Search

In this phase I/II study, we explored the combination of Temsirolimus with Bendamustine and Rituximab (BeRT) in patients with relapsed or refractory (r/r) follicular lymphoma (FL) or mantle cell lymphoma (MCL). Patients with 1 to 3 previous therapies received Bendamustine (90 mg/m2, day 1 + 2) and Rituximab (375 mg/m2, day 1) with Temsirolimus in doses from 25 to 75 mg in phase I and 50 mg Temsirolimus in phase II, added on day 1, 8, 15 of a 28 days cycle. The primary endpoint of the phase II was ORR at the end of treatment. Overall, 39 (29 MCL, 10 FL) patients were included. Median age was 71 years and median pretreatment number was 2. Grade 3/4 non-hematologic adverse events were rare and included hyperglycemia in 3 patients (7%) and angioedema in 2 patients (5%). Infectious complications grade 3/4 were observed in 9 patients (23%). Hematologic grade 3/4 events included leukopenia in 22 (56%), neutropenia in 18 (46%), lymphopenia in 16 (41%) and thrombocytopenia in 14 patients (36%). An objective response (best response) was observed in 33/39 patients (89%; 24 MCL (89%) and 9 FL (90%)), including 14 CR (38%; 12 MCL (36%) and 2 FL (20%)). Median PFS is 1.5y for MCL and 1.82 years for FL, and median OS has not been reached for either entity. This data demonstrates promising efficacy of Temsirolimus in r/r MCL and FL with acceptable toxicity. The BeRT regimen may be used as a treatment option for both entities.

BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study.METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968.FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, pINTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed.FUNDING: F Hoffmann-La Roche.

Carcinoembryonic antigen (CEA) response may be a surrogate for response and long-term outcome in (K)RAS wild-type mCRC receiving first-line targeted therapy. FOLFIRI and cetuximab induced a greater CEA response than FOLFIRI and bevacizumab. CEA response correlated with longer survival. Hypothesizing that CEA reflects tumor burden, greater CEA response may indicate greater antitumor efficacy.To examine the relation of carcinoembryonic antigen (CEA) response with tumor response and survival in patients with (K)RAS wild-type metastatic colorectal cancer receiving first-line chemotherapy in the FIRE-3 trial comparing FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab. CEA response assessed as the percentage of CEA decrease from baseline to nadir was evaluated for its association with tumor response and survival. Receiver operating characteristic analysis revealed an optimal cut-off value of 75% using the maximum of sensitivity and specificity for CEA response to discriminate CEA responders from non-responders. In addition, the time to CEA nadir was calculated. Of 592 patients in the intent-to-treat population, 472 were eligible for analysis of CEA (cetuximab arm: 230 and bevacizumab arm: 242). Maximal relative CEA decrease (%) significantly (P = 0.003) differed between the cetuximab arm (median 83.0%;IQR 40.9%-94.7%) and the bevacizumab arm (median 72.3%;IQR 26.3%-91.0%). In a longitudinal analysis, the CEA decrease occurred faster in the cetuximab arm and was greater than in the bevacizumab arm at all evaluated time points until 56 weeks after treatment start. CEA nadir occurred after 3.3 months (cetuximab arm) and 3.5 months (bevacizumab arm), (P = 0.49). In the cetuximab arm, CEA responders showed a significantly longer progression-free survival [11.8 versus 7.4 months;hazard ratio (HR) 1.53;95% Cl, 1.15-2.04;P = 0.004] and longer overall survival (36.6 versus 21.3 months;HR 1.73;95% Cl, 1.24-2.43;P = 0.001) than CEA non-responders. Analysis of extended RAS wild-type patients revealed similar results. In the FIRE-3 trial, CEA decrease was significantly faster and greater in the cetuximab arm than in the bevacizumab arm and correlated with the prolonged survival observed in patients receiving FOLFIRI plus cetuximab. NCT00433927 (ClinicalTrials.gov);AIO KRK0306 FIRE-3.

