Rash management and treatment persistence of cancer patients treated with epidermal growth factor receptor inhibitors in the Truven MarketScan® research database.

PURPOSE: Rash toxicity is a common, expected class effect of epidermal growth factor receptor (EGFR) inhibitors. Although rash management is practiced, it is not well characterized in the real-world setting. We describe the management of rash that developed while receiving EGFR-inhibitor therapy and how rash affects treatment duration, using Truven MarketScan® Research Database, a US medical claims database. METHODS: Adult patients who received EGFR-inhibitor treatment between 2004 and 2015 after a diagnosis of colon, head and neck, lung, breast, or thyroid cancer were identified. Descriptive analyses were conducted to describe occurrence of rash during the EGFR-inhibitor treatment period, EGFR-inhibitor treatment persistence and management of rash, including treatment and cost. RESULTS: Of 44,533 eligible patients, 4649 (10.4%) had records of rash during the EGFR-inhibitor treatment period, and of patients experiencing rash, 2891 (62.2%) received prescription drugs for rash treatment. Treatment persistence with an EGFR inhibitor was longer among patients experiencing rash compared with no rash (median 178 vs. 80 days for EGFR-TKIs, 85 vs. 57 days for EGFR-monoclonal antibodies), especially among patients with rash who were treated for rash (208 days for EGFR-tyrosine kinase inhibitors, 104 days for EGFR- monoclonal antibodies). Annualized cost during EGFR-inhibitor treatment was lowest among patients not experiencing rash (US$185,619), followed by rash patients receiving drugs for rash management (US$215,561), and highest among rash patients not treated for rash (US$267,105). CONCLUSION: Our findings suggest that management of EGFR inhibitor-associated rash could be important for EGFR-inhibitor treatment persistence.

Cetuximab plus platinum-based chemotherapy in head and neck squamous cell carcinoma: a randomized, double-blind safety study comparing cetuximab produced from two manufacturing processes using the EXTREME study regimen.

BACKGROUND: Cetuximab, in combination with platinum chemotherapy plus 5-fluoruracil (5-FU), is approved for the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Cetuximab manufactured by ImClone (US commercial cetuximab) potentially results in higher systemic exposures than cetuximab manufactured by Boehringer Ingelheim (BI-manufactured cetuximab). This prospective, randomized, double-blind study compared the safety profiles of the two cetuximab formulations. METHODS: Patients with previously untreated locoregionally recurrent and/or metastatic SCCHN were randomly assigned to receive the same dose of US commercial cetuximab (Arm A) or BI-manufactured cetuximab (Arm B), each in combination with cisplatin or carboplatin plus 5-FU. The primary outcome was all-grade, all-cause treatment-emergent adverse events (TEAEs). RESULTS: The majority of patients experienced ≥ 1 TEAE, regardless of causality (Arm A: 75/77 patients, 97.4%; Arm B: 68/71 patients, 95.8%). TEAEs with the highest incidence included nausea, fatigue, and hypomagnesemia in both arms. The absolute risk difference between the two arms for patients experiencing at least one adverse event (AE) was 0.029 (p = 0.281, 95% confidence interval [CI]: -0.024, 0.082) for AEs regardless of causality and 0.005 (p = 0.915, 95% CI: -0.092, 0.103) for AEs possibly related to study drug. There were no significant differences between the two arms in the incidence of acneiform rash, cardiac events, infusion reactions, or hypomagnesemia. Overall survival, progression-free survival, and overall response rates were similar in the two arms. CONCLUSIONS: There were no clinically meaningful differences in safety between US commercial cetuximab and BI-manufactured cetuximab in combination with platinum-based therapy with 5-FU in patients with locoregionally recurrent and/or metastatic SCCHN. The use of US commercial cetuximab in this combination chemotherapy regimen did not result in any unexpected safety signals. The efficacy results of this study are consistent with the efficacy results of the cetuximab arm of the EXTREME study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01081041 ; date of registration: March 3, 2010).

Gemcitabine plus enzastaurin or single-agent gemcitabine in locally advanced or metastatic pancreatic cancer: results of a phase II, randomized, noncomparative study.

