Summary Background Angiogenesis is an important therapeutic target in colorectal carcinoma. Ramucirumab is a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2. ...We assessed the efficacy and safety of ramucirumab versus placebo in combination with second-line FOLFIRI (leucovorin, fluorouracil, and irinotecan) for metastatic colorectal cancer in patients with disease progression during or after first-line therapy with bevacizumab, oxaliplatin, and a fluoropyrimidine. Methods Between Dec 14, 2010, and Aug 23, 2013, we enrolled patients into the multicentre, randomised, double-blind, phase 3 RAISE trial. Eligible patients had disease progression during or within 6 months of the last dose of first-line therapy. Patients were randomised (1:1) via a centralised, interactive voice-response system to receive 8 mg/kg intravenous ramucirumab plus FOLFIRI or matching placebo plus FOLFIRI every 2 weeks until disease progression, unacceptable toxic effects, or death. Randomisation was stratified by region, KRAS mutation status, and time to disease progression after starting first-line treatment. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov , number NCT01183780 .ld Findings We enrolled 1072 patients (536 in each group). Median overall survival was 13·3 months (95% CI 12·4–14·5) for patients in the ramucirumab group versus 11·7 months (10·8–12·7) for the placebo group (hazard ratio 0·844 95% CI 0·730–0·976; log-rank p=0·0219). Survival benefit was consistent across subgroups of patients who received ramucirumab plus FOLFIRI. Grade 3 or worse adverse events seen in more than 5% of patients were neutropenia (203 38% of 529 patients in the ramucirumab group vs 123 23% of 528 in the placebo group, with febrile neutropenia incidence of 18 3% vs 13 2%), hypertension (59 11% vs 15 3%), diarrhoea (57 11% vs 51 10%), and fatigue (61 12% vs 41 8%). Interpretation Ramucirumab plus FOLFIRI significantly improved overall survival compared with placebo plus FOLFIRI as second-line treatment for patients with metastatic colorectal carcinoma. No unexpected adverse events were identified and toxic effects were manageable. Funding Eli Lilly.
Background.
Recent studies of pemetrexed have identified a predictive role for non‐small cell lung cancer (NSCLC) histology. We further reviewed the differential efficacy of pemetrexed according to ...histology in two large, phase III NSCLC trials.
Methods.
One study tested pemetrexed versus docetaxel in previously treated patients (n = 571) and the other tested cisplatin plus pemetrexed versus cisplatin plus gemcitabine in chemotherapy‐naive patients (n = 1,725) with advanced NSCLC. Cox proportional hazard models were used to test for covariate‐adjusted treatment‐by‐histology interactions (THIs) for overall survival (OS) and progression‐free survival (PFS). For each histologic subgroup, the Kaplan–Meier method was used to estimate unadjusted within‐arm medians, and Cox models were used to estimate covariate‐adjusted between‐arm hazard ratios (HRs).
Results.
In both studies, treatment arms were well balanced for histology. THIs were statistically significant (p < .005) for both OS and PFS. Nonsquamous patients treated with pemetrexed‐based therapy experienced longer survival than the comparators (HR, 0.78 and 0.84, respectively), whereas squamous patients had shorter survival (HR, 1.56 and 1.23, respectively). Whereas the efficacy of pemetrexed regimens differed according to histology, it did not differ for docetaxel or for cisplatin plus gemcitabine. Pemetrexed was well tolerated across histologic groups.
Conclusions.
The consistency of these results across studies confirms the predictive effect of histology for pemetrexed and the survival advantage for pemetrexed in patients with nonsquamous histology. These analyses suggest pemetrexed should not be recommended for the treatment of squamous cell carcinoma, but, because of efficacy and safety advantages, pemetrexed may be preferable to other agents for treatment of patients with nonsquamous NSCLC.
This review of two large, randomized, phase III studies of pemetrexed treatment for non‐small cell lung cancer provides evidence of a significant and consistent interaction between non‐small cell cancer histology and a pemetrexed treatment effect, confirming a treatment advantage for pemetrexed in patients with nonsquamous histology.
Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown ...activity in this setting.
This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio HR < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m(2) on day 1 and gemcitabine 1,250 mg/m(2) on days 1 and 8 (n = 863) or cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 (n = 862) every 3 weeks for up to six cycles.
Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P <or= .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.
In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.
The objective of this phase III global study was to compare the efficacy of gemcitabine plus paclitaxel (GT) versus paclitaxel in patients with advanced breast cancer. It was designed as a pivotal ...study for the approval of G for a breast cancer treatment indication.
Patients who relapsed after adjuvant anthracyclines were randomly assigned to gemcitabine,1,250 mg/m(2) days 1 and 8 plus paclitaxel, 175 mg/m(2) on day 1; or, to paclitaxel at same dose on day 1 (both arms administered every 21 days, unblinded). The primary end point was overall survival (OS) and secondary end points were time to progression (TTP), response rate (RR), progression-free survival, response duration, and toxicity. This final OS analysis was planned at 380 deaths.
