A soluble LAG-3 protein (eftilagimod alpha) and an anti-PD-L1 antibody (avelumab) tested in a phase I trial: a new combination in immuno-oncology.

BACKGROUND: Eftilagimod alpha (efti) is a major histocompatibility complex class II agonist activating antigen-presenting cells which leads to greater systemic type 1 T helper response and more cytotoxic CD8+ T-cell activation. This phase I trial evaluated the administration of efti, a soluble lymphocyte activation gene-3 (LAG-3) protein, combined with the anti-programmed death-ligand 1 (PD-L1) antibody avelumab in advanced solid tumors. PATIENTS AND METHODS: Patients with heavily pretreated metastatic solid tumors received intravenous avelumab (800 mg) combined with subcutaneously administered efti (6 or 30 mg) for up to 12 cycles, followed by avelumab monotherapy. The primary endpoint was the assessment of the recommended phase II dose (RP2D) of efti in combination with avelumab. RESULTS: Twelve patients with different tumor entities were enrolled (six patients in each cohort). During treatment, no dose-limiting toxicities occurred, and the severity of most adverse events was grade 1 or 2. In total, nine serious adverse events were documented, resulting in a fatal outcome in two cases, but none of them were assessed to be treatment related. Five patients (42%) achieved partial response. The median progression-free survival was 1.96 months and the median overall survival was not reached, with a 12-month survival rate of 75%. CONCLUSION: Subcutaneously administered efti plus avelumab was well tolerated, and efti of 30 mg was determined to be RP2D. The activity is promising and warrants further investigation in future phase II trials.

FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma.

BACKGROUND: Claudin 18.2 (CLDN18.2) is contained within normal gastric mucosa epithelial tight junctions; upon malignant transformation, CLDN18.2 epitopes become exposed. Zolbetuximab, a chimeric monoclonal antibody, mediates specific killing of CLDN18.2-positive cells through immune effector mechanisms. PATIENTS AND METHODS: The FAST study enrolled advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients (aged ≥18 years) with moderate-to-strong CLDN18.2 expression in ≥40% tumour cells. Patients received first-line epirubicin + oxaliplatin + capecitabine (EOX, arm 1, n = 84) every 3 weeks (Q3W), or zolbetuximab + EOX (loading dose, 800 mg/m2 then 600 mg/m2 Q3W) (arm 2, n = 77). Arm 3 (exploratory) was added after enrolment initiation (zolbetuximab + EOX 1000 mg/m2 Q3W, n = 85). The primary endpoint was progression-free survival (PFS) and overall survival (OS) was a secondary endpoint. RESULTS: In the overall population, both PFS [hazard ratio (HR) = 0.44; 95% confidence interval (CI), 0.29-0.67; P < 0.0005] and OS (HR = 0.55; 95% CI, 0.39-0.77; P < 0.0005) were significantly improved with zolbetuximab + EOX (arm 2) compared with EOX alone (arm 1). This significant PFS benefit was retained in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells (HR = 0.38; 95% CI, 0.23-0.62; P < 0.0005). Significant improvement in PFS was also reported in the overall population of arm 3 versus arm 1 (HR = 0.58; 95% CI, 0.39-0.85; P = 0.0114) but not in high CLDN18.2-expressing patients; no significant improvement in OS was observed in either population. Most adverse events (AEs) related to zolbetuximab + EOX (nausea, vomiting, neutropenia, anaemia) were grade 1-2. Grade ≥3 AEs showed no substantial increases overall (zolbetuximab + EOX versus EOX alone). CONCLUSIONS: In advanced gastric/gastro-oesophageal junction and oesophageal adenocarcinoma patients expressing CLDN18.2, adding zolbetuximab to first-line EOX provided longer PFS and OS versus EOX alone. Zolbetuximab + EOX was generally tolerated and AEs were manageable. Zolbetuximab 800/600 mg/m2 is being evaluated in phase III studies based on clinical benefit observed in the overall population and in patients with moderate-to-strong CLDN18.2 expression in ≥70% of tumour cells.

Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study.

BACKGROUND: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. PATIENTS AND METHODS: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. RESULTS: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. CONCLUSIONS: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial.

