Eduardo J. Pennella

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.

Treatment rationale and study design for the pointbreak study: a randomized, open-label phase III study of pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab versus paclitaxel/carboplatin/bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer.

We present the treatment rationale and study design of the PointBreak study, a phase III study of pemetrexed/ carboplatin/bevacizumab induction followed by pemetrexed/bevacizumab maintenance (arm A) compared with paclitaxel/carboplatin/bevacizumab induction followed by bevacizumab maintenance (arm B) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC). Treatment consists of up to 4 cycles of induction therapy followed by maintenance therapy until disease progression or treatment discontinuation in approximately 900 patients (450 per treatment arm). The efficacy objectives of this study are to compare overall survival (OS), response rates, disease control rates, progression-free survival, and time to progressive disease between the 2 treatment arms. In addition, safety, quality of life, pharmacokinetics, and translational research will be investigated for both treatment arms. If the primary objective (OS) is achieved, this study will provide robust results on an alternative treatment option, pemetrexed/carboplatin/bevacizumab followed by maintenance therapy with pemetrexed/bevacizumab, for patients with nonsquamous NSCLC.

Brain Metastases as the Primary Site of Relapse in Two Randomized Phase III Pemetrexed Trials in Advanced Non–Small-Cell Lung Cancer

BACKGROUND Symptomatic brain metastases (BM) frequently occurs after initial treatment of non-small-cell lung cancer (NSCLC). Therefore, 2 large randomized trials that involved pemetrexed were retrospectively analyzed to determine the pattern of symptomatic relapse in the brain and to gauge if pemetrexed could influence the incidence. METHODS Two large phase III studies of pemetrexed in advanced NSCLC were included. One study compared pemetrexed with docetaxel in previously treated patients (n = 571); the other study tested cisplatin plus pemetrexed vs. cisplatin plus gemcitabine in chemotherapy-naive patients with advanced NSCLC (n = 1725). Patients with known BM at study entry were excluded from this analysis. Each study was analyzed separately, then jointly to determine the rate of BM reported as the only site of progressive disease by treatment group and histology. Logistic regression was used to obtain an odds ratio for the treatment effect on the overall occurrence of BM while controlling for potential confounding factors. RESULTS Overall, 71.5% of patients in pemetrexed-containing arms (819 of 1145), and 68.2% of patients in non-pemetrexed-containing arms (785 of 1151) experienced progressive disease. BM recurrence rates were 3.2% (95% confidence interval [CI], 2.1%-4.6%) in the pemetrexed-containing arms vs. 6.6% (95% CI, 5.0%-8.6%) in the non-pemetrexed-containing arms (P = .002). The odds ratio for BM recurrence associated with exposure to pemetrexed was 0.49 (95% CI, 0.32-0.76; P = .001). The beneficial effect of pemetrexed on BM was confined to patients with nonsquamous NSCLC. CONCLUSIONS Patients with advanced nonsquamous NSCLC treated with pemetrexed either in first-line or second-line therapy may reduce the risk of developing BM as the first site of progressive disease. This retrospective analysis is limited due to the lack of baseline and periodic brain scans, and it reflects symptomatic BM only. Regardless, these findings suggest a potential beneficial effect of pemetrexed-based treatments on the control of BM.

An exploratory subgroup analysis of race and gender in squamous cancer of the head and neck: Inferior outcomes for African American males in the LORHAN database