A total of 266 patients were randomly assigned to GT and 263 to paclitaxel. Median survival on GT was 18.6 months versus 15.8 months on paclitaxel (log-rank P = . 0489), with an adjusted Cox hazard ratio of 0.78 (95% CI, 0.64 to 0.96; P = .0187). The TTP was longer (6.14 v 3.98 months; log-rank P = .0002) and the RR was better (41.4% v 26.2%; P = .0002) on GT. There was more grade 3 to 4 neutropenia on GT and grade 2 to 4 fatigue and neuropathy were slightly more prevalent on GT.
This phase III study documents a role for gemcitabine in advanced breast cancer after anthracycline-based adjuvant therapy. The results establish GT as a reasonable choice for women who require cytoreduction with manageable toxicities and validate ongoing testing of GT in the adjuvant setting.
The importance of non-small cell lung cancer (NSCLC) histologic subtype has increased during the last few decades because of an unprecedented shift in epidemiology and an increasing number of ...target-specific chemotherapeutic agents. This review examined histology as a potential prognostic and/or predictive factor of clinical outcomes in advanced NSCLC.
Literature searches of articles from 1982 to 2007 were conducted. We identified publications detailing phase II or III studies, retrospective analyses, and meta-analyses that reported a statistically significant prognostic or predictive role for histology.
Of 408 publications identified, 11 reported a prognostic association between histology and clinical outcomes, and 7 suggested that histologic subtype was predictive of outcomes in patients with advanced NSCLC treated with specific cytotoxic chemotherapy regimens. Fourteen publications reported histology was prognostic and/or predictive in patients treated with epidermal growth factor receptor inhibitors. Inadequate data collection, test methodology, or study design—including insufficient sample size, misclassified samples, and grouping of histologic subtypes for analysis—may have obscured the interpretation of the role of histology in many of the studies.
Although differences in study design and analyses make definitive conclusions difficult, evidence suggests that histology may be prognostic or predictive of clinical efficacy outcomes. To determine which patients would benefit from specific treatments and to further understand the role of histology, future studies should focus on establishing a definitive histologic diagnosis, and should include an analysis of histologic subtypes and efficacy outcomes.
Summary Background Available preclinical and phase 2 clinical data suggest that the addition of cetuximab, a monoclonal antibody directed against the epidermal growth factor receptor (EGFR), to ...chemotherapy might improve outcome in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to assess whether the addition of cetuximab to chemotherapy improved progression-free survival in patients with recurrent or progressive NSCLC after platinum-based therapy. Methods In this unmasked, open-label randomised phase 3 trial we enrolled patients with metastatic, unresectable, or locally advanced NSCLC from 121 sites in Canada and the USA. Eligible patients were those aged 18 years or older who had experienced progressive disease during or after one previous platinum-based regimen. Initially, patients were randomly assigned to receive either pemetrexed (500 mg/m2 ) or docetaxel (75 mg/m2 ) and then randomly assigned within each group to receive their chemotherapy with or without cetuximab (400 mg/m2 at first dose and 250 mg/m2 weekly thereafter) until disease progression or unacceptable toxicity. However, after a change in the standard of care, investigators chose whether to treat with pemetrexed or docetaxel on a patient-by-patient basis. The primary analysis was changed to compare progression-free survival with cetuximab plus pemetrexed versus pemetrexed, on an intention-to-treat basis. This study is registered with ClinicalTrials.gov , number NCT00095199. Findings Between Jan 10, 2005, and Feb 10, 2010, we enrolled 939 patients; data for one patient was accidentally discarded. Of the remaining 938 patients, 605 received pemetrexed (301 patients with cetuximab and 304 alone) and 333 received docetaxel (167 in combination with cetuximab and 166 alone). Median progression-free survival with cetuximab plus pemetrexed was 2·9 months (95% CI 2·7–3·2) versus 2·8 months (2·5–3·3) with pemetrexed (HR 1·03, 95% CI 0·87–1·21; p=0·76). The most common grade 3–4 adverse events with cetuximab plus pemetrexed were fatigue (33 11% of 292 patients), acneiform rash (31 11%), dyspnoea (29 10%), and decreased neutrophil count (28 10%), and with pemetrexed alone were dyspnoea (35 12% of 289 patients), decreased neutrophil count (26 9%), and fatigue (23 8%). A significantly higher proportion of patients in the cetuximab plus pemetrexed group (119 41% of 292 patients) experienced at least one serious adverse event than those patients in the pemetrexed group (85 29% of 289 patients; p=0·0054). Nine (3%) of 292 treated patients in the cetuximab and pemetrexed group died of adverse events compared with five (2%) of 289 treated patients in the pemetrexed alone group. Interpretation The use of cetuximab is not recommended in combination with chemotherapy in patients previously treated with platinum-based therapy. Funding Eli Lilly and Company and ImClone Systems LLC, a wholly owned subsidiary of Eli Lilly and Company.