PURPOSE: Gemcitabine (G) is standard therapy for pancreatic cancer. Enzastaurin (E) inhibits PKCß and PI3K/AKT signaling pathways with a dose-dependent effect on growth of pancreatic carcinoma xenografts. Data suggest that the GE combination may improve clinical outcomes. METHODS: Primary objective was overall survival (OS); secondary objectives assessed progression-free survival (PFS), response rate (RR), quality of life (QOL), toxicity, and relationships between biomarker expression and clinical outcomes. Patients were randomly assigned (2:1) to GE or G treatment; GE arm: E 500 mg p.o. daily; loading-dose (1200 mg; Day 1 Cycle 1 only) and G 1000 mg/m(2) i.v. Days 1, 8, and 15 in 28-day cycles; G arm: G as in GE. Biomarker expression was assessed by immunohistochemistry. RESULTS: Randomization totaled 130 patients (GE = 86, G = 44); 121 patients were treated (GE = 82, G = 39). GE/G median OS was 5.6/5.1 months; median PFS was 3.4/3.0 months. GE responses: 1 complete response (CR, 1.2%), 6 partial response (PR, 7.4%), and 33 stable disease (SD, 40.7%); disease control rate (DCR=CR+PR+SD, 49.4%). G responses: 2 PR (5.3%) and 16 SD (42.1%); DCR (47.4%). No QOL differences were noted between arms. GE/G Grade 3-4 toxicities included: neutropenia (18.3%/28.2%); thrombocytopenia (14.6%/25.6%); and fatigue (11.0%/7.7%). No statistically significant relationships between biomarker expression and outcomes were observed. However, patients with low expression of cytoplasmic pGSK-3ß trended toward greater OS with GE treatment. CONCLUSIONS: OS, PFS, QOL, and RR were comparable between arms. Adding E to G did not increase hematologic toxicities. GE does not warrant further investigation in unselected pancreatic cancer patients.

Phase III trial of induction gemcitabine or paclitaxel plus carboplatin followed by paclitaxel consolidation in ovarian cancer.

OBJECTIVE: The safety and efficacy of gemcitabine plus carboplatin (GC) or paclitaxel plus carboplatin (TC) induction regimens with or without paclitaxel consolidation therapy were assessed in ovarian cancer (OC). METHODS: Patients with stage IC-IV OC were randomized to either GC (gemcitabine 1,000 mg/m(2), days 1 and 8, plus carboplatin area under the curve [AUC] 5, day 1) or TC (paclitaxel 175 mg/m(2) plus carboplatin AUC 6, day 1) every 21 days for up to six cycles. Patients with complete response (CR) were allowed optional consolidation with paclitaxel 135 mg/m(2) every 28 days for ≤ 12 months. Patients without CR received single-agent crossover therapy at induction doses/schedules until CR, disease progression (PD), or unacceptable toxicity. PD or death in 636 patients was required to compare induction arms with 80% statistical power for progression-free survival (PFS), the primary endpoint. RESULTS: Randomized induction therapy was received by 820 of 919 patients enrolled; 352 patients with CR received paclitaxel consolidation whereas 155 patients without CR received single-agent crossover therapy. PFS was similar for GC and TC (median, 20.0 and 22.2 months, respectively; P=.199). Despite high censoring rates (>52%), overall survival was longer for TC (median, 57.3 versus 43.8 months for GC; P=.013). Controlling for patient characteristics including performance status, residual tumor size, and tumor stage, there was no statistical difference in a multivariate analysis (HR=1.22; 95% CI=0.99-1.52; P=.067). CONCLUSIONS: GC does not improve PFS over TC as first-line induction chemotherapy in OC. Although favoring TC, overall survival analyses were limited by the study design and high censoring rates.

Efficacy and safety of pemetrexed in elderly cancer patients: results of an integrated analysis.