Abstract 2697 Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas. Based on a phase III trial in relapsed MCL which proved superiority of temsirolimus to standard options, the drug is approved for this indication in the EU. Additionally, promising response rates could be observed in patients with follicular and diffuse large B-cell lymphoma (Smith et al, JCO 2010). Whereas combination to single agent rituximab seems feasible and with improved efficacy (Ansell et al, Lancet Oncology 2011), there is limited information on the feasibility and efficacy in combination with chemotherapy. Bendamustine has been shown to be effective in indolent lymphoma and has a beneficial side effect profile (Rummel et al, JCO, 2005). To evaluate the potential of the combination of temsirolimus with bendamustine and rituximab an ongoing phase I/II trial was initiated. Methods: This is a multicenter, national, prospective trial, approved by the centralized EC. Patients were eligible if they had histologically proven follicular (FL) or mantle cell lymphoma (MCL), the latter with Cyclin D1 positivity or detectable t(11;14), 1–3 prior treatment lines, no curative option available, no refractoriness to bendamustine, measurable disease, ECOG < 3, sufficient bone marrow reserve, no severe concomitant diseases and given informed consent. Treatment consisted of bendamustine 90mg/m2 day 1–2, rituximab 375mg/m2 day 1 and temsirolimus day 2, 8, 15 of a 28d cycle. A total of 4 cycles was planned with interim staging after 2 cycles. In the ongoing phase I part (3+3 design) the following dose cohorts for temsirolimus were planed: A 25mg, B 50mg, C 75mg. Currently cohort C is ongoing. Toxicity was evaluated throughout the treatment and analysis for DLT was performed after 2 cycles. An independent data safety monitoring board decided on the escalation to the next dose level. Results: Overall 9 patients have been included until now (6 pts cohort A, 3 patients cohort B) and 4 patients are in the prescreening period (cohort C). Median age 64; Histology: 8MCL/1FL; sex 2F/7M, median number of pretreatments 2 (1–3). Adverse events: overall the treatment was well tolerated. Toxicity was predominant hematologic with mostly leukopenia and thrombocytopenia. In 29 evaluable cycles of chemotherapy the following grade 3/4 toxicities were noted: Thrombocytopenia in 3 (all grade 3); leukopenia in 11 (9 grade 3; 2 grade 4), and increase in triglycerides, hyperglycemia and hypertension in one patient each (all grade 3). Importantly, one case of pneumonitis occurred, which resolved after steroid treatment and study treatment could be resumed w/o further problems. In addition, one reaction to contrast agent, an allergic reaction to berries and a transient parasthesia during the study phase were noted, leading to hospitalization. All of these events occurred several days after the last application of study drug and were considered not to be associated to the study treatment. As the episode of hypertension led to hospital admission, it was considered to be potentially a DLT, and cohort A was escalated to 6 patients w/o further DLT. In cohort B no DLT were observed in 3 patients and cohort C has been opened for inclusion. 5 patients have completed the entire treatment, in one patient treatment was stopped after cycle 3 due to delayed recovery of platelets, and treatment is ongoing in 3 patients. At interim staging all 9 patients evaluable achieved a partial remission (ORR 100%). After completion of the entire treatment ORR was 100% with 1 CR and 5 PR in 6 evaluable patients. Summary: In this ongoing phase I/II trial the combination of temsirolimus with bendamustine and Rituximab was feasible applying 3 weekly doses of up to 50mg temsirolimus in a 4 week cycle. Until now promising response rates have been noticed. Cohort C is currently recruiting patients (Temsirolimus 75mg), updated results of the phase I part of the trial will be presented at the meeting. If no dose limiting toxicities are observed, the extended phase II part of the trial will be initiated with patients stratified according to lymphoma subtype (30 patients each with FL and MCL). Disclosures: Hess: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria. Keller:Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees. Witzens-Harig:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy. Dreyling:Pfizer: Research Funding, Speakers Bureau, scientific advisory.

3589 Background: The FIRE-3 study (AIO KRK-0306) was designed as a randomized multicenter trial to compare the efficacy of FOLFIRI plus cetuximab (cet) to FOLFIRI plus bevacizumab (bev) as first-line treatment in KRAS WT mCRC patients. FOLFIRI plus cet as first-line treatment of KRAS WT mCRC patients resulted in comparable overall response rates (ORR) and progression free survival (PFS) when compared to FOLFIRI plus bev. Overall survival (OS) was significantly longer in the FOLFIRI plus cet arm. Methods: In this exploratory analysis outcome parameters were calculated in dependence of progression during antibody treatment. As reported before by Saltz et al. (ASCO GI 2007) an “on study treatment” population was defined using all RAS wild-type pts that were treated until progression or death occurred. To exclude early progressing patients the analysis was also performed in patients with a PFS >6 months. Results: See Table. Conclusions: In general, patients progressing during 1st-line treatment had a shorter ...

3581 Background: Recently, Prager et al. proposed the hypothesis that carcinoembryonic antigen (CEA) is involved in tumor angiogenesis and therefore might predict bevacizumab-based treatment response in metastatic colorectal cancer (mCRC) (Cancer Research, 2013; Cancer Science, 2014). The present study aimed to evaluate this hypothesis in the FIRE-3 trial where patients (pts) with KRAS exon 2 wild-type mCRC were randomized to receive first-line chemotherapy with either FOLFIRI + cetuximab (cet) or FOLFIRI + bevacizumab (bev). Methods: Baseline CEA levels were analyzed either as continuous variable (ln) or categorized in two groups ( ≤ / > 25% quartile; ≤ / > 6.2ng/ml) with regard to their predictive impact on PFS and OS in the two different treatment arms. Correlations relied on Cox regression analysis. Survival was estimated by Kaplan-Meier. Results: For analysis of CEA, 522/592 pts (cet: 257 pts; bev: 265 pts) were eligible. When CEA baseline level was evaluated as a continuous variable, CEA (ln) was in...

