed that continuation maintenance therapy with pem after induction therapy with pem plus CP significantly reduced the risk of disease progression (HR = 0.62) and death (HR = 0.78) in patients (pts) with advanced NS-NSCLC. The purpose of this abstract is to present the updated safety and patients' QoL results from the continuation maintenance treatment of the PARAMOUNT trial. Methods In this phase III, randomized, double-blind, PBO-controlled study, 939 pts were treated with pem (500 mg/m2) plus CP (75 mg/m2) on day 1 of four 21-day cycles. Patients (n = 539) who had not progressed and had an Eastern Cooperative Oncology Group performance status (PS) of 0/1, were randomized (2:1; stratified for PS, induction response, and disease stage) to maintenance pem (500 mg/m2, day 1) plus BSC (n = 359) or PBO plus BSC (n = 180) until disease progression. All pts received vitamin B12, folic acid, and dexamethasone. All randomized pts were qualified for the maintenance phase safety analyses, which included summaries of the incidence of adverse events by maximum Common Terminology Criteria Adverse Events, version 3, grade. All enrolled patients that had provided baseline and at least 1 subsequent measurement for EuroQol 5-dimensional (EQ-5D) scale were included in the analysis of patient-reported outcomes. Results Safety and the QoL analyses in the continuation maintenance therapy will be presented. Conclusions The long-term and low-grade toxicities of continuation maintenance therapy with pem will be discussed. Disclosure C.M. Visseren-Grul: Employed by and own stock in Eli Lilly and Company. L. Paz-Ares: I have advisory board relationship and honararia to disclose with Eli Lilly and Company, Bayer, Roche, Pfizer. I. M. Dediu: Advisory Board - Eli Lilly and Company. M. Thomas: Advisory Board - Eli Lilly and Company Corporate Sponsored Trial - Eli Lilly and Company. N. Chouaki: Employed by and own stock in Eli Lilly and Company. A. Zimmermann: Employed by and own stock in Eli Lilly and Company. J. Pujol: Advisory Board - Eli Lilly and Company. C. Gridelli: Advisory Board, corporate-sponsored research, and honoraria/speaker bureau with Eli Lilly and Company. All other authors have declared no conflicts of interest.

Aim: EGFR is detectable in most pts with sq-NSCLC tumors. Efficacy and safety of necitumumab (N), a human IgG1 anti-EGFR monoclonal antibody that inhibits ligand-binding and receptor activation, were evaluated in pts with advanced sq-NSCLC tumors. Methods: Pts with stage IV sq-NSCLC were randomized 1:1 to GC (G = 1250 mg/m2 iv, days 1 and 8; C = 75 mg/m2 iv, day 1) plus N (800 mg iv, days 1 and 8) (GC + N arm), or GC alone (GC arm) every 21 days for up to 6 cycles. GC + N pts with no progression continued on N alone until progressive disease or intolerable toxicity. The primary endpoint was overall survival (OS). Progression-free survival and safety were secondary endpoints. Subgroup analyses, evaluating efficacy by age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), gender, and race, were also performed. Planned sample size was 1080 pts, with 90% power and a 2-sided alpha level of 0.05. ClinicalTrials.gov identifier: NCT00981058. Results: 1093 pts were randomized. Baseline characteristics, exposure to chemotherapy, and post-progression anticancer therapy were similar between GC + N and GC arms. The table shows key OS results. The addition of N to GC statistically significantly improved OS (HR = 0.84, p = 0.012), and the safety profile of GC + N was acceptable across subgroups. OS Results N mOS, GC + N* N mOS, GC* HR† ITT population 545 11.5 548 9.9 0.84 Subgroups Age, y 520 11.5 529 9.9 0.84 ≥75 25 10.3 19 7.4 0.98 ECOG PS 0 164 13.8 180 12.9 0.82 1 332 10.7 320 9.2 0.85 2 49 9.5 47 6.9 0.78 Gender Female 95 13.0 90 11.4 0.88 Male 450 11.1 458 9.7 0.84 Race Caucasian 457 11.4 456 9.7 0.86 Non-Caucasian 88 12.6 92 11.8 0.78 mOS = median overall survival. *Data = median (months) estimated by the Kaplan-Meier method. †HR Conclusions: This study met its primary endpoint. GC + N demonstrated improved OS, with an acceptable safety profile, across all subgroups. Disclosure: M.A. Socinski: Steering Committee; L. Paz-Ares: I have provided scientific advice asn received honararium from Lilly; M. Reck: Member of advisory boards (compensated): Lilly, Hoffmann-La Roche, BMS, AstraZeneca, Pfizer, Boehringer Ingelheim, Novartis; K. Park: Advisory Board; Eli Lilly; F.R. Hirsch: Research funding (through University of Colorado) from ImClone - Lilly. Participated in steering committee for the study and advisory borad for Lilly – ImClone; H. Depenbrock: Lilly Employee S. Nanda: I am a lilly employee and I have stock ownership; N. Chouaki: I am a Lilly Employee, I have stock ownership; N. Thatcher: Honoraria :Advsiory Board and Speaker Bureau Member Lilly Imclone. All other authors have declared no conflicts of interest.