OBJECTIVES Previous retrospective analyses show poor outcomes for African American (AA) patients with head and neck carcinoma (HNC). Such racial disparities are not well understood, and generally studies have been too small to investigate subgroups and interactions related to race. MATERIALS AND METHODS The longitudinal oncology registry of head and neck carcinoma registry was used to identify patients ⩾18 years of age with squamous cell carcinoma of the head and neck, with no baseline metastases, and with an adequate record of survival time. Patient demographic and treatment characteristics were evaluated as a function of race and other known potential confounders of outcome. Associations between patient characteristics, including smoking, stage, performance status, and overall survival (OS) and progression-free survival (PFS) outcomes were also examined. RESULTS Analysis of OS and PFS confirmed prior reports of inferior outcomes in AA patients vs. Whites with median OS/3-yr rate 41.7 mo/52% in AAs vs. 56.6 mo/70% in Whites (hazard ratio: 1.69 [95% confidence interval: 1.42, 2.01]). The elevated risk for worse OS and PFS in AAs remained, after multivariate adjustment. African American males incurred most of the excess risk compared to AA females. CONCLUSION This exploratory study confirmed a worse OS and PFS prognosis for AA patients, and it documents that most of the excess risk occurs in AA males. Future studies should confirm these findings and should investigate biological and other factors that account for such profound differences in outcomes.

A pharmacokinetics and pharmacodynamics equivalence trial of the proposed pegfilgrastim biosimilar, MYL-1401H, versus reference pegfilgrastim

PurposePegfilgrastim is a long-acting granulocyte colony-stimulating factor indicated for prevention of febrile neutropenia in patients receiving myelosuppressive chemotherapy by promoting neutrophil recovery.MethodsThis phase 1, randomized, double-blind, three-way crossover trial in healthy volunteers evaluated the pharmacokinetics (PK), pharmacodynamics (PD), safety, and tolerability of the proposed biosimilar, comparing MYL-1401H, reference pegfilgrastim (Neulasta®, Amgen Inc, Thousand Oaks, CA, USA) sourced from the European Union, and reference pegfilgrastim sourced from the USA. Primary PK end points were peak plasma concentration of pegfilgrastim (Cmax) and area under the plasma concentration–time curve from the time of dosing to infinity (AUC0−inf). Primary PD end points were area under the curve above baseline for absolute neutrophil counts (ANC AUC0−t) and maximum change from baseline for ANC (ANC Cmax). Adverse events were also recorded.ResultsThe primary PK and PD end points were similar across all groups. For the PK parameters, the 90% confidence intervals (CIs) of the ratios of geometric means ranged between 0.91 and 1.18, which were within the predefined bioequivalence interval of 0.8000 to 1.2500 for all comparisons. For the PD parameters, the 95% CIs of the ratios of geometric means ranged between 0.94 and 1.06 for all comparisons, which were within the predefined PD equivalence interval of 0.8500 to 1.1765. The safety profiles were similar, with the most common adverse events being back pain and headache.ConclusionsMYL-1401H demonstrated similar PK, PD, and safety to reference pegfilgrastim in healthy volunteers and may be an equivalent option for the prevention of febrile neutropenia.

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.

A pharmacokinetics phase 1 bioequivalence study of the trastuzumab biosimilar MYL‐1401O vs. EU‐trastuzumab and US‐trastuzumab

Trastuzumab is a humanized monoclonal antibody that binds the human epidermal growth factor receptor 2 (HER2) oncoprotein and is an effective therapy for HER2‐overexpressing breast cancer. MYL‐1401O is a trastuzumab biosimilar. Here, we report results from a phase 1 study that investigated bioequivalence among MYL‐1401O, reference EU‐trastuzumab and US‐trastuzumab.

Abstract B77: Asian-American response to pemetrexed: Results from an observational study of second-line treatment of non-small cell lung cancer.