Cisplatin and 5-fluorouracil with or without epidermal growth factor receptor inhibition panitumumab for patients with non-resectable, advanced or metastatic oesophageal squamous cell cancer: a prospective, open-label, randomised phase III AIO/EORTC trial (POWER).

BACKGROUND: Palliative chemotherapy of advanced oesophageal squamous cell cancer (ESCC) consists of cisplatin/5-fluorouracil (CF) to target epidermal growth factor receptor (EGFR) with panitumumab (P); chemotherapy enhanced overall survival (OS) in advanced colorectal or squamous cell head and neck cancers. With prospective serum and tumour biomarkers, we tested if P added to CF (CFP) improved OS in advanced ESCC. PATIENTS AND METHODS: Eligible patients with confirmed ESCC that was not curatively resectable or did not qualify for definitive radiochemotherapy, were randomised 1 : 1 to receive CF [cisplatin (C) 100 mg/m2 i.v., day 1; 5-fluorouracil (F) 1000 mg/m2 i.v., days 1-4] or CF plus P (9 mg/kg, i.v., day 1, each q3-week cycle) until progressive disease or unacceptable toxicity. Safety was reviewed by the Data Safety Monitoring Board after 40, 70 and 100 patients who completed at least one cycle. After 53 enrolled patients, cisplatin was reduced from 100 mg/m2 to 80 mg/m2. RESULTS: The trial was stopped early based on interim efficacy results triggered by the third safety analysis: median OS (mOS) favoured CF over CFP, regardless of cisplatin dose [hazard ratio (HR) 1.77, 95% confidence interval (CI) 1.06-2.98; P = 0.028]. In the final analysis, mOS was 10.2 versus 9.4 months for CF versus CFP, respectively (HR 1.17, 95% CI 0.79-1.75; P = 0.43). One hundred (70.4%) of 142 patients in the safety population died, 51 (51.0%) with CFP. Most deaths were related to disease progression [44/49 (90%) deaths in CF versus 34/51 (67%) deaths in CFP]; objective responses [27/73 (37.0%)] were identical. The most common serious adverse events were kidney injury [3 (4.3%) versus 7 (9.7%)], general health deterioration [5 (7.1%) versus 5 (6.9%)] and dysphagia [4 (5.7%) versus 4 (5.6%)] in CF versus CFP, respectively. There were three (4.3%) and 17 (23.6%) common terminology criteria for adverse events (CTCAE) grade 5 events in CF versus CFP, respectively. Low soluble (s)EGFR levels were associated with better progression-free survival; sEGFR was induced under CFP. CONCLUSION: EGFR inhibition added to CF did not improve survival in unselected advanced ESCC patients. The results support further liquid biopsy studies. TRIAL REGISTRATION: ClinicalTrials.gov (NCT01627379) and EudraCT (2010-020606-15).

A multicentre, phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study.

BACKGROUND: Claudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.2 epitopes being exposed on the cancer cell surface. The first-in-class monoclonal antibody, zolbetuximab (formerly known as IMAB362), binds to CLDN18.2 and can induce immune-mediated lysis of CLDN18.2-positive cells. PATIENTS AND METHODS: Patients with advanced gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinomas with moderate-to-strong CLDN18.2 expression in ≥50% of tumour cells received zolbetuximab intravenously every 2 weeks for five planned infusions. At least three patients were enrolled in two sequential cohorts (cohort 1300 mg/m2; cohort 2600 mg/m2); additional patients were enrolled into a dose-expansion cohort (cohort 3600 mg/m2). The primary end point was the objective response rate [ORR: complete and partial response (PR)]; secondary end points included clinical benefit [ORR+stable disease (SD)], progression-free survival, safety/tolerability, and zolbetuximab pharmacokinetic profile. RESULTS: From September 2010 to September 2012, 54 patients were enrolled (cohort 1, n = 4; cohort 2, n = 6; cohort 3, n = 44). Three patients in cohort 1 and 25 patients in cohorts 2/3 received at least 5 infusions. Antitumour activity data were available for 43 patients, of whom 4 achieved PR (ORR 9%) and 6 (14%) had SD for a clinical benefit rate of 23%. In a subgroup of patients with moderate-to-high CLDN18.2 expression in ≥70% of tumour cells, ORR was 14% (n = 4/29). Treatment-related adverse events occurred in 81.5% (n = 44/54) patients; nausea (61%), vomiting (50%), and fatigue (22%) were the most frequent. CONCLUSIONS: Zolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with response rates similar to those reported for single-agent targeted agents in gastric/GEJ cancer trials. CLINICALTRIALS.GOV NUMBER: NCT01197885.

