Phase 1/2 Dose Escalating Study of Twice-Monthly Pemetrexed and Gemcitabine in Patients with Advanced Cancer and Non-small Cell Lung Cancer

IntroductionPemetrexed is synergistic with gemcitabine in preclinical models of non-small cell lung cancer (NSCLC). The optimal dose and utility of gemcitabine and pemetrexed was evaluated in a dose-escalating study.MethodsThe phase 1 study included patients with advanced tumors, whereas the phase 2 study included patients with locally advanced or metastatic NSCLC. Gemcitabine was infused over 30 minutes, followed by pemetrexed administered over 10 minutes on day 1 of a 14-day cycle. Treatment continued for 12 cycles or until disease progression. All patients received folic acid, Vitamin B12, and steroid prophylaxis.ResultsMaximum tolerated dose was gemcitabine 1500 mg/m2, followed by pemetrexed 500 mg/m2. Fifty-three patients (29 male, 24 female) were enrolled in the phase 2 study. Response rate was 20.8% (95% CI: 0.108–0.341), and the clinical benefit rate (CR + PR + SD) was 64.2%. Median time to disease progression was 4.6 months (95% CI: 2.79–6.18), median survival was 10.1 month (95% CI: 5.95–14.09, censorship = 20.75%), and 1-year survival was 41.0%. Common grade 3 or 4 adverse events (% of patients) were neutropenia (28.3%), fatigue (22.6%), and febrile neutropenia (9.4%).ConclusionsTwice-monthly gemcitabine and pemetrexed was well tolerated, with overall survival and clinical benefit indicating disease activity in NSCLC patients

A Comparison of White and African American Outcomes from a Three-Arm, Randomized, Phase III Multicenter Trial of Advanced or Metastatic Non-small Cell Lung Cancer

PURPOSE: To investigate the effect of race on the efficacy and safety of standard chemotherapy doublet regimens in African American patients, we conducted a subgroup analysis of a phase III randomized trial. PATIENTS AND METHODS: Chemonaïve patients with a performance status of 0 or 1 and stage IIIB or IV non-small cell lung cancer were randomized to arm A: gemcitabine 1000 mg/m2 on days 1 and 8 plus carboplatin area under the curve 5.5 on day 1; arm B: the same schedule of gemcitabine plus paclitaxel 200 mg/m2 on day 1; or arm C: paclitaxel 225 mg/m2 on day 1 plus carboplatin area under the curve 6.0 on day 1. Cycles were repeated every 21 days up to 6. A site selection tool identified institutions with potential to recruit a minority population. Outcome and toxicity data of white and African American patients were compared. RESULTS: Of 1135 total patients, 972 were white (85.6%) and 138 were African American (12.2%). Median survival was 8.3 months for white patients (95% confidence interval [CI]: 7.7-9.3) and 9.1 months for African American patients (95% CI: 8.2-11.1). Response rates were 29.1 and 29.0%, respectively. Rates of grade 3 or 4 toxicities were comparable. Among African Americans, median survival was 7.2 months (95% CI: 5.1-10.1) for gemcitabine-carboplatin (n = 47), 10.5 months (95% CI: 7.1-15.4) for gemcitabine-paclitaxel (n = 42), and 10.2 months (95% CI: 8.5-13.2) for paclitaxel-carboplatin (n = 49). CONCLUSION: Whites and African Americans had similar outcomes, although there was some variability in survival among African Americans across the three treatment groups

Evaluation of the Patterrns and Risks of Erythropoietin Stimulating Agents in Head and Neck Cancers