Background: The association of race with clinical outcomes has been increasingly investigated in non-small cell lung cancer (NSCLC). This prospective observational study evaluated the impact of race on disease control rate (DCR) in patients with NSCLC treated with second-line pemetrexed. Our previous report of this study showed the DCR of African-Americans was non-inferior to that of Caucasians (C). This report compares outcomes for Asian-Americans (AS) and C. Methods: Patients with stage IIIB/IV NSCLC who received one prior chemotherapy regimen and second-line therapy with pemetrexed were eligible. The primary endpoint was DCR (complete/partial response or stable disease). Secondary endpoints were overall survival (OS), progression-free survival (PFS), and adverse events. Logistic regression was used to analyze the DCR after therapy, controlling for 15 predefined covariates including prognostic and socioeconomic factors. Survival was estimated using Kaplan-Meier and compared with a log-rank test. Analyses were not adjusted for multiple race comparisons. Results: Challenges in enrolling minorities led to a lower than anticipated enrollment (AS=37 vs. 200 planned; C=304 vs. 400 planned), leaving a small sample size from which to draw conclusions. The mean age was 65 years (range, 34-90) for AS and 66 years (range, 37-86) for C. There were 17 males/20 females in the AS group and 161 males/143 females in the C group. Most patients had stage IV disease (AS=78.4%; C=80.3%). A higher percentage of AS had adenocarcinoma (AS=89.2%; C=62.8%; p=0.004) and a higher percentage of C were current smokers (AS=0.0%; C=27.7%; p=0.0002). The mean number of cycles received was 5.8 for AS and 4.1 for C. For the evaluable patients (AS=30; C=268), the DCR was numerically higher for AS (53.3% vs. 43.7%, OR=0.609, 95% CI: 0.253-1.469), but this difference was not statistically significant (p=0.270). AS had a significantly longer unadjusted median OS and PFS than C: OS of 16.0 (95% CI: 5.75-16.0) vs. 6.73 months (95% CI: 5.65-7.92), p=0.041; PFS of 5.08 (95% CI: 2.50-11.1) vs. 2.66 months (95% CI: 2.40-3.35), p=0.045. Adverse events, regardless of causality, occurred in <15% of patients, except for fatigue (AS=60%; C=68%). Conclusions: Despite the small sample size, this study provides insight into characteristics and outcomes of AS treated with second-line pemetrexed. Citation Format: A A. Adjei, E Pennella, A C. Girvan, G Peltz, G Pohl, C Obasaju, K Winfree, M S. Walker, E J. Stepanski, L S. Schwartzberg. Asian-American response to pemetrexed: Results from an observational study of second-line treatment of non-small cell lung cancer. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B77.

Abstract B57: Tolerability of pemetrexed: Results from an observational study of second-line treatment of non-small cell lung cancer (NSCLC) among racial groups.

