Belen San Antonio

PROCLAIM: Randomized Phase III Trial of Pemetrexed-Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non–Small-Cell Lung Cancer

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/m(2) and cisplatin 75 mg/m(2) 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/m(2) and cisplatin 50 mg/m(2) 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.

Final Efficacy and Safety Results of Pemetrexed Continuation Maintenance Therapy in the Elderly from the PARAMOUNT Phase III Study

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 (<70 years) patients. Methods: Final efficacy and safety data from the PARAMOUNT study were analyzed post hoc using subgroup analyses for elderly and non-elderly patients. Results: The median age was 73 years in the elderly subgroup (n = 92) and 60 years in the non-elderly subgroup (n = 447). Subgroups had similar baseline characteristics, except for a higher percentage of males and patients with a performance status of one in the elderly subgroup. For elderly patients, the median PFS was 6.4 months for pemetrexed and 3.0 months for placebo; the median OS was 13.7 months for pemetrexed and 12.1 months for placebo. For non-elderly patients, the median PFS was 4.0 months for pemetrexed and 2.8 months for placebo; the median OS was 13.9 months for pemetrexed and 10.8 months for placebo. Elderly patients experienced similar levels of low-grade toxicities, but had a higher percentage of grade 3/4 anemia and neutropenia than non-elderly patients, although importantly, this did not translate into increased febrile neutropenia. Conclusions: Continuation maintenance pemetrexed had comparable survival and toxicity profiles in the elderly and non-elderly subgroups. However, grade 3/4 anemia and neutropenia were numerically higher for elderly patients.

A Phase II Randomized Study of Cisplatin-Pemetrexed plus either Enzastaurin or Placebo in Chemonaive Patients with Advanced Non-Small Cell Lung Cancer

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.

Classical markers like ER and ki-67, but also survivin and pERK, could be involved in the pathological response to gemcitabine, adriamycin and paclitaxel (GAT) in locally advanced breast cancer patients: results from the GEICAM/2002-01 phase II study.

IntroductionThe identification and validation of biomarkers of chemotherapy sensitivity is critical in order to individualise therapy in breast cancer. We evaluated pathological complete response (pCR) to GAT, and its correlation with tumour biomarkers before and after neoadjuvant chemotherapy.Materials and methodsStage III (and stage II with T≥5 cm) breast cancer patients were included. Treatment consisted of adriamycin (40 mg/m2) day 1, and paclitaxel (150 mg/m2) followed by gemcitabine (2000 mg/m2) day 2, every 14 days for six cycles. Tissue from pre-treatment biopsy and surgery was evaluated for biologic markers by immunohistochemistry. Two XPD single nucleotide polymorphisms (SNP) were also analysed.ResultsForty-six patients entered the trial. Median age was 49.5 years (range 31–72); 25 patients (54%) were pre-menopausal; 12 (26%) were ER-PgR-negative; pCR was observed in 17% (95% CI: 6.4–28.4) of patients. Significant differences in marker expression (mean±SD) in correlation to pathological response were only found in Ki-67. After treatment, tumours showed lower Ki-67-, surviving- and pERK-positive cells. No correlation between XPD polymorphisms and pCR was found. The overall response rate was 89% (95% CI: 80.1–98.1). Fifteen patients (33%) underwent breast-conserving surgery. The most frequent grade 3 or 4 toxicities were neutropenia (with one febrile neutropenia) and asthenia.ConclusionThese results show an effective regimen with acceptable tolerability. Our data suggest that not only classical markers (ER, Ki-67), but also survivin and pERK could be involved in the response to GAT, which may contribute to therapy individualisation in future study designs.