PURPOSE: To analyze pemetrexed in elderly patients (>or=65 years) based on data collected in three randomized, phase III registration trials. METHODS: Patients who received pemetrexed as monotherapy or in combination with another drug were included in this analysis (N=764). In all studies, pemetrexed 500 mg/m(2) was administered every 21 days. Data from patients receiving pemetrexed were stratified by age +/-65 years. RESULTS: Out of the 764 patients randomized, 271 were >or=65 years of age (35.4%). Of these, 28% had non-small cell lung cancer, 41% pancreatic cancer, and 31% had malignant pleural mesothelioma that was either locally advanced or metastatic. The overall response rate of the integrated database of elderly patients was 21.4%, with complete response in three patients (1.11% in >or=65 years vs. 1.01% in <65 years), partial response in 55 (20.30% vs. 19.68%), and stable disease in 116 (42.80% vs. 43.00%). Median survival time was 8.34 months in both groups, and median time to progressive disease was 4.80 months versus 4.60. Toxicity observed in the elderly group included 70 patients (25.8% vs. 17.0%; p=0.005) with grade 4 toxicity; myelosuppression was the major toxicity, with grade 3/4 neutropenia in 33% versus 22% (p<0.05), and thrombocytopenia in 13% versus 6% (p<0.05). Febrile neutropenia occurred in 4.8% versus 4.7% of patients. Non-hematological grade 3/4 events were fatigue (10.3% vs. 9.5%) and nausea (6.3% vs. 6.5%). CONCLUSIONS: Pemetrexed produced similar treatment effects in older and younger patients, and appeared to be well tolerated in the elderly population. This analysis was limited by the pooling of different disease types and the lack of uniform treatment regimens.

Pemetrexed Continuation Maintenance Phase 3 Trials in Nonsquamous, Non-Small-Cell Lung Cancer: Focus on 2-Year Overall Survival and Continuum of Care.

Although lung cancer prognosis remains poor for most patients, treatments developed in the past 2 decades have extended survival for many. For those with disease that responded to or those with stable disease after receipt of platinum-based chemotherapy, maintenance regimens enable continued targeting of tumors beyond the induction phase, which is limited by toxicity. This overview summarizes completed phase 3 trials of pemetrexed continuation maintenance treatment in nonsquamous, non-small-cell lung cancer with a focus on 2-year survival, and highlights similar ongoing trials. Some studies showed survival benefits of pemetrexed maintenance treatment versus control arms, with the potential for added benefit when combined with bevacizumab. Two-year survival rates underscore the value of maintenance therapy and suggest progress toward a clinical goal of managing non-small-cell lung cancer as a treatable chronic disease.

Single-arm, open label study of pemetrexed plus cisplatin in chemotherapy naïve patients with malignant pleural mesothelioma: outcomes of an expanded access program.

BACKGROUND: An expanded access program (EAP) provided patient access to pemetrexed prior to its commercial availability. The current report consists of US patients in the EAP who had chemotherapy naïve pleural mesothelioma. METHODS: Eligible patients had a histologic or cytologic diagnosis of malignant mesothelioma that was not amenable to curative treatment with surgery. Study treatment consisted of pemetrexed 500mg/m(2) in combination with cisplatin 75mg/m(2) once every 21 days. Vitamin B12, folic acid, and dexamethasone were administered as prophylaxis. Serious adverse events (SAEs) were reported by investigators and compiled in a pharmacovigilance database for all patients enrolled in the EAP. RESULTS: Of 1056 patients receiving at least one dose of pemetrexed in the EAP, 728 had chemotherapy naïve pleural mesothelioma. Median age of this group was 70 years (range 23-89 years) and 84% were male. Among 615 patients, overall response rate was 20.5%, including 12 complete responses (2.0%) and 114 partial responses (18.5%). An additional 290 patients (47.2%) had stable disease. Median survival for all 728 patients was 10.8 months (95% CI=9.8, 12.3; 60.3% censorship) and 1 year survival was 45.4%. The most commonly reported SAEs in the overall EAP irrespective of causality were dehydration (7.2%), nausea (5.2%), vomiting (4.9%), dyspnea (3.8%), and pulmonary embolism (2.4%). CONCLUSIONS: In this large cohort, 67.7% of patients treated with first-line chemotherapy experienced a response or stable disease. Survival time and toxicity from this EAP were promising for this difficult-to-treat disease.

Administration of pemetrexed immediately following gemcitabine as front-line therapy in advanced non-small cell lung cancer: a phase II trial.