Phase III, randomised trial of avelumab versus physician's choice of chemotherapy as third-line treatment of patients with advanced gastric or gastro-oesophageal junction cancer: primary analysis of JAVELIN Gastric 300.

Background: There currently are no internationally recognised treatment guidelines for patients with advanced gastric cancer/gastro-oesophageal junction cancer (GC/GEJC) in whom two prior lines of therapy have failed. The randomised, phase III JAVELIN Gastric 300 trial compared avelumab versus physician's choice of chemotherapy as third-line therapy in patients with advanced GC/GEJC. Patients and methods: Patients with unresectable, recurrent, locally advanced, or metastatic GC/GEJC were recruited at 147 sites globally. All patients were randomised to receive either avelumab 10 mg/kg by intravenous infusion every 2 weeks or physician's choice of chemotherapy (paclitaxel 80 mg/m2 on days 1, 8, and 15 or irinotecan 150 mg/m2 on days 1 and 15, each of a 4-week treatment cycle); patients ineligible for chemotherapy received best supportive care. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety. Results: A total of 371 patients were randomised. The trial did not meet its primary end point of improving OS {median, 4.6 versus 5.0 months; hazard ratio (HR)=1.1 [95% confidence interval (CI) 0.9-1.4]; P = 0.81} or the secondary end points of PFS [median, 1.4 versus 2.7 months; HR=1.73 (95% CI 1.4-2.2); P > 0.99] or ORR (2.2% versus 4.3%) in the avelumab versus chemotherapy arms, respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 90 patients (48.9%) and 131 patients (74.0%) in the avelumab and chemotherapy arms, respectively. Grade ≥3 TRAEs occurred in 17 patients (9.2%) in the avelumab arm and in 56 patients (31.6%) in the chemotherapy arm. Conclusions: Treatment of patients with GC/GEJC with single-agent avelumab in the third-line setting did not result in an improvement in OS or PFS compared with chemotherapy. Avelumab showed a more manageable safety profile than chemotherapy. Trial registration: ClinicalTrials.gov: NCT02625623.

EVITA-a double-blind, vehicle-controlled, randomized phase II trial of vitamin K1 cream as prophylaxis for cetuximab-induced skin toxicity.

Background: Acne-like skin rash is a frequently occurring adverse event associated with drugs against the epidermal growth factor receptor. This randomized vehicle-controlled study investigated the addition of vitamin K1 cream to doxycycline in patients with metastatic colorectal cancer treated with cetuximab. Patients and methods: Patients receiving first-line cetuximab + FOLFIRI were randomly assigned to prophylactic treatment with doxycylin and vitamin K1 cream or doxycycline and the vehicle. The primary end point of the study was the incidence of grade ≥ 2 skin rash (NCI CTCAE version 4.02) during 8 weeks of skin treatment. Secondary end points comprised skin rash according to a more thorough tripartite skin toxicity score (WoMo), quality of life, efficacy, and compliance. The study had 80% power to show a 20% reduction of the incidence of grade ≥ 2 skin rash. Results: A total of 126 patients were analyzed. The incidence of skin rash grade ≥ 2 was comparable between the arms. Likewise, no difference was seen in the WoMo score with respect to the percentage of skin affected. However, starting in week 5 and increasing over time patients treated with vitamin K1 cream had less severe rash and fewer fissures. Quality of life as well as efficacy and compliance with study medication and anticancer treatment was comparable in both arms. Conclusion: The primary end point of decreasing grade ≥ 2 skin rash was not met. However, using vitamin K1 cream as part of prophylactic treatment decreased the severity of acne-like skin rash according to WoMo, an alternative and more thorough skin toxicity scoring tool.