Aim: Characterize QoL, tolerability, and supportive care of patients (pts) receiving necitumumab (N) + gemcitabine-cisplatin (GC) in the SQUIRE study. Methods: Pts with ECOG performance status (PS) 0-2, stage IV squamous NSCLC were randomized 1:1 to GC (G = 1250 mg/m2 IV days 1, 8; C = 75 mg/m2 IV day 1) + N (800 mg absolute dose IV), or GC alone (every 21 days up to 6 cycles). Pts treated with GC + N with no disease progression (PD) continued on N monotherapy until PD. Pt reported symptoms were measured by the Lung Cancer Symptom Scale (LCSS) prior to the start of each cycle (1-6) and every 6 weeks thereafter until PD. Physician reported PS was measured before every cycle. Tolerability was measured by number of cycles received, treatment discontinuation for adverse events (AEs), rates of serious AEs (SAEs), % of pts receiving N monotherapy post-induction. AEs (Safety Common Terminology Criteria [v3.0]) and supportive care data were collected while pts were on study. Results: 1093 pts were randomized (545 GC + N Arm, 548 GC Arm); 7 pts in each arm were not treated. 88.3% (GC + N) and 88.0% (GC) pts had a baseline and ≥ 1 post-baseline LCSS assessment. 95% CIs for the hazard ratios (HRs) for time to deterioration (TTD) of all 12 variables contained 1. The HR for TTD of PS by ≥1 point (cycles 1-6) was 0.861 (95% CI: 0.692-1.071). GC + N pts received a median of 6 cycles (interquartile [IQ] range 3-6) of GC, and a median of 6 cycles (IQ range 3-10) of N. GC pts received a median of 5 cycles (IQ range 3-6). Treatment discontinuation rates due to AEs were 13.6% (GC + N) and 14.6% (GC). SAEs were 47.8% (GC + N) and 37.5% (GC). The most common grade ≥3 AE was neutropenia, 24.3% (GC + N) and 27.5% (GC). 51% of GC + N pts continued on N monotherapy (median: 4 additional cycles). Select supportive care for treated patients is summarized in Table below. GC + N (538 pts) (%) GC (541 pts) (%) Concomitant medications 100 100 Transfusions 21.9 20.5 Hospitalizations 41.1 34.0 Colony stimulating factors 13.4 16.8 Erythropoietin 0.2 1.5 Conclusions: Long-term use of N was well tolerated. There were no major differences in AE rates, no detrimental effect overall of adding N to GC in terms of patients' QoL (symptoms and PS). Supportive care and associated resource use were modest. Disclosure: M. Reck: Member of Advisory Board: Hoffmann-La Roche, Lilly, AstraZeneca, BMS, Novartis, Pfizer, Boehringer – Ingelheim Honoraria for lectures: Hoffmann-La Roche, Lilly, AstraZeneca, BMS, Novartis, Pfizer, Boehringer-Ingelheim; M. Dediu: Consultant and Advisory Role (C) - Eli Lilly, Amgen, Boehringer-Ingleheim, Novartis. Speaker fee - TEVA, Boehringer-Ingelheim, MSD, GlaxoSmithkline, Amgen, Astra-Zeneca, Roche, Janssen, Eli Lilly, Pfizer; O. Molinier: Dr Olivier MOLINIER declares -consultant and advisory role for Eli Lilly and Roche -Speaker for Boehringer-Ingleheim; C. Schumann: Consultant and Advisory Role: -Eli Lilly, Pfizer, Roche, Boehringer-Ingelheim Speaker fee: -Eli Lilly, Novartis, Pfizer, Roche, Astra-Zeneca, Amgen, Boehringer-Ingelheim; J. Brown: I am an employee of Eli Lilly and Company and hold stock options and equity with Eli Lilly and Company; V. Soldatenkova: Employment: Lilly Deutschland GmbH, stock ownership. N. Chouaki: Employee of Eli Lilly and Company, I have stock ownership; N. Thatcher: Honoraria for advisory boards and speaker bureaus Eli Lilly and other companies. All other authors have declared no conflicts of interest.

