Primary Analysis Set Research Articles

Panitumumab (pmab) with FOLFIRI as first-line treatment of patients (pts) with metastatic colorectal cancer (mCRC): Resections and curative surgery in a phase II single arm, multicenter study (20060314).

3545 Background: Pmab, a fully human monoclonal antibody directed against the epidermal growth factor receptor (EGFR), is approved in Europe as monotherapy for pts with chemotherapy-refractory, EGFR-expressing, KRAS wild-type (WT) mCRC. Methods: Ptsreceived pmab (6 mg/kg) and FOLFIRI every 2 weeks. Eligibility criteria included histologically confirmed mCRC (no prior systemic treatment for metastatic disease), ECOG PS 0–2 and availability of tumor tissue for biomarker analysis. The primary endpoint was objective response rate and secondary endpoints included progression-free survival and safety. All analyses are descriptive, this abstract discusses resections. Results: A total of 154 pts were enrolled. At time of primary analysis (June 09), KRAS evaluable samples were available for 94% (n = 145) of pts: 86 (59%) pts had KRAS WT tumors and 59 (41%) pts had KRAS mutant (MT) tumors. Demographics in the primary analysis set (all KRAS evaluable pts) by KRAS WT and MT were: 78%/54% male; median age (range) 63.5 years (21–84)/65.0 years (37-80); ECOG PS 0-1 95%/93%. Response rate in the KRAS WT group was 56% vs 38% in the MT group and median progression-free survival was 8.9 months vs 7.2 months. Resection rate was 15% (95% CI 8.3%, 24.5%) and 7% (95% CI 1.9%, 16.5%), and the majority of pts that underwent surgery had liver only mets 12 (92%) and 2 (50%), in the KRAS WT and MT groups respectively. One pt in the KRAS WT group had surgery for skin lesion mets and in the KRAS MT group, one pt underwent surgery for ovary and colon mets and another for lung mets. Complete removal was achieved in 8% (95% CI 3.3%, 16.1%) of pts in the KRAS WT group and 5% (95% CI 1.1%, 14.2%) in the KRAS MT group. Adverse events (AEs) were in line with previously reported data and KRAS status did not appear to influence incidence of these AEs. There were 3 treatment-related grade 5 events (haematemesis and rectal haemorrhage in the WT group and vena cava thrombosis in the MT group). Conclusions: Pmab combined with FOLFIRI in the first-line setting appears to be a well-tolerated regimen. These data suggest that pmab may increase incidence of resection in the WT group versus MT group. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen Amgen Amgen Amgen Amgen Amgen

Bendamustine Produces Durable Responses with An Acceptable Long-Term Safety Profile in Patients with Rituximab-Refractory Non-Hodgkin's Lymphoma: A Pooled Analysis.