Meta-analysis examining impact of age on overall survival with pemetrexed for the treatment of advanced non-squamous non-small cell lung cancer

OBJECTIVE In clinical practice, elderly patients are often undertreated relative to younger patients. This meta-analysis was designed to determine whether older patients with non-squamous non-small cell lung cancer (NSCLC) could derive an overall survival (OS) benefit from pemetrexed treatment comparable to that experienced by younger patients in the first-line, second-line, or maintenance settings. METHODS Data from 2671 patients with non-squamous NSCLC participating in four pemetrexed phase III studies were included in a meta-analysis using a random-effects model. Studies included were: JMEI (second-line pemetrexed, N=399); JMDB (first-line pemetrexed/cisplatin, N=1252); JMEN (pemetrexed maintenance after non-pemetrexed/platinum doublet, N=481); and PARAMOUNT (pemetrexed maintenance after first-line pemetrexed/cisplatin, N=539). Patients were predominantly Eastern Cooperative Oncology Group performance status (PS) 0/1. The ratio of OS hazard ratio (HR) (pemetrexed versus control) for younger patients over that for older patients within each study was used as the measure of the differential effect of pemetrexed. Data were examined using age cutoffs of 65 and 70 years. RESULTS Among the four studies, 32% of patients were aged ≥65 years and 14% were aged ≥70 years. The test of heterogeneity among studies was non-significant for subgroups defined by age 65 (P=0.083) and age 70 (P=0.848). The pooled ratio of the OS HR (pemetrexed versus control) in patients <65years to that in patients ≥65 years was 0.92 (95% confidence intervals [CI] 0.67-1.25). Similar results were seen for the analysis using the age 70 years cut-off (0.80 [95% CI 0.62-1.04]). CONCLUSIONS In patients with non-squamous NSCLC with good PS, the effect of pemetrexed on OS was not found to be different in younger and older patients undergoing treatment in the first-line, second-line, or maintenance settings.

Safety Analyses of Pemetrexed-cisplatin and Pemetrexed Maintenance Therapies in Patients With Advanced Non-squamous NSCLC: Retrospective Analyses From 2 Phase III Studies

BACKGROUND In a phase III study, maintenance pemetrexed showed superior survival over placebo (PARAMOUNT) for patients with advanced non-squamous non-small cell lung cancer (NSCLC) who completed 4 cycles of pemetrexed plus cisplatin (PC) induction therapy, with low incidence of treatment-emergent adverse events (TEAEs) generally associated with pemetrexed. Prior analyses did not account for toxicities carried over from induction; thus, the current analysis was developed to understand toxicities that may be attributed to pemetrexed maintenance versus PC induction, and how treatment duration affects toxicity. PATIENTS AND METHODS Selected clinically relevant TEAEs were explored in 2 analyses: assessing induction versus maintenance treatment in PARAMOUNT, and comparing PC from PARAMOUNT with toxicity data from a previous phase III study that established the role of PC in front-line therapy of non-squamous NSCLC (JMDB trial). RESULTS In PARAMOUNT, the incidence of most drug-related TEAEs was higher during induction than maintenance, for both the pemetrexed and placebo randomized populations. The majority of TEAEs during maintenance, except renal events, were carried over from induction with no change in severity from the end of induction; the incidence of TEAEs associated with pemetrexed maintenance was low. The cross-trial analysis showed that 6 cycles of PC in JMDB compared with 4 cycles in PARAMOUNT increased grade 1/2 fatigue (34.1% vs. 25.0%), anemia (24.0% vs. 13.5%), and renal events (11.8% vs. 3.6%). CONCLUSIONS Safety data presented here support the favorable risk benefit of 4 cycles of PC followed by maintenance pemetrexed in patients with advanced non-squamous NSCLC.

Meta-analysis of pemetrexed plus carboplatin doublet safety profile in first-line non-squamous non-small cell lung cancer studies