Evaluation of survival across several treatment lines in metastatic colorectal cancer: Analysis of the FIRE-3 trial (AIO KRK0306).

BACKGROUND: We explored the impacts of sequential application of various treatment lines on survival kinetics. Therefore, differences in overall survival (OS) observed in FIRE-3 were investigated in the context of time and exposure to applied treatment. PATIENTS AND METHODS: OS analyses (stratified by treatment with FOLFIRI plus either cetuximab or bevacizumab) were performed according to time intervals as well as using a Cox model to define changes of hazard ratio (HR) over time. RESULTS: The fraction of patients with systemic treatment and time on treatment markedly decreases over treatment lines and time. OS evaluation by a Cox model indicated a trend towards a non-proportional hazard between treatment arms (P = 0.12/P = 0.09 for KRAS-intention-to-treat (ITT)/all-RAS wild-type populations, respectively). To improve the fit of the model, a change-point (point of curve separation) was estimated at 22.6 months (day 687) after randomisation. The HR between the two arms before 22.6 months was not significantly different from one. However, markedly different survival kinetics in favour of the cetuximab arm were apparent after the change-point (KRAS-ITT: P = 0.0018; HR, 0.60 [95% confidence interval [CI], 0.44-0.83] and RAS: P = 0.0006; HR, 0.51 [95% CI, 0.35-0.75]). CONCLUSION: The differences in OS favouring the cetuximab arm become apparent about 22.6 months after randomisation, indicating that only those patients who survive 22.6 months after randomisation benefit from the superiority of the cetuximab arm. When OS curves separate, only few patients receive active systemic treatment in short courses, suggesting that earlier treatment effects are responsible for later kinetics of survival curves.

Impact of BRAF and RAS mutations on first-line efficacy of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab: analysis of the FIRE-3 (AIO KRK-0306) study.

BACKGROUND: RAS and BRAF mutations have been identified as negative prognostic factors in metastatic colorectal cancer. Efficacy of 5-fluorouracil, leucovorin, irinotecan (FOLFIRI) plus bevacizumab in patients with RAS-mutant tumours needs to be further evaluated. Whether to treat patients with BRAF-mutant tumours with either bevacizumab or anti-epidermal growth factor receptor (EGFR) antibodies remains unclear. METHODS: Patients treated within the FIRE-3 trial were retrospectively tested for BRAF and RAS mutations using formalin fixated paraffin embedded (FFPE) tumour material applying pyrosequencing for KRAS and NRAS exon 2, 3 and 4 mutations as far as for BRAF mutations. Survival analysis was done using Kaplan-Meier estimation and differences were expressed using the log-rank test. Overall response rate (ORR) was compared using Fisher's exact test. Data from a central independent radiological response evaluation were used to calculate early tumour shrinkage (ETS) and depth of response (DpR). RESULTS: Overall, 188 patients with RAS-mutant tumours and 48 with BRAF-mutant tumours were identified. In BRAF-mutant patients, ORR was numerically higher in the cetuximab versus the bevacizumab arm (52% versus 40%), while comparable results were achieved for progression-free survival (PFS; hazard ratio [HR] = 0.84, p = 0.56) and overall survival (OS; HR 0.79, p = 0.45). RAS mutation was associated with a trend towards lower ORR (37% versus 50.5%, p = 0.11) and shorter PFS (7.4 versus 9.7 months; HR 1.25; p = 0.14) in patients receiving FOLFIRI plus cetuximab versus bevacizumab, but OS was comparable (19.1 versus 20.1 months; HR 1.05; p = 0.73), respectively. ETS identified subgroups sensitive to cetuximab-based treatment in both BRAF- (9/17) and RAS-mutant (18/48) patients and was associated with significantly longer OS. DpR was comparable between both treatment arms in RAS- and BRAF-mutant patients, respectively. CONCLUSIONS: In BRAF- and RAS-mutant patients, cetuximab- and bevacizumab-based treatment had comparable survival times. ETS represents an early parameter associated with the benefit from anti-EGFR, while this was not the case with vascular endothelial growth factor A blockade.