Events associated with decreased renal function are reported in ≥1% and

Aim: This single arm multicenter Phase II study showed that Pem-Cis induction chemotherapy (CT) followed by full-dose Pem-Cis + concurrent radiotherapy (RT) was well tolerated and effective in pts with LA NS-NSCLC. The 1 yr PFS rate (primary endpoint) was 51% (ECCO 2013). Here, we present final data for younger vs. elderly pts (≤70/ > 70 yrs). Methods: Pts with unresectable Stage IIIA/B NS-NSCLC (AJCC V6) and ECOG-PS 0-1 received two 21-day cycles of Pem 500/Cis 75 mg/m2 on Day (d)1 (supplementation per Pem label). Eligible pts who did not progress continued with 2 cycles of full dose Pem-Cis + concurrent RT (66 Gy, 33 fractions). Results: Of 73/17 pts ≤70/ > 70 yrs enrolled, 59/16 (81/94%) completed induction CT and started concurrent CT + RT (≤70/ > 70 yrs: male 56/59%, ECOG-PS 0 66/65%, adeno 89/94%, Stage IIIA 32/53%). The 1 yr PFS rate [95%CI] was 44.9% [32.6%, 56.4%] in pts ≤70 yrs and 53.3% [26.3%, 74.4%] in pts >70 yrs. Median OS was 26.2 mo in pts ≤70 yrs and 25.1 mo in pts >70 yrs. ORR (CR + PR) in pts ≤70/ > 70 yrs was 59/65%, DCR (CR + PR + SD) was 74/94%. Tumor response in pts >70 yrs included 2 CRs (1 after CT + RT alone). 53 of 59 pts ≤70 yrs and 12 of 17 pts >70 yrs starting CT + RT received the full RT dose. Of the 17 pts >70 yrs overall, 15 received all 4 CT cycles, 3 had ≥1 cycle delay for toxicity, 2 had 1 CT dose reduction, 1 had 1 CT dose omitted. Safety data are reported as table. No elderly, but 1 pt ≤70 yrs died from study-drug related toxicity (enteritis) during Cycle 4. No pt >70 yrs required blood transfusions. During concurrent CT + RT, 1 pt >70 yrs had G2 pneumonitis (no G3/4 pneumonitis). Safety % patients ≤70 yrs >70 yrs TEAE Induction CT N = 73 Concurr CT + RT N = 59 Induction CT N = 17 Concurr CT + RT N = 16 Any 76.7 96.6 82.4 93.8 Related 63.0 93.2 70.6 87.5 G3/4 15.1 42.4 35.3 50.0 Related 11.0 40.7 17.6 43.8 Serious 8.2 23.7 11.8 25.0 Related 2.7 20.3 5.9 25.0 Conclusions: Pem-Cis induction CT followed by full-dose Pem-Cis and concurrent RT was effective in younger (≤70 yrs) and elderly (>70 yrs) pts with good PS. In both age groups, toxicity was manageable and consistent with the known safety profile of pemetrexed. Disclosure: P. Garrido Lopez: PG has worked as consultant for and has received speaker honoraria from Eli Lilly and Company; W. Engel-Riedel: WE-R has been Advisory Board Member for Eli Lilly, Amgen, Boehringer, and Roche, and has received speaker honoraria from Lilly, Amgen and Pierre Fabre; M. Serke: MS was consultant for ISCLC, Advisory Board Member for Lilly, Roche, Boehringer, and received speaker honoraria from ISCLC, Roche, Lilly, Astra Zeneca, Pfizer and Boehringer. She has received research funding for the study disclosed (S128) from Lilly; P. Giraud: PG has been Advisory Board Member for Merck Serono, and has received honoraria from Astellas and Merck Serono. He also has received research funding from Eli Lilly for the study (S128) disclosed here; C.M. Visseren-Grul: CVG is an employee of Eli Lilly and Company and owns Lilly stock; S. Ameryckx: SA is an employee of Eli Lilly and Company; V. Soldatenkova: VS is an employee of Eli Lilly and Company and owns Lilly stock; N. Chouaki: NC is an employee of Eli Lilly and Company. All other authors have declared no conflicts of interest.