BACKGROUND: Pemetrexed and gemcitabine have demonstrated independent anti-tumor activity in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). The combination of these two therapies may produce synergistic anti-tumor effects. Previous studies of this combination have included a 90-min separation between the two drugs. More recent preclinical studies have suggested that this delay in administration might be unnecessary. This phase II study was designed to determine the objective tumor response rate and toxicity when pemetrexed was administered immediately after gemcitabine on day 1. METHODS: Chemonaïve patients stage IIIB with pleural effusion or stage IV NSCLC were enrolled. Treatment consisted of gemcitabine 1250 mg/m2 (30-min intravenous infusion on days 1 and 8) and pemetrexed 500 mg/m2 (10-min i.v. infusion, immediately following gemcitabine, on day 1) every 21 days. All patients received folic acid, vitamin B12, and steroid prophylaxis. RESULTS: The 53 enrolled patients completed a total of 199 cycles (median=4.0, mean=3.8). Best tumor response consisted of 1 complete response (2.0%), 15 partial responses (30.6%), 17 with stable disease (34.7%), and 16 with progressive disease (32.7%). Median time to disease progression was 3.3 months and median survival was 10.3 months. Grades 3/4 hematologic toxicities (% patients) consisted of: neutropenia (43.4), anemia (9.4), febrile neutropenia (7.5%) and thrombocytopenia (1.9). The most common grades 3 or 4 non-hematologic events were: dyspnea (15.1), fatigue (11.3), and pyrexia (9.4). One patient (1.9%) experienced grade 2 alopecia. CONCLUSION: This schedule of pemetrexed plus gemcitabine is tolerable and offered the advantage of not requiring a 90-min delay between the two drugs. Response rate, survival, time to disease progression, and toxicity were acceptable and similar to other NSCLC regimens.

Gemcitabine/carboplatin in patients with metastatic non-small-cell lung cancer: phase II study of 28-day and 21-day schedules.

BACKGROUND: The combination of gemcitabine/carboplatin is active and is widely used for advanced non-small-cell lung cancer (NSCLC). The optimum schedule for the administration of these agents is not currently known. This study compared 2 different combinations of carboplatin/gemcitabine to identify a schedule with a superior therapeutic index. PATIENTS AND METHODS: The 28-day schedule used gemcitabine 1,100 mg/m2 on days 1 and 8 plus carboplatin to an area under the curve (AUC) of 5 on day 8. The 21-day schedule used gemcitabine 1,000 mg/m2 on days 1 and 8 plus carboplatin to an AUC of 5 on day 1. RESULTS: Four hundred ninety-nine chemotherapy-naive patients with stage IIIB NSCLC (with malignant pleural effusion) or stage IV NSCLC were accrued. Grade 3/4 toxicities with the 28-day and 21-day schedules were anemia (4.8% and 6.9% of cycles, respectively), neutropenia (9.1% and 10.7% of cycles, respectively), and thrombocytopenia (8% and 14.4% of cycles, respectively). Thirty-four patients (13.2%) received blood transfusions with the 28-day regimen, as did 43 (20%) with the 21-day regimen, and no bleeding episodes occurred. Overall response rates were 22.8% with the 28-day schedule and 32.6% with the 21-day schedule (P=0.0338). Median survival and 1-year and 2-year survival rates were 9.8 months, 38.6%, and 15.7%, respectively, with the 28-day schedule and 12 months, 49.1%, and 15.8%, respectively, with the 21-day schedule (P=0.5098). CONCLUSION: Gemcitabine/carboplatin demonstrated efficacy comparable to other platinum agent doublets. Either schedule can be recommended, as differences in survival between groups were not significant.

Open-label study of pemetrexed alone or in combination with cisplatin for the treatment of patients with peritoneal mesothelioma: outcomes of an expanded access program.