Abstract 2681Poster Board II-657▪▪This icon denotes an abstract that is clinically relevant. Background:Although initially very responsive to therapy, indolent non-Hodgkin's lymphomas (NHLs) are generally incurable. Therefore, it is important to identify active and tolerable treatments for patients (pts) with relapsed or refractory disease. Bendamustine (B, Treanda®), a mechlorethamine alkylator with novel mechanisms of action, is approved in the US for the treatment of indolent B-cell NHL that has progressed during or after rituximab (R) or an R-containing regimen. Methods:Data from 2 North American, multicenter studies with similar design and enrollment and response assessment criteria were pooled to examine safety and durability of response and allow meaningful comparisons between groups receiving prior therapies. B 120 mg/m2 was given IV on D 1, 2 q 21 days × 6-8 cycles to pts with R-refractory indolent NHL. Pts with transformed disease were excluded from efficacy analyses. Endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and safety. Results:The primary analysis set consisted of all randomized pts (N=176; median 61 yr; 81% stage III/IV; median 2 prior chemotherapy- and 2 R-containing courses) and comprises the population for safety analyses. Histologies included follicular (68%), small lymphocytic (20%), marginal zone (11%), and lymphoplasmacytic (1%) lymphomas. Fifty-four (35%) pts were refractory to their last chemotherapy; 49 (28%) were refractory to their last alkylator-based regimen. Sixty-six (38%) pts received prior purine analogs (PA); 22 (33%) of these pts were PA refractory. Ninety-four (53%) pts received ≥6 cycles of B; early withdrawals were primarily due to adverse events (AEs, 28%, mostly myelosuppression [18%]) or disease progression (14%). Dose reduction occurred in 14% of cycles; 18% of cycles involved a treatment delay. Common nonhematologic AEs, primarily grade 1/2, were nausea (75%), fatigue (57%), vomiting (40%), and diarrhea (37%). 97% of pts received antiemetic therapy during study treatment. Grade 3/4 hematologic AEs included neutropenia (58%), thrombocytopenia (25%), and anemia (11%). Overall, 50 opportunistic infections in 48 pts were reported: herpes zoster (HZ, 18), herpes simplex (7), candidiasis (16), cytomegaloviral infection (5), Pneumocystis jiroveci pneumonia (2), atypical mycobacterial infection (1), and tuberculosis (1). HZ reactivation tended to be higher in pts with prior PA exposure (13% vs 8 %, P=NS); pts receiving prophylactic antivirals (n=18) did not experience HZ outbreaks, while an 11% incidence of outbreaks was observed in those not prophylaxed. Second malignancies occurred in 6 pts: 3 MDS, 1 CMML, 1 squamous cell carcinoma, and 1 AML. Two pts had tumor lysis syndrome (1 each grades 3 and 4) in the first cycle. Grade 3/4 AE frequencies were similar by prior PA exposure, except for neutropenia (41% vs 29%) and infection rate (26% vs 14%), which were higher in PA-pretreated pts. Grade 3/4 AEs were higher in pts '60 yr vs <60 yr (78% vs 63%), mainly due to fatigue (15% vs 6%), thrombocytopenia (23% vs 6%), and cardiac disorders (8% vs 2%). In 161 pts evaluable for efficacy (i.e., without transformed disease), B produced a 76% ORR (23% complete response [CR]/unconfirmed complete response [CRu]); in 75% of responders, the best response was recorded during cycles 1 to 3. Median (range) follow-up was 17 (11.5–24) months and DOR was 9 (7.1–10.5) months. At 1 and 2 years, 34% and 24% of responders continued to respond. Stratified by FLIPI, ORR was 77%, 75%, and 79% for low-, intermediate-, and high-risk groups, respectively; corresponding median DOR was 7.8, 9.0, and 7.0 months. Among 127 pts previously treated with alkylators, ORR was 88% (28% CR/CRu) in sensitive and 59% (12% CR/CRu) in refractory populations; corresponding median DOR was 9.3 and 7.7 months. Overall PFS was 9.0 (95% CI: 8–10.9) months; median PFS for alkylator-sensitive and -refractory pts was 10.9 (8.4–12.5) and 7.1 (4.0–9.3) months, respectively. Among 66 pts previously treated with PA, ORR was 81% and 64% for sensitive and refractory PA groups, respectively. ORR and DOR were similar by age (< or >65 yr), gender, histology, prior chemotherapy (' or >1). Conclusions:Durable responses and acceptable safety support the use of bendamustine in R-refractory pts with indolent NHL, even those who were refractory to prior alkylator- and PA-based treatments. PFS will be updated and pooled, and presented at the ASH meeting. Disclosures:Cheson:Cephalon, Inc.: Consultancy, Honoraria. Friedberg:Cephalon, Inc.: Research Funding. Kahl:Cephalon, Inc.: Consultancy, Research Funding. van der Jagt:Cephalon, Inc.: Research Funding. Tremmel:Cephalon, Inc.: Employment, Equity Ownership. Zaks:Cephalon, Inc.: Employment, Equity Ownership.

Low Incidence of Neutropenic Events in Patients with Lymphoma Receiving First-Cycle Pegfilgrastim with Chemotherapy: Results from a Prospective Community-Based Study

BackgroundMost alterations to chemotherapy dose and schedule are because of neutropenic events, which mainly occur in the first chemotherapy cycle. This prospective, community-based study evaluated the effectiveness of pegfilgrastim in patients with lymphoma who were also receiving chemotherapy. Patients and MethodsPatients aged ≥ 18 years with cancer other than leukemia or myelodysplastic syndromes were eligible, including patients with major comorbidities who were generally not eligible for most clinical trials. Key exclusions were weekly chemotherapy and concurrent radiation therapy. Patients received pegfilgrastim 6 mg approximately 24 hours after chemotherapy in each cycle (up to 8 cycles). Endpoints included neutropenic complications and serious adverse events. ResultsThis open-label single-arm study enrolled 2249 patients at 319 sites. Of these 2249 patients, 325 patients with non-Hodgkin lymphoma (NHL) and 46 patients with Hodgkin disease were included in the primary analysis set. The median age was 65 years for patients with NHL and 41 years for patients with Hodgkin disease, and 31% and 26% had major comorbidities, respectively. Few patients experienced neutropenic complications, including grade 4 febrile neutropenia (patients with Hodgkin disease: 0 [95% confidence interval (CI), 0-8%]; patients with NHL: 13% [95% CI, 10%-17%]); febrile neutropenia-related hospitalization (patients with Hodgkin disease: 0 [95% CI, 0-8%]; patients with NHL: 10% [95% CI, 7%-14%]), neutropenia-related dose reduction (patients with Hodgkin disease: 0 [95% CI, 0-8%]; patients with NHL: 5% [95% CI, 3%-8%]), and neutropenia-related dose delay (patients with Hodgkin disease: 0 [95% CI, 0-8%]; patients with NHL: 5% [95% CI, 3%-8%]). Serious adverse events were consistent with those observed in patients receiving myelosuppressive chemotherapy. ConclusionPatients with lymphoma receiving myelosuppressive chemotherapy supported by pegfilgrastim experienced few neutropenic complications or neutropenia-related alterations in chemotherapy dose and schedule.