7539^ Background: This single arm multicenter phase II study assessed the efficacy and safety of Pem-Cis induction chemotherapy (CT) followed by full-dose Pem-Cis + concurrent RT in patients (pts) ...

LBA8006^ Background: RAM is a human IgG1 monoclonal antibody that targets the extracellular domain of VEGFR-2. The REVEL study evaluated the efficacy and safety of RAM+DOC vs. PL+DOC (DOC) in patients (pts) with stage IV nonsquamous (NSQ) and squamous (SQ) NSCLC after platinum-based therapy. Methods: Pts with NSQ and SQ stage IV NSCLC were randomized 1:1 (stratified by sex, region, ECOG PS, and prior maintenance therapy) to receive DOC 75 mg/m2 in combination with either RAM 10 mg/kg or PL on day 1 of a 21-day cycle until disease progression, unacceptable toxicity, or death. The primary endpoint was overall survival (OS). Secondary efficacy endpoints included progression-free survival (PFS), and objective response rate (ORR). Results: Between Dec 2010 and Feb 2013, 1,253 pts (26.2% SQ) were randomized (RAM+DOC: 628; DOC: 625). Pt characteristics were balanced between arms. ORR was 22.9% for RAM+DOC and 13.6% for DOC (P5% of pts on RAM+DOC were neutropenia (34.9% vs. 28.0%), febrile neutropenia (15.9% vs. 10.0%), fatigue (11.3% vs. 8.1%), leukopenia (8.5% vs. 7.6%), hypertension (5.4% vs. 1.9%), and pneumonia (5.1% vs. 5.8%). Grade 5 AEs were comparable between arms (5.4% vs. 5.8%), as was pulmonary hemorrhage (any grade; all pts: 2.1% vs. 1.6%; SQ pts: 3.8% vs. 2.4%). Conclusions: REVEL demonstrated a statistically significant improvement in ORR, PFS, and OS for RAM+DOC vs DOC in NSCLC pts with stage IV NSCLC as second-line treatment after platinum-based therapy. Benefits were similar in NSQ and SQ pts, and no unexpected AEs were identified. Clinical trial information: NCT01168973.

8068 Background: The PARAMOUNT phase III trial showed that mtc pem after pem-cisplatin induction was well tolerated and effective for patients (pts) with advanced nonsquamous NSCLC. Here we present the final OS and safety data from this study in elderly (≥70 yrs) vs. non-elderly (2, day 1, 21 day cycle) or placebo (plc) (n=180). The study was powered for PFS (previously reported) and key secondary OS. Subgroup analyses were done for pts ≥70 yrs and