BACKGROUND: To date, few large studies have been reported of patients with peritoneal mesothelioma, and treatment of this disease has been largely extrapolated from the treatment of pleural disease. Hence, it was considered important to study and report on this specific patient population. Before the regulatory approval of pemetrexed, an expanded access program (EAP) provided access to eligible patients with malignant pleural or peritoneal mesothelioma. PATIENTS AND METHODS: Patients received pemetrexed 500 mg/m2 alone or in combination with cisplatin 75 mg/m2 once every 21 days for > or = 6 cycles. All patients received folic acid, vitamin B12, and steroid prophylaxis. Serious adverse events (SAEs) were compiled in a pharmacovigilance database, which included all patients in the EAP with pleural or peritoneal mesothelioma. From June 12, 2002 to February 18, 2004, 1056 patients with malignant mesothelioma were enrolled and received > or = 1 dose of treatment at 462 sites in the United States. Of these patients, 98 (9.3%) had peritoneal mesothelioma (57 previously treated, 38 chemotherapy-naive, and 3 with missing data). RESULTS: Response data were available for 73 patients (43 previously treated, 28 chemotherapy-naive, and 2 not classified), indicating response rates of 23.3% for previously treated patients (0 complete responses [CRs], 10 partial responses [PRs], 21 cases of stable disease [SDs], 12 cases of progressive disease [PDs]) and 25% for chemotherapy-naive patients (3 CRs, 4 PRs, 12 SDs, and 9 PDs). Median survival was 13.1 months for previously treated patients and has not been reached for chemotherapy-naive patients. The most commonly reported SAEs for the total EAP were dehydration (7.2%), nausea (5.2%), and vomiting (4.9%). CONCLUSION: Pemetrexed with or without cisplatin had a favorable safety profile, and the disease control rate (CR + PR + SD) of 71.2% in the subset of patients with peritoneal mesothelioma indicated activity in this patient population.

Phase II study of pemetrexed-gemcitabine combination in patients with advanced-stage non-small cell lung cancer.

PURPOSE: Cisplatin is one of the most active agents for the treatment of non-small cell lung cancer (NSCLC). It is also known for significant toxicity, which makes it unsuitable for certain patients. Our purpose was to evaluate the efficacy and toxicity of a promising cisplatin-free combination, gemcitabine plus pemetrexed, in NSCLC. EXPERIMENTAL DESIGN: Chemo-naive patients with inoperable NSCLC were eligible for this study. Gemcitabine (1250 mg/m2) was given intravenously on days 1 and 8, followed by intravenous pemetrexed (500 mg/m2) on day 8. After inclusion of 13 patients, folic acid and vitamin B12 supplementation was added to lower pemetrexed-induced toxicity. Quality of life was assessed with the Lung Cancer Symptom Scale. RESULTS: Sixty patients enrolled; 58 were evaluable for response. All patients had a World Health Organization performance status of 0 or 1. Eighty-seven percent had stage IV disease. Nine patients had a confirmed partial response [overall response rate, 15.5%; 95% confidence interval (CI), 7.3-27.4%]. Twenty-nine (50.0%) patients had stable disease. Median overall survival was 10.1 months (95% CI, 7.9-13.0 months), with a 1- and 2-year overall survival of 42.6% (95% CI, 30.0-55.3%) and 18.5% (95% CI, 7.9-29.1%). Median progression-free survival was 5.0 months. Median response duration was 3.3 months. There were no deaths attributed to treatment. Common Toxicity Criteria grade 3/4 toxicities were neutropenia (61.7%), febrile neutropenia (16.7%), fatigue (23.3%), and elevations of aspartate aminotransferase (15.0%) and alanine aminotransferase (20.0%). CONCLUSIONS: This combination had good tolerance and achieved promising overall survival with extended 1- and 2-year survival rates. This cisplatin-free regimen warrants further evaluation in randomized trials.

Exploratory Subset Analysis of African Americans From the PointBreak Study: Pemetrexed-Carboplatin-Bevacizumab Followed by Maintenance Pemetrexed-Bevacizumab Versus Paclitaxel-Carboplatin-Bevacizumab Followed by Maintenance Bevacizumab in Patients With Stage IIIB/IV Nonsquamous Non-Small-Cell Lung Cancer.

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

PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer.

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

Pemetrexed in head and neck cancer: a systematic review.