Quality of life assessment in patients with metastatic colorectal cancer receiving maintenance therapy after first-line induction treatment: a preplanned analysis of the phase III AIO KRK 0207 trial.

BACKGROUND: First-line maintenance strategies are a current matter of debate in the management of mCRC. Their impact on patient's health-related quality of life (HRQOL) has not yet been evaluated. The objective of this study was to assess whether differences in HRQOL during any active maintenance treatment compared with no maintenance treatment exist. PATIENT AND METHODS: Eight hundred and thirty-seven patients were enrolled in the AIO KRK 0207 trial. Four hundred and seventy-two underwent randomization (after 24 weeks of induction treatment) into one of the maintenance arms: FP plus Bev (arm A), Bev alone (arm B), or no active treatment (arm C). HRQOL were assessed every 6 weeks during induction and maintenance treatment independent from treatment stop, delay, or modification, and also continued after progression, using the EORTC QLQ-C30, QLQ-CR29. The mean value of the global quality of life dimension (GHS/QoL) of the EORTC QLQ-C30, calculated as the average of all available time points after randomization was considered as pre-specified main endpoint. Additionally, EORTC QLQ-C30 response scores were analyzed. RESULTS: For HRQOL analysis, 413 patients were eligible (arm A: 136; arm B: 142, arm C: 135). Compliance rate with the HRQOL questionnaires was 95% at time of randomization and remained high during maintenance (98%, 99%, 97% and 97% at week 6, 12, 18 and 24). No significant differences between treatment arms in the mean GHS/QoL scores were observed at any time point. Also, rates of GHS/QoL score deterioration were similar (20.5%; 17.2% and 20.7% of patients), whereas a score improvement occurred in 36.1%; 43.8% and 42.1% (arms A, B and C). CONCLUSION: Continuation of an active maintenance treatment with FP/Bev after induction treatment was neither associated with a detrimental effect on GHS/QoL scores when compared with both, less active treatment with Bev alone or no active treatment. CLINICAL TRIALS NUMBER: NCT00973609 (ClinicalTrials.gov).

[HER2 testing in gastric cancer - results of a German expert meeting]. / HER2-Testung beim Magenkarzinom - Ergebnisse eines deutschen Expertentreffens.

Valid HER2 testing is essential for optimal therapy of patients with HER2 positive gastric cancer and the correct use of first-line treatment. While each breast cancer is routinely being tested for the HER2 status, HER2 testing in gastric cancer has still not become part of the routine and is often only done upon request by the therapist. An interdisciplinary German expert group took the challenges of HER2 testing in gastric cancer as an opportunity to address essential aspects and questions for the practical use of HER2 testing in this indication from the perspective of pathologists and therapists. The recommendations made in this manuscript reflect the consensus of all participants and correspond to their opinions and long-term experience.

A phase I trial of the trifunctional anti Her2 × anti CD3 antibody ertumaxomab in patients with advanced solid tumors.

BACKGROUND: Ertumaxomab (ertu) is a bispecific, trifunctional antibody targeting Her2/neu, CD3 and the Fcγ-receptors I, IIa, and III forming a tri-cell complex between tumor cell, T cell and accessory cells. METHODS: Patients (pts) with Her2/neu (1+/SISH positive, 2+ and 3+) expressing tumors progressing after standard therapy were treated to investigate safety, tolerability and preliminary efficacy. In this study, ertu was applied i.v. in 2 cycles following a predefined dose escalating scheme. Each cycle consisted of five ascending doses (10-500 µg) applied weekly within 28 days with a 21 day treatment-free interval. If 2 pts experienced a dose limiting toxicity (DLT) at a given dose level, the maximum tolerated dose (MTD) had been exceeded. RESULTS: Fourteen heavily pretreated pts (e.g. breast, rectal, gastric cancer) were enrolled in the four main cohorts. Three (21 %) pts had to be replaced. Two serious adverse events (SAE) with possible relation to the investigational drug were seen, both fully reversible. A DLT was not detected. Consequently, the MTD could not be determined. All adverse events (AE) were transient and completely reversible. Most frequent AEs were fatigue (14/14), pain (13/14), cephalgia (12/14), chills (11/14), nausea (8/14), fever (7/14), emesis (7/14) and diarrhea (5/14). Single doses up to 300 µg were well tolerated (total dose up to 800 µg per cycle). We observed one partial remission and two disease stabilizations after first treatment cycle. CONCLUSIONS: Single doses up to 300 µg could be safely administered in an escalating dose scheme. Immunological responses and clinical activity warrant further evaluation in patients with Her2 over expressing tumors. TRIAL REGISTRATION: EudraCT number: 2011-003201-14; ClinicalTrials.gov identifier: NCT01569412.