Background As previously reported, the PARAMOUNT trial showed that pemetrexed (pem) continuation maintenance therapy after pem–cisplatin induction therapy significantly reduced the risk of disease progression over placebo (HR = 0.62; 95% CI: 0.49–0.79; P = 0.00007) in patients with advanced nonsquamous NSCLC. Here we present the final OS data. Methods In a double-blind, placebo-controlled study, 939 patients were treated with induction therapy [four cycles of induction pem (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle], after which 539 patients who had not progressed and had an Eastern Cooperative Oncology Group performance status (PS) of 0/1 were randomized (2:1; stratified for PS, induction response, disease stage) to maintenance pem (500 mg/m2, day 1 of a 21-day cycle) plus BSC (n = 359) or placebo plus BSC (n = 180) until disease progression. All patients received vitamin B12, folic acid, and dexamethasone. After 390 deaths, the final analysis of OS was done on randomized patients and was based on a nominal alpha level of 0.0498. Results Patient characteristics were balanced between the arms: median age = 61 years; 58% male; 32% PS 0; 91% stage IV; 95% Caucasian; 86% adenocarcinoma; and 45% complete/partial response (CR/PR) to induction. (No OS data available.) Conclusions (Conclusion will be presented based on updated data.)

LBA7507 Background: The PARAMOUNT trial showed that pem continuation maintenance therapy significantly reduced the risk of disease progression over plb (HR=0.62; 95% CI: 0.49-0.79; p 2 and cis 75 mg/m2 on d1 of 21d cycles), and 539 pts who had not progressed and had an ECOG performance status (PS) of 0/1 were randomized (2:1) to maintenance pem (500 mg/m2, on day 1 of 21-day cycles) plus BSC or plb plus BSC until disease progression. All received B12, folic acid, and dexamethasone. After 397 deaths, a log-rank test compared OS between arms using anominal α level of 0.0498. Results: Pt characteristics were balanced between arms: median age 61 years; 58% men; 32% PS 0; 95% Caucasian; 86% adenocarcinoma; 45% complete/partial response (CR/PR) to induction. Pem resulted in a statistically significant 22% reduction in risk of death (HR=0.78). The HR was the same when measured from the beginning of induction. Survival improvement was similar for pts with an induction outcome of CR/PR versus stable disease. Conclusions: Pem continuation maintenance therapy offers superior OS compared with plb. These final results confirm that pem-cis induction followed by continuation pem further benefits pts compared with induction therapy alone, offering a change in the treatment paradigm for advanced NS NSCLC. [Table: see text]

CRA7510 Background: The PARAMOUNT trial investigated whether pem continuation maintenance therapy improves progression-free survival (PFS) after pem-cisplatin induction therapy in patients (pts) with advanced nonsquamous NSCLC. Methods: In this double-blind, placebo-controlled trial, 939 pts participated in the induction phase, specified as four cycles of induction pem (500 mg/m2) and cisplatin (75 mg/m2) on day 1 of a 21-day cycle. Pts who had not progressed during pem-cisplatin induction and had an Eastern Cooperative Oncology Group performance status (PS) of 0/1 (n=539; 57.4%) were randomized (2:1, stratified for disease stage, PS, and induction response) to maintenance pem (500 mg/m2 on day 1 of a 21-day cycle) plus BSC (n=359) or placebo plus BSC (n=180) until disease progression. All pts received vitamin B12, folic acid, and dexamethasone. The primary endpoint was PFS (target: HR=0.65, two-sided alpha=0.05; 90% power with minimum of 238 events). Results: Pt characteristics were balanced between arms: median age=61 years; 58% male; 95% Caucasian; 32% PS 0; 91% stage IV; 87% adenocarcinoma; and 45% induction complete/partial response. Pem continuation maintenance resulted in a 36% reduction in the risk of progression (HR=0.64, 95% CI: 0.51-0.81; P=0.00025). The median independently reviewed PFS (472 pts, 297 events), measured from randomization, was 3.9 months (95% CI: 3.0-4.2) on the pem arm, and 2.6 months (95% CI: 2.2-2.9) on the placebo arm. The disease control rate (% pts with response/stable disease) was 71.8% on the pem arm, and 59.6% on the placebo arm (P=0.009). The drug-related serious adverse event (AE) rate was 8.9% on the pem arm, and 9.2% of pts had grade 3/4 laboratory Common Toxicity Criteria AEs. On the placebo arm, the rates were 2.8% and 0.6%, respectively. Discontinuations due to AEs were 5.3% on the pem arm, 3.3% on the placebo arm. Conclusions: PARAMOUNT met its primary endpoint and showed that pem continuation maintenance following pem-cisplatin induction is an effective and well tolerated treatment for pts with advanced nonsquamous NSCLC.