Final Results of a Large, Community Based Study Evaluating the Impact of First and Subsequent Cycle Pegfilgrastim on Neutropenic Events in NHL and HD Patients.

Introduction: Most alterations to chemotherapy (CT) dose and schedule are due to neutropenic events, which mainly occur in the 1st cycle. A nationwide survey found that of 4522 patients (pts) with diffuse, aggressive non-Hodgkin's lymphoma (NHL) treated with CHOP-like regimens in community practice, 40% experienced CT dose reductions, and 24% experienced CT dose delays (Lyman 2004). The ability of pegfilgrastim to reduce complications of CT-induced neutropenia has been established in clinical trials for pts receiving moderately (Vogel 2005) and highly (Holmes 2002) myelosuppressive CT. This prospective, community-based study evaluated the efficacy of 1st cycle pegfilgrastim in pts with NHL receiving CT in community practice.Methods: Pts ≥ 18 yrs with cancers other than leukemia or MDS were eligible, including those with major comorbidities who are generally not eligible for clinical trials. Key exclusions were weekly CT and concurrent radiotherapy. Pts received pegfilgrastim 6mg ~24 hours after CT in each cycle (up to 8 cycles). Endpoints included neutropenic complications and CT dose reductions and delays. Additionally, average relative dose intensity (ARDI) was calculated for major standard regimens. Point estimates and 95% confidence limits (CL) are provided.Results: This open-label, single-arm study enrolled 2249 pts at 319 sites. Of these, 325 pts with NHL and 46 pts with Hodgkin's disease (HD) were included in the primary analysis set. The mean (SD) age was 65 (13) years for NHL pts and 41 (14) for HD pts. 69% of NHL pts and 26% HD pts had advanced (III–IV) disease, 90% of NHL pts and 98% of HD pts had ECOG status 0 or 1, and 31% of NHL pts and 26% of HD pts had major comorbidities (eg. vascular disease, diabetes). 49% of NHL pts received standard CHOP ± R (cyclophosphamide, doxorubicin, vincristine, and prednisone ± rituximab) and 78% of HD pts received standard ABVD (bleomycin, dacarbazine, doxorubicin, vinblastine). Few pts experienced neutropenic complications (table). All serious adverse events were consistent with those observed in pts receiving myelosuppressive CT.Conclusions: These results represent ‘real-world' data as the only major entry criterion for pts was a confirmed diagnosis of malignancy. Pts in our study received myelosuppressive CT with very few neutropenia-related alterations in CT dose and schedule supporting the use of pegfilgrastim from the 1st cycle of CT. Use of pegfilgrastim allowed maintenance of RDI with minimal CT dose delays and reductions.Incidence % (95% CL)NHLHDHospitalization related to neutropenia in cycle 19 (6, 13)4 (0.5, 15)Hospitalization related to FN in cycle 16 (4, 9)0 (0, 8)FN in cycle 1 (ANC<0.5×109/L and temperature 38.2°C)8 (5, 12)0 (0, 8)Incidence of grade 3/4 neutropenia in cycle 137 (32, 42)4 (0.5, 15)Neutropenia-related IV antibiotic use in cycle 19 (6, 12)4 (0.5, 15)Neutropenia-related CT dose reductions in cycle 212 (1, 5)0 (0, 8)Neutropenia-related CT dose delays in cycle 212 (1, 5)0 (0, 8)ARDI (mean % [SD])2CHOP ± R every 21 days77 (23)ABVD every 14 days83 (26)1physician reported2standard reference dose and planned cycle length were used to calculate DI in the denominator of RDI

First-Cycle Pegfilgrastim Reduces Chemotherapy-Induced Febrile Neutropenia among Older Patients with NHL Treated in Community Practice: Results from a Large, Randomized, Controlled Trial.