CEA response is associated with tumor response and survival in patients with KRAS exon 2 wild-type and extended RAS wild-type metastatic colorectal cancer receiving first-line FOLFIRI plus cetuximab or bevacizumab (FIRE-3 trial).

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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. CLINICAL TRIALS NUMBER: NCT00433927 (ClinicalTrials.gov); AIO KRK0306 FIRE-3.

Quality-of-life and performance status results from the phase III RAINBOW study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated gastric or gastroesophageal junction adenocarcinoma.

BACKGROUND: The phase III RAINBOW trial demonstrated that the addition of ramucirumab to paclitaxel improved overall survival, progression-free survival, and tumor response rate in fluoropyrimidine-platinum previously treated patients with advanced gastric/gastroesophageal junction (GEJ) adenocarcinoma. Here, we present results from quality-of-life (QoL) and performance status (PS) analyses. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group PS of 0/1 were randomized to receive ramucirumab (8 mg/kg i.v.) or placebo on days 1 and 15 of a 4-week cycle, with both arms receiving paclitaxel (80 mg/m(2)) on days 1, 8, and 15. Patient-reported outcomes were assessed with the QoL/health status questionnaires EORTC QLQ-C30 and EQ-5D at baseline and 6-week intervals. PS was assessed at baseline and day 1 of every cycle. Time to deterioration (TtD) in each QLQ-C30 scale was defined as randomization to first worsening of ≥10 points (on 100-point scale) and TtD in PS was defined as first worsening to ≥2. Hazard ratios (HRs) for treatment effect were estimated using stratified Cox proportional hazards models. RESULTS: Of the 665 patients randomized, 650 (98%) provided baseline QLQ-C30 and EQ-5D data, and 560 (84%) also provided data from ≥1 postbaseline time point. Baseline scores for both instruments were similar between arms. Of the 15 QLQ-C30 scales, 14 had HR < 1, indicating similar or longer TtD in QoL for ramucirumab + paclitaxel. Treatment with ramucirumab + paclitaxel was also associated with a delay in TtD in PS to ≥2 (HR = 0.798, P = 0.0941). Alternate definitions of PS deterioration yielded similar results: PS ≥ 3 (HR = 0.656, P = 0.0508), deterioration by ≥1 PS level (HR = 0.802, P = 0.0444), and deterioration by ≥2 PS levels (HR = 0.608, P = 0.0063). EQ-5D scores were comparable between treatment arms, stable during treatment, and worsened at discontinuation. CONCLUSION: In patients with previously treated advanced gastric/GEJ adenocarcinoma, addition of ramucirumab to paclitaxel prolonged overall survival while maintaining patient QoL with delayed symptom worsening and functional status deterioration. CLINICALTRIALSGOV: NCT01170663.

[Estrogen Receptors and their Impact for Prognosis and Therapy of Lung Cancer - New Insights to an Underestimated Mechanism]. / Östrogenrezeptoren und ihre Bedeutung für die Prognose und Therapie des Lungenkarzinoms - neue Erkenntnisse zu einem bisher unterschätzten Mechanismus.