This phase I study was conducted to determine the toxicities, pharmacokinetics, and recommended doses of pemetrexed in cancer patients with normal and impaired renal function.
Patients received a ...10-minute infusion of 150 to 600 mg/m2 of pemetrexed every 3 weeks. Patients were stratified for independent dose escalation by measured glomerular filtration rate (GFR) into four cohorts ranging from > or = 80 to less than 20 mL/min. Pemetrexed plasma and urine pharmacokinetics were evaluated for the first cycle. Patients enrolled after December 1999 were supplemented with oral folic acid and intramuscular vitamin B12.
Forty-seven patients were treated with 167 cycles of pemetrexed. Hematologic dose-limiting toxicities occurred in vitamin-supplemented patients (two; 15%) and non-supplemented patients (six; 18%), and included febrile neutropenia (four patients) and grade 4 thrombocytopenia (two patients). Nonhematologic toxicities included fatigue, diarrhea, and nausea, and did not correlate with renal function. Accrual was discontinued in patients with GFR less than 30 mL/min after one patient with a GFR of 19 mL/min died as a result of treatment-related toxicities. Pemetrexed plasma clearance positively correlated with GFR (r2 = 0.736), resulting in increased drug exposures in patients with impaired renal function. With vitamin supplementation, pemetrexed 600 mg/m2 was tolerated by patients with a GFR > or = 80 mL/min, whereas patients with a GFR of 40 to 79 mL/min tolerated a dose of 500 mg/m2.
Pemetrexed was well tolerated at doses of 500 mg/m2 with vitamin supplementation in patients with GFR > or = 40 mL/min. Additional studies are needed to define appropriate dosing for renally impaired patients receiving higher dose pemetrexed with vitamin supplementation.
Several prognostic factors in oncology have been established over the years, such as performance status, tumor size, and disease stage. The identification of prognostic and predictive factors is ...becoming increasingly important in medical research, particularly as scientific discoveries have led to better understanding of diseases and genetics, resulting in tailored therapy. Advances in drug discovery and better understanding of the mechanism of action, may also identify factors that may be prognostic and/or predictive. Prognostic or predictive factors may include patient characteristics such as age, ethnicity, sex, or smoking status, disease characteristics such as disease stage or nodal status, and molecular markers such as HER2 amplification and K ras mutation.
It can be challenging to distinguish whether a factor is prognostic or predictive, based on what is reported in the literature. This article is intended to help the reader assess whether a factor is prognostic and/or predictive.
Hazard ratios (HRs) are used commonly to report results from randomized clinical trials in oncology. However, they remain one of the most perplexing concepts for clinicians. A good understanding of ...HRs is needed to effectively interpret the medical literature to make important treatment decisions. This article provides clear guidelines to clinicians about how to appropriately interpret HRs. While this article focuses on the commonly used methods, the authors acknowledge that other statistical methods exist for analyzing survival data.
Pemetrexed has shown varied response rates in advanced breast cancer. This randomized, double-blind, phase II study was conducted to assess the efficacy and safety of two doses of pemetrexed in a ...homogeneous population. A secondary objective was to identify molecular biomarkers correlating with response and toxicity.
Patients with newly diagnosed metastatic breast cancer or locally recurrent breast cancer received 600 mg/m(2) (P600 arm) or 900 mg/m(2) (P900 arm) of pemetrexed on day 1 of a 21-day cycle. All patients received folic acid and vitamin B(12) supplementation.
The P600 (47 patients) and P900 (45 patients) arms had response rates of 17.0% (95% confidence interval, 7.7-30.8%) and 15.6% (95% confidence interval, 6.5-29.5%) with approximately 50% stable disease per arm, median progression-free survival of 4.2 and 4.1 months, and median times to tumor progression of 4.2 and 4.6 months, respectively. Both arms exhibited minimal toxicity (grade 3/4 neutropenia <20%, leukopenia <9%, and other toxicities <5%). Tumor samples from 49 patients were assessed for the expression levels of 12 pemetrexed-related genes. Folylpolyglutamate synthetase and thymidine phosphorylase correlated with efficacy. Best response rates and median time to tumor progression for high versus low thymidine phosphorylase expression were 27.6% versus 6.3% (P = 0.023) and 5.4 versus 1.9 months (P = 0.076), and for folylpolyglutamate synthetase were 37.5% versus 10.0% (P = 0.115) and 8.6 versus 3.0 months (P = 0.019), respectively. gamma-Glutamyl hydrolase expression correlated with grade 3/4 toxicities: 78.6% for high versus 27.3% for low gamma-glutamyl hydrolase (P = 0.024).
The two pemetrexed doses yielded similar efficacy and safety profiles. Exploratory biomarker analysis identified efficacy and toxicity correlations and warrants further evaluation.
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