Abstract Objectives: This meta-analysis compared safety profiles (selected drug-related treatment-emergent adverse events [TEAEs]) of first-line pemetrexed plus carboplatin (PCb) area under the concentration-time curve 5 mg/min•mL (PCb5) or 6 mg/min•mL (PCb6), two widely used regimens in clinical practice for advanced non-squamous non-small cell lung cancer. Methods: All patients received pemetrexed 500 mg/m2 every 21 days with either of two carboplatin doses for up to 4–6 cycles. Safety profiles of PCb doses were compared using three statistical analysis methods: frequency table analysis (FTA), generalized linear mixed effect model (GLMM), and the propensity score method. Efficacy outcomes of PCb5 and PCb6 regimens were summarized. Results: A total of 486 patients mainly from the US, Europe, and East Asia were included in the analysis; 22% (n = 105) received PCb5 in one trial and 78% (n = 381) received PCb6 in four trials. The FTA comparison demonstrated that PCb5 vs PCb6 was associated with a statistically significantly lower incidence of TEAEs, including all-grade thrombocytopenia, anemia, fatigue, and vomiting, and grade 3/4 thrombocytopenia. In the GLMM analysis, PCb5 patients were numerically less likely to experience all-grade and grade 3/4 neutropenia, anemia, and thrombocytopenia. The propensity score regression analysis showed PCb5 group patients were significantly less likely than PCb6 group patients to experience all-grade hematologic TEAEs and grade 3/4 thrombocytopenia and anemia. After applying propensity score 1:1 matching, FTA analysis showed that the PCb5 group had significantly less all-grade and grade 3/4 hematologic toxicities. Overall efficacy outcomes, including overall survival, progression-free survival, and response rate, were similar between the two carboplatin doses. Conclusions: Acknowledging the limitations of this meta-analysis of five trials, heterogeneous in patient’s characteristics and trial designs, the results show that the PCb5 regimen was generally associated with a better safety profile than PCb6 across three statistical approaches, with no apparent impact on survival outcomes.

Safety profiles of non-small cell lung cancer patients treated with pemetrexed plus carboplatin: a real-world retrospective, observational, cohort study

Abstract Objective: Pemetrexed plus carboplatin (PCb) is a frequently used first-line treatment in advanced non-small cell lung cancer (NSCLC). This study examined the characteristics and safety profile of a NSCLC population treated with PCb area under the concentration-time curve 5 (PCb5) or 6 mg/mL•min (PCb6) under real-world conditions. Research design and methods: A retrospective, observational, cohort study was conducted, utilizing data from the IMS Oncology US clinic-based, longitudinal, patient-level electronic medical records (EMR), including patients with NSCLC on PCb5 or PCb6 regimens initiated concomitantly on or after the diagnosis of lung cancer during 2004–2014. Patient characteristics and incidence of adverse events (AEs) were described for each cohort. Propensity scores were calculated based on baseline demographic and clinical factors. Propensity score stratification was used to further adjust for cohort differences. Results: In total, 636 NSCLC patients receiving PCb5 (37% aged ≥70 years) and 184 patients receiving PCb6 (34% aged ≥70 years) who met the inclusion criteria were identified in the EMR. Patients with more comorbidities were more likely to have received PCb5. Overall incidence rates (IRs) per 100 person-years were similar for neutropenia in both cohorts, were numerically higher for anemia (IR = 43.6 vs 101.0) and thrombocytopenia (IR = 1.5 vs 17.9), and were numerically lower for nausea (IR = 14.4 vs 9.9) in the PCb6 vs PCb5 cohort. Within the PCb6 cohort, the IR per 100 person-years was higher for neutropenia for ≥70 year-old patients (IR = 41.1) compared to <70 year-old patients (IR = 14.5). After propensity score stratification, adjusted IRs showed similar patterns. Limitations: Limitations included lack of power for AEs other than anemia, given the nature of EMR. Conclusions: Results from this real-world analysis add to existing evidence from randomized clinical trials about PCb safety profiles in the overall NSCLC population and in elderly patients. These results may guide physicians when making treatment decisions.

The Impact of Staging by Positron Emission Tomography on Overall Survival and Progression-free Survival in Patients with Locally Advanced Non-Small Cell Lung Cancer

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.

Evaluation of changes in renal function in PARAMOUNT: a phase III study of maintenance pemetrexed plus best supportive care versus placebo plus best supportive care after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer

Abstract 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 < .05). The risk of experiencing renal events leading to dose delays and discontinuations was higher with higher increases in sCr but reversible in most patients. sCr increases of ≥30% and ≥40% were associated with gender (female), age (<70 years) and longer exposure to pemetrexed compared with placebo. Sixteen (4%) pemetrexed patients and 1 (1%) placebo patient discontinued treatment due to drug-related renal events; 13/16 (81%) of those pemetrexed patients had sCr increases ≥30% and 7/13 (54%) had pre-existing conditions and/or were receiving nephrotoxic drugs. Conclusions: The appearance of renal events leading to dose delays and/or treatment discontinuations was associated with sCr increase of at least 30%. However, it was difficult to identify patients at a higher risk of treatment discontinuation due to a drug-related renal event based only on changes in pre-maintenance laboratory values.