Though tobacco smoking is the leading cause of lung cancer, during the last decades the prevalence increased in never smoking patients, especially in women. Sex steroid hormones and particularly the estrogen receptors (ERs) seem to play an important but still underestimated role in non-small cell lung cancer (NSCLC). Beside long existing hints that hormone replacement therapy (HRT) increases the risk of lung tumors recent analyses on cell lines, xenografts and human tumors of both sexes gave clear evidence of ER expression and proliferation in NSCLC. Most recently, the expression of ERs apparently has prognostic and predictive value. Recently, an intracellular "cross-talk" between the ER and the epithelial growth factor receptor (EGFR) could be demonstrated. EGFR are important targets of approved tyrosinkinases (TKIs), like gefitinib, erlotinib or afatinib. Currently, clinical studies are enrolling lung tumor patients for combination treatment with EGFR TKI and antihormonal drugs, e. g. fulvestrant.

The impact of docetaxel-related toxicities on health-related quality of life in patients with metastatic cancer (QoliTax).

BACKGROUND: Docetaxel is a widely used cytotoxic agent. This study evaluates the impact of docetaxel toxicities on patient's health-related quality of life (QoL). PATIENTS AND METHODS: We conducted a multicenter, prospective, non-interventional trial, in which the QoL was assessed using the EORTC QLQ-C30 questionnaires at baseline and every 4 weeks up to 40 weeks in patients receiving a docetaxel-based chemotherapy for metastatic disease. Treatment-related adverse events were correlated with the corresponding QoL scores. Uni- and multivariate analyses were applied. RESULTS: From January 2008 to June 2011, a total of 2659 patients were included. The majority of patients (48.1%) had prostate cancer, followed by breast (17.1%) and non-small-cell-lung cancer (15.8%). Patients received a median of 5 docetaxel cycles with the median dose of 75 mg/m(2). The presence of grade 3/4 diarrhea showed the strongest effect on global health status/QoL average scores (50.91 versus 33.06), followed by vomiting (50.91 versus 35.17), dyspnea (50.94 versus 35.81), mucositis/stomatitis (50.88 versus 36.41), nausea (50.91 versus 36.68), infection (50.90 versus 37.14), fatigue (50.90 versus 43.82) and anemia (50.91 versus 41.03), P < 0.05 for all comparisons. Grade 3/4 leukopenia/neutropenia, alopecia, constipation, neurotoxicity and nail disorders had no significant impact on the global health status/QoL or other items. CONCLUSION: In this large non-interventional trial, docetaxel-associated grade 3 or 4 toxicities were shown to have a strong detrimental effect on patient's QoL. Notably, diarrhea and vomiting had the strongest negative impact on QoL measures. This has to be kept in mind while making therapeutic decisions and providing optimized supportive treatment measures. CLINICAL TRIALS NUMBER: This study was registered at Deutsches Krebsstudienregister (DKSR, primary registry in the WHO Registry Network) with the ID 527.

Prognostic role of microRNA polymorphisms in advanced gastric cancer: a translational study of the Arbeitsgemeinschaft Internistische Onkologie (AIO).

BACKGROUND: To determine the prognostic role of selected microRNA (miRNA) polymorphisms in advanced gastric cancer (AGC). PATIENTS AND METHODS: Six hundred and seventy-four AGC patients received 5-fluorouracil (F), leucovorin (L), oxaliplatin (O) or FL + cisplatin (P) or additional docetaxel (T) to FLO (FLOT) within four clinical trials. Polymorphisms of mir-26a1 (rs7372209), mir-27a (rs895819), mir-100 (rs1834306), mir-146a (rs2910164), mir-196-a2 (rs11614913), mir-219-1 (rs107822) and mir-423 (rs6505162) were genotyped. Variable selection for the final multivariate model (n = 487) was based on univariate and multivariate Cox-regression analyses with a cut-off P-value of ≤ 20%. RESULTS: Genetic factors significantly associated with overall survival (OS) were rs7372209 (mir-26a1) variant genotypes (hazard ratio, HR 1.307 [95% confidence interval (CI) 1.031-1.656], P = 0.0272), rs895819 (mir-27a) variant genotypes (HR 1.304 [95% CI 1.031-1.650], P = 0.0270) and rs11614913 (mir-196a2) variant genotypes (HR 0.791 [95% CI 0.625-1.000], P = 0.0497). Clinical factors with significant impact on OS were Eastern Cooperative Oncology Group (ECOG) 2 performance status (HR 1.880 [95% CI 1.254-2.820], P = 0.0023), curative surgery of advanced disease (HR 0.235 [95% CI 0.123-0.449], P < 0.0001) and addition of docetaxel in locally AGC patients (HR 0.348 [95% CI 0.145-0.838], P = 0.0301). Combined analyses revealed an improved OS in patients without any unfavourable genotype of 18 months compared with 14, 12 and 10 months in patients with 1, 2 and 3 unfavourable genotypes, respectively (P = 0.0257). CONCLUSIONS: These data suggest a significant impact of selected miRNA polymorphisms on prognosis in AGC.