Introduction: Although non-Hodgkin's lymphoma (NHL) is frequently diagnosed in older patients, few randomized clinical trials are conducted in this setting. Furthermore, older patients who are included in clinical studies are a highly selected group and are not likely to be representative of patients treated in the community. Increased age is an established risk factor for chemotherapy-induced neutropenia, and older patients often receive suboptimal doses of chemotherapy as a result, especially in community practice (Lyman et al, J Clin Oncol 2004; 22:1–10). In a large (n=528) study of older patients with diffuse large B-cell lymphoma receiving CHOP or R-CHOP with no cycle-1 growth factor, 41% of patients had febrile neutropenia over all cycles and 20% in cycle 1 (Morrison et al, ASH 2004 poster). The benefit of pegfilgrastim in supporting moderately to highly myelosuppressive chemotherapy regimens has previously been shown.Methods: As part of a large (n=852), prospective, randomized, open-label study, we assessed the effectiveness of first-cycle pegfilgrastim among patients ≥ 65 years old receiving chemotherapy for NHL in community practice. Patients were randomized to 1 of 2 treatment arms - pegfilgrastim in first and subsequent cycles (Arm A) or no pegfilgrastim in cycle 1 with subsequent use at the physician's discretion (Arm B).Results: The primary analysis set included 146 patients with NHL, 73 per treatment arm. Median age was 73 years, range 65 to 87, with nearly 75% of patients aged 70 and older. R-CHOP was the most common chemotherapy, administered to 82% of patients. The overall incidence of febrile neutropenia was significantly lower for patients in Arm A (15%; [95% confidence limit (CL): 8, 25]) compared with patients in Arm B (37% [95% CL 26, 49]; p=0.0043). The first cycle incidence of febrile neutropenia was also lower in Arm A (7% [95% CL: 2, 15]) than in Arm B (25% [95% CL: 15, 36]), as was the overall incidence of hospitalization due to neutropenia-related events (17% [95% CL: 10, 28] vs 37% [95% CL: 26, 49]). Pegfilgrastim was administered frequently in Arm B, with 61% of patients initiating treatment in cycle 2, and 91% of patients (29/32) receiving pegfilgrastim by cycle 6. The main reasons for pegfilgrastim use in Arm B were grade 3/4 neutropenia, followed by febrile neutropenia. Dose reductions occurred in 16% of Arm A patients (95% CL: 9, 27) and in 8% of Arm B patients (95% CL: 3, 17) and dose delays occurred in 29% (95% CL: 19, 41) and 23% (95% CL: 14, 35) respectively; however, 19% of patients in Arm B discontinued from the study after cycle 1 compared with only 5% in Arm A, confounding the incidence of both parameters. Adverse event profiles were similar between the 2 treatment arms and were consistent with the population under study.Conclusions: The results of this study support the feasibility of conducting community-based trials in older patients, demonstrate that older patients can safely receive myelosuppressive chemotherapy, and show the effectiveness of first-cycle use of pegfilgrastim among older patients with NHL treated in the community setting.

A Randomized Comparison of Every-2-Week Darbepoetin Alfa and Weekly Epoetin Alfa for the Treatment of Chemotherapy-Induced Anemia in Patients With Breast, Lung, or Gynecologic Cancer

An important clinical question is the relative efficacy of the most common dosages of darbepoetin alfa (Aranesp; Amgen Inc.; Thousand Oaks, CA) 200 microg every 2 weeks (Q2W) and epoetin alfa (Procrit; Ortho Biotech Products, LP; Raritan, NJ) 40,000 U weekly (QW) for the treatment of chemotherapy-induced anemia. We designed three concurrent randomized, open-label, multicenter, identical trials (with the exception of tumor type criteria of breast, gynecologic, or lung cancer) of darbepoetin alfa and epoetin alfa in patients with chemotherapy-induced anemia to validate the Patient Satisfaction Questionnaire for Anemia (PSQ-An) treatment tool and to compare the efficacies and safety profiles of these two agents. In each trial, patients were randomized 1:1 to receive either darbepoetin alfa at a dose of 200 microg Q2W or epoetin alfa at a dose of 40,000 U QW for up to 16 weeks. The PSQ-An was assessed for validity, feasibility, and reliability. Secondary clinical endpoints were analyzed using the primary analysis set. Both individual trial analyses and a protocol-specified combined analysis of data from all three trials were conducted. Overall, 312 patients (157 darbepoetin alfa; 155 epoetin alfa) were randomized and received study drug. Baseline characteristics were similar in both treatment groups in each trial and overall. The PSQ-An was valid, feasible, and reliable. In general, no difference between treatment groups was observed for hemoglobin- and transfusion-based endpoints in each individual trial or in the combined analysis. From exploratory analyses, achievement and maintenance of a hemoglobin target range (11-13 g/dl) were similar in both groups. No differences in safety were observed. With the PSQ-An, formal comparisons of the impact of anemia therapies on patients and caregivers can be made in future prospective studies. Further, darbepoetin alfa (200 microg Q2W) and epoetin alfa (40,000 U QW) appear to achieve comparable clinical and hematologic outcomes.