7550 Background: In the CALGB Study Cis with Gem followed by concomitant chemoradiation for inoperable LA-NSCLC was effective, however with significant toxicity (E. Vokes et al; JCO 20: 2002). The aim of this study was to improve tolerability by reducing the Gem dose during radiotherapy and adding one cycle of induction chemotherapy. Methods: Patients with histological proven stage IIIA and IIIB NSCLC were included in this study from 8/04 to 9/07. All patients were to receive 3 induction cycles (21 days) of Cis 80 mg/m2 d1 plus Gem 1250 mg/m2 over 30 minutes d1, 8. After a 3 weeks rest period, 2 cycles of concomitant chemoradiation Cis 80 mg/m2 d1, Gem 300 mg/m2 d1, 8 and RTX (about 60 Gy; 5 times 1,8 Gy fractions / week) were given. Results: A total of 49 patients, median age 63.4 yrs, 73.5% male, with Karnofsky performance status 80/85/90/100: 16.3% / 2.0% / 49.0% / 32.7% were entered. Disease stage IIIA/IIIB: 28.6% / 71.4%. Median dose intensity during chemoradiation Gem 98.4%, Cis 99.0% and radiation median total dose was 63 Gy. Number of grade 3/4 toxicities during induction chemotherapy (N=49): neutropenia 9/9, thrombocytopenia 4/1. Acute grade 3/4 toxicities during chemoradiation phase (N=31): neutropenia 4/0, thrombocytopenia 5/1, radiation esophagitis 4/0 and radiation pneumonitis 1/0. No toxic death. Tumor Response Rate of enrolled patients was 22 (44.9%) (95% CI: 30.7–59.8). Conclusions: Concurrent Cis Gem chemoradiation after Cis Gem induction is an active treatment for LA-NSCLC with managable toxicity. [Table: see text]

Objectives This single-arm multicenter Phase II study investigated the efficacy and safety of pemetrexed (Pem) and cisplatin (Cis) induction chemotherapy (CT) followed by full-dose Pem-Cis plus concurrent radiotherapy (RT) in patients with locally advanced non-squamous NSCLC. Materials and methods Patients with unresectable Stage III non-squamous NSCLC received two 21-day cycles of Pem 500 mg/m2 (vitamin/folic acid supplementation and dexamethasone prophylaxis per Pem-label) + Cis 75 mg/m2 on Day 1. Eligible patients who had not progressed continued with 2 further cycles of full-dose Pem-Cis plus concurrent RT (2 Gy/fraction, 5 days/week, 66 Gy total). Primary endpoint was the 1-year progression-free survival (PFS) rate. Results Of 90 patients enrolled (all treated; median age 61 years, male/female 57%/43%, ECOG performance status 0/1 66%/34%, adenocarcinoma 90%, Stage III 36%/62%), 75 (83%) completed induction CT and started concurrent CT + RT. 64 (71%) patients received all 4 CT cycles and an RT dose ≥60 Gy. The 1-year PFS rate was 51.3% (95%CI: 42.0, 60.5). Median PFS was 10.6 months (95%CI: 8.6, 17.3), median OS was 26.2 months (95%CI: 16.7, not estimable). One patient died from enteritis (treatment-related) during Cycle 4. Four patients discontinued due to treatment-related adverse events, 1 on induction CT (renal failure), 3 on concurrent CT + RT (1 hypoacusis, 2 acute esophagitis). During induction CT, 18.9% of patients reported Grade 3/4 CTCAEs, only neutropenia (2.2%) and syncope (2.2%) were reported by >1 patient. During concurrent CT + RT, 41.3% of patients reported G3/4 CTCAEs, mainly esophagitis (12.0%), neutropenia (10.7%), and leukopenia (9.3%). Conclusion In this study of Pem-Cis induction CT followed by full-dose Pem-Cis with concurrent RT, median PFS was 10.6 months and toxicity was manageable, in line with previous data on Pem-Cis plus RT.

7506 Background: Efficacy and safety of concurrent Pem+Cis and TRT followed by consolidation Pem vs other CTX regimens were evaluated; interim safety results (concurrent phase) were presented previ...