Impact of pathologic complete response on disease-free survival in patients with esophagogastric adenocarcinoma receiving preoperative docetaxel-based chemotherapy.

BACKGROUND: The aim of this study was to evaluate the impact of pathologic complete response (pCR) on outcome in patients with gastric or esophagogastric junction (EGJ) adenocarcinoma after neoadjuvant docetaxel/platin/fluoropyrimidine-based chemotherapy. PATIENTS AND METHODS: Patients received at least one cycle of chemotherapy for potentially operable disease. Pretreatment clinicopathologic factors and pCR were investigated. Disease-free survival (DFS), overall survival (OS) and tumor-related death were correlated with pCR. RESULTS: One hundred twenty patients were included in this analysis. Eighteen patients (15%) achieved a pCR. Tumor localization in the EGJ was identified as the only significant predictor of pCR (P = 0.019). Median follow-up was 41.1 months. Median DFS and OS for all patients were 24.1 and 48.6 months, respectively. Median DFS for patients with a pCR was not reached versus 22.1 months non-pCR patients (hazard ratio, HR 0.38; 3-year DFS: 71.8% and 37.7%, respectively, P = 0.018). While OS was not significantly different, the risk for tumor-related death was significantly lower for pCR patients compared with non-pCR patients (3-year cumulative incidences of 6.4% and 45.4%, respectively, P = 0.009). CONCLUSION: A pCR following preoperative docetaxel/platin/fluoropyrimidine indicates favorable outcome in patients with gastric or EGJ adenocarcinoma. Tumor location in the EGJ is associated with a higher pCR rate.

Feasibility of perioperative chemotherapy with infusional 5-FU, leucovorin, and oxaliplatin with (FLOT) or without (FLO) docetaxel in elderly patients with locally advanced esophagogastric cancer.

BACKGROUND: The aim of this exploratory subgroup analysis of the fluorouracil, oxaliplatin, docetaxel (FLOT)65+ trial was to determine tolerability and feasibility of perioperative chemotherapy in elderly, potentially operable esophagogastric cancer patients. METHODS: Patients aged ≥65 with locally advanced esophagogastric adenocarcinoma were randomized to perioperative chemotherapy consisting of four pre- and four postoperative cycles of infusional 5-FU, leucovorin, and oxaliplatin (FLO) without or with docetaxel 50 mg m(-)(2) (FLOT), every 2 weeks. RESULTS: Forty-four patients with a median age of 70 years were randomized and 43 patients started preoperative chemotherapy (FLO, 22; FLOT, 21). Thirty-eight (86.4%) patients completed four cycles of preoperative chemotherapy and 32 (74.4%) proceeded to surgery, with 67.4% R0 resections on intent-to-treat analysis (90.1% of the 32 patients who underwent resection). Median overall survival was not reached and median progression-free survival (PFS) was 17.3 months. Compared with the FLO group, the FLOT group showed a trend towards an improved median PFS (21.1 vs 12.0 months; P=0.09), however, associated with increased chemotherapy related toxicity. No perioperative mortality was observed. Postoperative morbidity was observed in 46.9% of patients (FLO, 35.3%; FLOT, 60%). CONCLUSION: Neoadjuvant FLO or FLOT may offer a reasonable chance of curative surgery in elderly patients with locally advanced resectable gastroesophageal cancer. However, the increase in side effects with the FLOT regimen and postoperative morbidity should be carefully considered when an intensive chemotherapy regimen is planned.