Background: Second-line treatment with pemetrexed (Pem) has demonstrated safety and efficacy in NSCLC patients. A prospective observational study was conducted to evaluate the impact of race on disease control rate (DCR) in NSCLC patients treated with 2nd line Pem. This analysis focuses on the association of race with tolerability of treatment and patient-reported activities of daily living and symptoms. Methods: Patients with stage IIIB/IV NSCLC who received at least one dose of Pem for 2nd line treatment were eligible for the study. Tolerability of Pem was evaluated in two ways: reason for discontinuation of treatment and the worst post-baseline patient-reported outcomes (PROs). Treatment duration and reasons for discontinuation between Caucasians (C) and African Americans (AA), Asian Americans (AS), or Hispanics (H) were compared using log-rank and chi-square tests. Two PROs were evaluated: activities of daily living as measured by Older Americans Resource-Services - Instrumental Activities of Daily Living (IADL) and symptom burden as measured by M.D. Anderson Symptom Inventory-Lung Cancer (MDASI-LC). Total IADL score is the sum of seven items (cooking, driving, shopping, doing housework, handling finances, taking medication, talking on telephone) and ranges from 0-14, with higher scores indicating less ability to conduct activities. The MDASI-LC includes 19 items and is scored as four factors: general symptom severity (GSS) subscale, gastrointestinal symptoms, overall distress, and lung cancer related symptoms, with higher scores indicating greater burden. Scores range from 0-10, obtained by averaging individual symptoms. ‘Worst post-baseline’ PRO scores were evaluated and were compared between C and AA, AS, or H using Wilcoxon-Mann-Whitney tests. For robustness, comparisons were also adjusted for predefined covariates (e.g. age, gender, income, insurance, smoking status, ECOG PS, disease stage, histology) using linear regression and least square means (LSM). Analyses were not adjusted for multiplicity; significance level was set at 0.05. Results: Among 434 eligible patients (n=304 C, 65 AA, 37 AS, 28 H), 61.52% patients stopped treatment due to progression or death; only 9.45% patients stopped treatment due to lack of tolerability. Discontinuation due to lack of tolerability was not significantly different between C and AA, AS, or H, but AS had a significantly longer treatment duration than C (median: 4 vs. 3 cycles, p = 0.02). Post-baseline outcomes were obtained from 75.81% patients, which was comparable across racial groups (range of 74.34% to 82.14%). Among racial groups, baseline PRO scores did not differ significantly. Post-baseline PRO scores did not differ significantly between C and AA or H, but AS reported lower ‘worst post-baseline’ total IADL scores (1.79 vs. 3.12, p=0.02) and GSS scores (2.66 vs. 3.68, p=0.01) than C. After adjusting for covariates, GSS subscale remained significant for AS (LSM difference = -0.97, p=0.01), and AA reported higher GSS (LSM difference = 0.53, p=0.04) and overall distress (LSM difference = 0.85, p=0.02) than C. Conclusions: Consistent with the literature, Pem is well-tolerated in patients with NSCLC during 2nd line treatment. Generally, few differences in tolerability, activities of daily living, and symptom burden were observed among racial groups. Citation Format: Alex Adjei, Li Li, Katherine B. Winfree, Gerhardt Pohl, Eduardo Pennella, Allicia C. Girvan, Coleman K. Obasaju, Mark S. Walker, Edward J. Stepanski, Lee Schwartzberg. Tolerability of pemetrexed: Results from an observational study of second-line treatment of non-small cell lung cancer (NSCLC) among racial groups. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B57.

Prospective observational comparison of outcomes in African American and Caucasian patients receiving second-line treatment with pemetrexed for advanced non-small cell lung cancer (NSCLC).

e18008 Background: Few prospective studies have evaluated the impact of race and ethnicity on clinical outcomes, during lung cancer treatment. This prospective observational study evaluated the impact of ethnicity on disease control rate (DCR) in patients (pts) with NSCLC treated with second-line pemetrexed (P). METHODS Eligibility criteria included stage IIIB or IV NSCLC pts receiving single-agent P for second-line therapy in routine clinical practice. Sites were selected to ensure high minority representation. Due to persistent challenges in achieving desired enrollment of Hispanic and Asian pts, the focus of the study was narrowed to a comparison of pts self-reporting as Caucasian (C) and African American (AA). This report describes findings regarding the primary endpoint of the study, DCR. Some pts remain under observation-full characterization of survival will be available in early 2011. Non-inferiority was evaluated using logistic regression analysis for DCR controlling for predefined covariates: age, gender, income, marital status, insurance type, smoking status, ECOG performance score, disease stage, histology, comorbidities, time from end of first-line to initiation with P, prior exposure to first-line platinum, first-line paclitaxel, and number of first-line cycles. The DCR of AAs was considered non-inferior to Cs if the upper 95% confidence bound on the adjusted odds ratio (OR) for Cs vs AAs was less than 1.78, corresponding to a difference in proportion of 14% assuming Cs to have a DCR of approximately 50%. The bound was chosen to be one-half of the anticipated difference between treatment and no second-line treatment. RESULTS The unadjusted DCR was 43.4% (116/267) for C and 45.8% (27/59) for AA (unadjusted OR=0.91). The adjusted OR for the comparison of C to AA in the final logistic regression model was 0.79 (95% CI, 0.41, 1.51). This upper 95% confidence bound was within the pre-specified acceptable bound of 1.78. CONCLUSIONS Based on pre-specified analyses, DCR of AAs was non-inferior to Cs. Hence, ethnicity is not considered a significant predictor of disease control following second-line treatment with P.