Pemetrexed has been evaluated as a novel chemotherapeutic for head and neck cancer (HNC). In this review, we examined the efficacy and tolerability of pemetrexed in patients with HNC. Relevant English-language literature was identified via PubMed and a review of published abstracts from the American Society of Clinical Oncology and European Society for Medical Oncology annual meetings from January 2000 through September 2012. Search terms were "pemetrexed" (or "LY231514") and "head and neck cancer." Completed prospective phase I to III trials of pemetrexed alone or in combination with other agents or radiotherapy evaluating objective response rate (ORR), progression-free survival (PFS), and/or overall survival (OS) were eligible; ten studies were reviewed. Results for ORR, PFS, and/or OS in patients receiving pemetrexed in combination with other chemotherapeutic agents and/or radiotherapy were promising in the first-line treatment setting. Pemetrexed was associated with acceptable grade 3-4 hematologic toxicities; it did not result in nonhematologic toxicities commonly seen with cisplatin, such as nephrotoxicity, ototoxicity, and neuropathy. In a single phase III randomized trial, although median OS was longer for patients treated with pemetrexed plus cisplatin (7.3 months) versus cisplatin plus placebo (6.3 months), the difference did not reach statistical significance (P=.082). Results of this review suggest that pemetrexed is an active chemotherapeutic in combination with other agents or radiotherapy in patients with HNC. In particular, the role of pemetrexed as a radiosensitizer and potential alternative to cisplatin warrants investigation. More research is needed to clearly define the role of pemetrexed in HNC treatment.

Prospective observational comparison of clinical outcomes between african-american and caucasian patients receiving second-line treatment with pemetrexed for advanced non-small-cell lung cancer.

INTRODUCTION: This prospective observational study evaluated the effect of race on disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in patients with NSCLC treated with second-line pemetrexed. PATIENTS AND METHODS: Eligibility criteria included stage IIIB or IV NSCLC patients receiving single-agent pemetrexed for second-line therapy in routine clinical practice. Noninferiority was evaluated using logistic regression analysis of DCR, controlling for predefined covariates. Noninferiority was considered if the upper 95% confidence bound on the adjusted odds ratio (OR) for Caucasian vs. African-American individuals was less than 1.78, corresponding to a difference in proportion of 14% assuming Caucasian individuals to have a DCR of approximately 50%. The bound was chosen to be half of the anticipated difference between treatment and no second-line treatment. PFS and OS were estimated using the Kaplan-Meier method. Tools were used to measure functional status and symptom burden. RESULTS: The unadjusted DCR was 43.7% (117/268) for Caucasian and 45.0% (27/60) for African-American individuals (unadjusted OR, 0.95; 95% confidence interval [CI], 0.54-1.66). The adjusted OR in the final logistic regression model was 0.82 (95% CI, 0.43-1.58). This upper 95% confidence bound was within the prespecified acceptable bound of 1.78. Median PFS times (months) were 2.7 (95% CI, 2.4-3.4) for Caucasian and 3.0 (95% CI, 2.3-4.7) for African-American individuals (P = .91). Median OS times (months) were 6.7 (95% CI, 5.7-7.9) for Caucasian and 6.9 (95% CI, 4.5-8.9) for African-American individuals (P = .92). Baseline and functional status after baseline assessment and mean symptom burden did not differ substantially among races. CONCLUSION: African-American race was not considered to be a significant predictor of disease control after second-line treatment with pemetrexed.

PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer.

PURPOSE: PointBreak (A Study of Pemetrexed, Carboplatin and Bevacizumab in Patients With Nonsquamous Non-Small Cell Lung Cancer) compared the efficacy and safety of pemetrexed (Pem) plus carboplatin (C) plus bevacizumab (Bev) followed by pemetrexed plus bevacizumab (PemCBev) with paclitaxel (Pac) plus carboplatin (C) plus bevacizumab (Bev) followed by bevacizumab (PacCBev) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with previously untreated stage IIIB or IV nonsquamous NSCLC and Eastern Cooperative Oncology Group performance status of 0 to 1 were randomly assigned to receive pemetrexed 500 mg/m(2) or paclitaxel 200 mg/m(2) combined with carboplatin area under the curve 6 and bevacizumab 15 mg/kg every 3 weeks for up to four cycles. Eligible patients received maintenance until disease progression: pemetrexed plus bevacizumab (for the PemCBev group) or bevacizumab (for the PacCBev group). The primary end point of this superiority study was overall survival (OS). RESULTS: Patients were randomly assigned to PemCBev (n = 472) or PacCBev (n = 467). For PemCBev versus PacCBev, OS hazard ratio (HR) was 1.00 (median OS, 12.6 v 13.4 months; P = .949); progression-free survival (PFS) HR was 0.83 (median PFS, 6.0 v 5.6 months; P = .012); overall response rate was 34.1% versus 33.0%; and disease control rate was 65.9% versus 69.8%. Significantly more study drug-related grade 3 or 4 anemia (14.5% v 2.7%), thrombocytopenia (23.3% v 5.6%), and fatigue (10.9% v 5.0%) occurred with PemCBev; significantly more grade 3 or 4 neutropenia (40.6% v 25.8%), febrile neutropenia (4.1% v 1.4%), sensory neuropathy (4.1% v 0%), and alopecia (grade 1 or 2; 36.8% v 6.6%) occurred with PacCBev. CONCLUSION: OS did not improve with the PemCBev regimen compared with the PacCBev regimen, although PFS was significantly improved with PemCBev. Toxicity profiles differed; both regimens demonstrated tolerability.