Background: Although head and neck cancer (HNC) is the sixth most common cancer type by incidence globally, few studies have focused on real world treatment patterns of this disease. A large, randomized study of erythropoietin stimulating agents (ESAs) produced worsened outcomes in patients with HNC. Real-world data on the treatment patterns HNC, and the use and outcomes of ESAs in this population is currently lacking. Methods: SEER Medicare was used to evaluate patients aged ≥65 years with a first diagnosis of HNC between 2002 and 2007. Logistic regression was used to evaluate predictors of treatment. An interrupted time series was used to estimate the changes in ESA use among patients receiving chemotherapy over time. Propensity weighted models predicted survival, thromboembolism (TEE), and disease recurrence outcomes associated with ESA exposure. Results: Characteristics associated with no treatment for HNC included being unmarried (adjusted OR=2.00, 95% CI: 1.75, 2.27) or African American (adjusted OR=1.65, 95% CI: 1.37, 1.98). ESA use was 50.0% among patients receiving chemotherapy and 3.1% among patients not receiving chemotherapy. ESA use was 50.0% among patients receiving chemotherapy and 3.1% among patients not receiving chemotherapy. Combination regimens such as cetuximab+taxane+platinum (63.8%) and taxane+platinum (56.0%) were associated with the highest rates of ESA use, while single-agent cetuximab was associated with the lowest rate of ESA use (22.3%). Use of ESAs significantly declined from 40.3% of patients receiving chemotherapy in January 2007 to 16.7% in August 2007. Patients receiving an ESA were more likely to have a TEE (adjusted HR=1.19 [95% CI: 1.31, 1.81), experience disease recurrence (adjusted HR=1.09 [95% CI: 1.00, 1.16]), or die (adjusted HR=1.17 [95% CI: 1.06, 1.30]). Discussion: Disparities in the diagnosis and treatment of patients with HNC were present, despite the uniform insurance status of patients in the database. Significant declines in ESA occurred following FDA action in January 2007. ESA use increased among HNC patients in the immediate aftermath of previous disclosure of negative trial data (June 2003). ESAs may be associated with modestly worsened outcomes in HNC

Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In the KEYNOTE-826 study, the addition of the anti-PD-1 monoclonal antibody pembrolizumab to chemotherapy with or without bevacizumab improved overall survival and progression-free survival (primary endpoints) versus placebo plus chemotherapy with or without bevacizumab, with manageable toxicity, in patients with persistent, recurrent, or metastatic cervical cancer. In this Article, we report patient-reported outcomes (PROs) from KEYNOTE-826. METHODS: KEYNOTE-826 is a multicentre, randomised, phase 3 trial in 151 cancer treatment centres in 19 countries. Eligible patients were aged 18 years or older with persistent, recurrent, or metastatic cervical cancer not previously treated with systemic chemotherapy (previous radiosensitising chemotherapy was allowed) and not amenable to curative treatment and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) centrally by means of an interactive voice response system in a double-blind manner to receive either pembrolizumab 200 mg or placebo every 3 weeks intravenously for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m FINDINGS: Between Nov 20, 2018, and Jan 31, 2020, of 883 patients screened, 617 were randomly assigned (pembrolizumab group, n=308; placebo group, n=309). 587 (95%) of 617 patients received at least one dose of study treatment and completed at least one post-baseline PRO assessment and were therefore included in the PRO analyses (pembrolizumab group, n=290; placebo group, n=297). Median follow-up was 22·0 months (IQR 19·1-24·4). At week 30, QLQ-C30 completion was 199 (69%) of 290 patients in the pembrolizumab group and 168 (57%) of 297 patients in the placebo group; compliance was 199 (94%) of 211 and 168 (90%) of 186, respectively. The least squares mean change in QLQ-C30 GHS-QoL score from baseline to week 30 was -0·3 points (95% CI -3·1 to 2·6) in the pembrolizumab group and -1·3 points (-4·2 to 1·7) in the placebo group, with a between-group difference in least squares mean change of 1·0 point (95% CI -2·7 to 4·7). Median time to true deterioration in GHS-QoL was not reached (NR; 95% CI 13·4 months-NR) in the pembrolizumab group and 12·9 months (6·6-NR) in the placebo group (hazard ratio 0·84 [95% CI 0·65-1·09]). 122 (42%) of 290 patients in the pembrolizumab group versus 85 (29%) of 297 in the placebo group had improved GHS-QoL at any time during the study (p=0·0003). INTERPRETATION: Addition of pembrolizumab to chemotherapy with or without bevacizumab did not negatively affect health-related quality of life. Along with the efficacy and safety results already reported from KEYNOTE-826, these data support the benefit of pembrolizumab and the value of immunotherapy in patients with recurrent, persistent, or metastatic cervical cancer. FUNDING: Merck Sharp & Dohme