Aim: FIRE-3 compared 1st-line therapy with FOLFIRI plus either cetuximab or bevacizumab in 592 KRAS exon 2 wild-type mCRC patients. An independent radiological review was carried out to evaluate tumor response according to RECIST 1.1 and to define early tumor shrinkage (ETS) and depth of response (DpR). Methods: Extended RAS analysis was carried out in KRAS and NRAS exon 2, 3 and 4 (codons 12, 13, 59, 61, 117 and 146) using pyro-sequencing technique. Radiological data were evaluated independently. ETS was defined as a reduction in tumor diameter of more than 20% at first-tumor assessment after baseline (week 6). DpR was defined as the maximal tumor shrinkage observed in a patient. Reviewers were blinded to patient data. Calculations were done for both, the ITT- and the extended RAS wild-type population. Results: Within the ITT population, 475 patients (80.2%) were successfully tested for all RAS locations. Primary outcome data for the RAS wt population (n = 400) (table). FOLFIRI + Cetuximab (n= 199) FOLFIRI + Bevacizumab (n = 201) p HR ORR (%) 65.8 58.2 0.92* PFS (months) (95% CI) 10.3 (9.5 - 11.8) 10.2 (9.3 - 11.7) 0.77 0.97 OS (months) (95% CI) 33.1 (24.5 - 39.4) 25.0 (23.0 - 28.1) 0.0059 0.697 p = log-rank test; * = one-sided Fisher's exact test; HR = Hazard ratio 459 patients (77.5%) were evaluable according to RECIST. ORR significantly favored the FOLFIRI plus cetuximab arm (71.4% vs. 56.4%; two sided Fisher's exact test p = 0.015). The proportion of patients reaching ETS was significantly greater in the FOLFIRI plus cetuximab treated population (67.5% vs. 47.9% p = 0.0013), and was significantly associated with PFS in the cetuximab arm (logrank test p = 0.023) and OS (logrank test p = 0.0005 and p = 0.0043) in the respective treatment arms. Depth of response was significantly greater in FOLFIRI plus cetuximab treated patients (48.2% vs. 33.0%, Wilcoxon test p = 0.0005) and associated with post progression survival (Bravais Pearson test p Conclusions: Based on an independent radiological review, FOLFIRI plus cetuximab induced a significantly higher ORR, a greater rate of ETS, and an increased DpR compared to FOLFIRI plus bevacizumab. These response-related outcomes may in part explain the significant OS advantage of FOLFIRI plus cetuximab observed in FIRE-3. Disclosure: S. Stintzing: Honoraria: Amgen, Merck, Roche, Sanofi Travel expenses: Amgen, Merck, Roche, Sanofi; D.P. Modest: Honoraria and travel grants: Merck, Roche, Amgen; C. Giessen: Travel support: Roche; M. Moehler: Merck: Research grants and advisory board member Roche: congress speaker and advisory board member; V. Heinemann: Honoraria and travel expenses: Roche, Merck, Amgen, Sanofi, Bayer Research Fund: Merck, Roche. All other authors have declared no conflicts of interest.

Background and Aim: The role of IV iron supplementation during treatment with erythropoiesis-stimulating agents (ESAs) in patients with CIA is of increasing interest as a possible means of improving response. This randomized, open-label, multicenter study was designed to evaluate the safety and efficacy of IV iron vs standard practice in CIA patients receiving darbepoetin alfa. Interim efficacy analyses showed a higher response rate for darbepoetin alfa with IV iron compared to darbepoetin alfa with standard iron practice with no difference in the safety profile between the treatment arms (Vanderbroek et al, EHA 2006). Iron parameters are reported here. Methods: Eligible patients were diagnosed with a non-myeloid malignancy and had CIA with a baseline hemoglobin (Hb) value < 11g/dL. All patients received darbepoetin alfa 500 mcg administered Q3W with the SureClick™ prefilled autoinjector. Patients were randomized 1:1 to IV iron 200 mg (single dose Q3W at the same time as darbepoetin alfa or in 2 doses of 100 mg within 3 weeks) or standard practice (oral iron or no iron). Randomization was stratified by tumor type and baseline Hb category (< 10 or ≥10 g/dL). Results: A total of 400 patients were randomized. Mean (SD) age of the study population was 61.4 (11.5) years; range, 20–86. Sixty percent (n=241) of participants were women; 28% (n=114) had lung or gynecological tumors; and 52% (n=208) had a baseline Hb value ≥10 g/dL. In the interim analysis population (n=196), the mean (SD) weekly dose of IV iron was 64.8 (6.6) mg in the IV iron group (n=100). In the standard practice group, 28 of 96 patients (29%) received oral iron and 2 (2%) received IV iron (these patients were analyzed as randomized). Mean (standard error) serum ferritin concentrations and percent transferrin saturation (TSAT) in the 2 groups from baseline (BL) to end of study (EOS) are shown in the figure. Conclusions: The combination of darbepoetin alfa Q3W and IV iron appeared to be associated with a trend toward increased mean serum ferritin levels compared to the standard practice control arm. In contrast, mean TSAT surprisingly appeared to be similar in the 2 groups for most of the study period, perhaps suggesting that TSAT is influenced by other factors. Iron management appears to be an important factor in the response to ESAs and the findings presented here suggest the need for additional exploration into iron uptake and demand in cancer patients treated with darbepoetin alfa. Serum Ferritin Concentration Serum Ferritin Concentration Transferrin Saturation (%) Transferrin Saturation (%)