Comparison of pemetrexed plus cisplatin with other first-line doublets in advanced non-small cell lung cancer (NSCLC): a combined analysis of three phase 3 trials.

INTRODUCTION: In a first-line study of advanced NSCLC, pemetrexed-cisplatin was more effective among patients with adenocarcinoma and large-cell carcinoma compared with gemcitabine-cisplatin (median survival of 11.8 versus 10.4 months, P=.005), while survival with pemetrexed-cisplatin was shorter than with gemcitabine-cisplatin in patients with squamous cell carcinoma. The comparability of pemetrexed-cisplatin to other commonly used regimens within histology subgroups needs to be explored. METHODS: This retrospective analysis combined the patient-level data from three phase 3 randomized controlled trials that compared the efficacy of different third generation platinum- and non-platinum based doublets. Unadjusted median survival times and Cox covariate-adjusted treatment hazard ratio (HR) estimates were calculated. Overall results and subgroups by histological type were reported. RESULTS: This combined analysis consisted of 3467 patients. In the overall analysis, adjusted HRs favored pemetrexed (HR <1.0) to each of the other 5 regimens, though none of these HRs were statistically significant. Among patients with non-squamous histology, pemetrexed-cisplatin produced favorable HRs to each of the other regimens, achieving statistical significance when compared with vinorelbine-cisplatin (HR=0.67; 95% confidence intervals [CI]: 0.50, 0.91) and gemcitabine-cisplatin (HR=0.85; 95% CI: 0.75, 0.97). Among patients with squamous histology, 4 of the 5 comparison regimens produced favorable HRs (HR >1.0) when compared with pemetrexed-cisplatin, with only the comparison with gemcitabine-cisplatin achieving statistical significance (HR=1.23; 95% CI: 1.00, 1.51). CONCLUSION: In the absence of randomized clinical trial data comparing pemetrexed-cisplatin to commonly used doublets in advanced NSCLC other than gemcitabine-cisplatin, this combined analysis of multiple trials provides estimates for such comparisons.

A retrospective analysis of outcomes by age in a three-arm phase III trial of gemcitabine in combination with carboplatin or paclitaxel vs. paclitaxel plus carboplatin for advanced non-small cell lung cancer.

PURPOSE: Sufficient data are currently unavailable to assist in defining suitable regimens for patients ≥ 70 years with advanced non-small cell lung cancer (NSCLC). METHODS: Chemonaïve patients with a performance status (PS) of 0 or 1 and stage IIIB or IV NSCLC were randomized to gemcitabine 1000mg/m(2) on days 1 and 8 plus carboplatin area under the curve (AUC) 5.5 on day 1; the same schedule of gemcitabine plus paclitaxel 200mg/m(2) on day 1; or paclitaxel 225mg/m(2) on day 1 plus carboplatin AUC 6.0 on day 1. Cycles were every 21 days up to 6. Efficacy and toxicity results were compared by age groups. RESULTS: Overall survival (OS) between patients <70 years (8.6 months, 95% CI: 7.9, 9.5) and ≥ 70 years (7.9 months, 95% CI: 7.1, 9.5) was similar. OS was 8.8 months (95% CI: 7.5, 10.3) among patients 70-74 years, 6.5 months (95% CI: 5.6, 9.3) among patients 75-79 years, and 7.9 months (95% CI: 6.3, 10.3) among patients ≥ 80 years. OS was lower among patients 75-79 years compared with patients 70-74 years (P=0.04). Compared with patients <70 years, patients ≥ 70 years experienced similar rates of myelosuppresion, but younger patients experienced more vomiting and nausea. There was no clear pattern with respect to differences in efficacy by treatments across age groups. CONCLUSIONS: Based on the similarity of patient outcomes across age groups, doublet chemotherapy is feasible among carefully selected elderly patients with good PS.

A retrospective analysis of outcomes across histological subgroups in a three-arm phase III trial of gemcitabine in combination with carboplatin or paclitaxel versus paclitaxel plus carboplatin for advanced non-small cell lung cancer.

PURPOSE: Three phase III trials have shown pemetrexed to be associated with improved clinical outcomes among patients with adenocarcinoma and large cell histology compared with patients with squamous histology in advanced non-small cell lung cancer (NSCLC). The current retrospective analysis examined whether differences were present by histology in a three-arm trial of gemcitabine-carboplatin (GCb) or gemcitabine-paclitaxel (GP) versus a standard regimen of paclitaxel-carboplatin (PCb). MATERIALS AND METHODS: 1135 chemonaïve patients with stage IIIB or IV NSCLC were randomly allocated to receive: gemcitabine 1000 mg/m(2) days 1 and 8 plus carboplatin area under the curve (AUC) 5.5 day 1 (GCb); or gemcitabine 1000 mg/m(2) days 1 and 8 plus paclitaxel 200mg/m(2) day 1 (GP); or paclitaxel 225 mg/m(2) plus carboplatin AUC 6.0 day 1 (PCb). Cycles were repeated every 21 days up to 6 cycles or disease progression. Clinical results were retrospectively analyzed in by patient histology. RESULTS: 202 patients (17.8%) had squamous, 555 (48.9%) had adenocarcinoma, 45 (4.0%) had large cell, and 333 (29.3%) had another histologic type. The overall response rate for squamous patients was greater than non-squamous (35.1% versus 27.8%, P=0.04). Median survival (9.5 months for squamous and 8.3 months for non-squamous) and median time to progression (5.0 months for squamous and 4.4 months for non-squamous) did not significantly vary by histologic group. For squamous histology, median survival was 6.6 months for GCb, 10.2 months for GP, and 10.3 months for PCb. For non-squamous disease, median survival was 8.2 months for GCb, 8.4 months for GP, and 8.3 months for PCb. A formal test for a histology-by-treatment interaction effect between GCb and PCb was significant (P=0.04). CONCLUSION: In this trial of commonly used agents for advanced NSCLC, overall survival and time to progression were similar when comparing patients across histologies. The effect of treatment, however, varied across histologies.

Outcomes associated with brain metastases in a three-arm phase III trial of gemcitabine-containing regimens versus paclitaxel plus carboplatin for advanced non-small cell lung cancer.

BACKGROUND: Brain metastases (BMs) are a common complication of non-small cell lung cancer (NSCLC). Because of historical data indicating a poor prognosis for patients with BM, few randomized phase III studies of advanced NSCLC have included patients with BM at presentation. Because the potential benefits of systemic therapy in patients with BM are uncertain, we analyzed data from a recent phase III study. METHODS: One thousand one hundred thirty-five chemonaïve patients with stage IIIB/IV NSCLC were randomized to receive gemcitabine/carboplatin, gemcitabine/paclitaxel, or paclitaxel/carboplatin. Stratification was based on presence or absence of BM, stage, and baseline weight loss. Patients with BM were required to be clinically stable after treatment with radiotherapy or surgery before entry. Results were retrospectively analyzed by presence or absence of BM at study entry. RESULTS: Rate of BM was 17.1% overall. The response rate was 28.9% for patients with BM (n = 194) versus 29.1% without BM (n = 941). Time to progression was 4.3 months with BM and 4.6 months without BM (p = 0.03). Median survival was 7.7 months (95% confidence interval: 6.7-9.3) among patients with BM (n = 194) and 8.6 months (95% confidence interval: 7.9-9.5) for patients without BM (n = 941), p = 0.09. Rates of hematologic adverse events were not different among patients with and without BM. CONCLUSIONS: There were no significant differences in response, survival, or hematologic toxicity for patients with or without BM; however, patients with BM had a small but significantly shorter time to progression. Nonprogressing patients with treated BM are appropriate candidates for systemic therapy and entry into clinical trials.