Bevacizumab Maintenance Research Articles

P3.02c-020 More Than 3 Years Long-Term Maintenance Treatment of Bevacizumab for Advanced-Stage NSCLC: A Report of Three Cases: Topic: Targeted Therapy

Bevacizumab has proven efficacy in extending OS and PFS as first-line treatment for advanced nonsquamous NSCLC. There were three advanced NSCLC patients received maintenance with bevacizumab for more than 3 years in our hospital, and here we share the data of these patients. All three patients with advanced-stage lung adenocarcinoma received bevacizumab (15mg/kg) plus paclitaxel and carboplatin for 6 cycles as first-line treatment and bevacizumab maintenance. In the maintenance, proteinuria occurred in all three patients after 6 months of treatment or longer and caused cessation of bevacizumab in two patients. It’s noteworthy that two patients presented spleen changes after long-term maintenance. In patient 01, proteinuria occurred after 8 cycles of bevacizumab, caused cessation of 7 doses, and lasted till one year after discontinuation of bevacizumab. In patient 02, splenomegaly was found after 44 cycles of bevacizumab, caused treatment discontinuation, and reversed after 6 months of discontinuation. In patient 03, proteinuria occurred after 29 cycles of bevacizumab and caused cessation of 5 doses of bevacizumab. Besides, increased serum creatinine and blood urea nitrogen were found after 18 months of protienuria, and CT scan indicated wedge-shaped defects in spleen after 55 cycles. After disease progression or discontinuation of bevacizumab, two patients were confirmed harboring EGFR mutations and received EGFR TKI treatment. The other patient, EGFR mutation and ALK-arrangement negative, received chemotherapy after disease progression. These patients received bevacizumab maintenance for more than 3 years were all enrolled in clinical trials, and the long-term maintenance brought them adverse effects as well as clinical benefit. In the real world, the cycles of maintenance and the best total dosage of bevacizumab for NSCLC remain uncertain. Is it true that the longer the treatment lasts, the more benefit the patients get with the maintenance treatment of bevacizumab?

P3.02c-015 Phase II Trial of S-1/Cisplatin Combined with Bevacizumab for Advanced Non-Squamous Non-Small Cell Lung Cancer: TCOG LC-1202: Topic: Targeted Therapy

S-1 plus cisplatin is a standard chemotherapy regimen for advanced non-small cell lung cancer (NSCLC) (Ann. Oncol. 2015; 26:1401-8). The addition of bevacizumab significantly improved overall survival (OS) in patients with advanced non-squamous (non-SQ) NSCLC who received carboplatin plus paclitaxel but failed to show an OS advantage in patients who received cisplatin plus gemcitabine. Few studies of bevacizumab have evaluated quality of life (QOL) in patients with non-SQ NSCLC. Chemotherapy-naïve patients with stage IIIB, IV, or recurrent non-SQ NSCLC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1, age 20–74 years, and measurable lesions were treated with a 3-week cycle of S-1 40 mg/m2 twice a day on days 1–14, cisplatin 60 mg/m2 on day 8, and bevacizumab 15 mg/kg on day 8, for 4–6 cycles. Patients without progressive disease received maintenance bevacizumab 15 mg/kg on day 1 with a 3-week cycle and S-1 40 mg/m2 twice a day every other day. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), OS, toxicity profile, and QOL. From June 2013 to January 2015, 39 evaluable patients were enrolled from 8 institutions: 10 women and 29 men; median age 65 (range, 38–74) years; epidermal growth factor receptor positive/anaplastic lymphoma kinase positive: two patients/two patients; performance status 0/1: 22/17; stage IIIB/IV/recurrence: 1/35/3; adeno/large cell/other: 35/1/3. Thirty one patients (80%) completed 4 cycles of induction chemotherapy, and 23 patients (59%) were started on maintenance chemotherapy. Median PFS, OS, and ORR were 7.3 months (95% confidence interval (CI): 5.9–8.7), 21.4 months (95% CI: 14.7–not reached), and 64%, respectively. The worst hematologic and non-hematologic adverse events were as follows (%): grade 3/4 leukopenia: 13/0; neutropenia: 18/5; thrombocytopenia: 0/0; anemia: 0/0; neutropenic fever: 3/0; and hypertension: 28/0; diarrhea: 3/0. QOL data will be presented at the meeting. S-1 plus cisplatin in combination with bevacizumab met the primary endpoint in patients with advanced non-SQ NSCLC in the present trial. Additionally, the response rate is anticipated to be high, and the regimen was well tolerated. Clinical trial information: UMIN000009476.

Efficacy and Safety of Onartuzumab in Combination With First-Line Bevacizumab- or Pemetrexed-Based Chemotherapy Regimens in Advanced Non-Squamous Non–Small-Cell Lung Cancer

BackgroundOnartuzumab is a monovalent monoclonal antibody that binds with the extracellular domain of the MET receptor. Given the role of MET in non–small-cell lung cancer (NSCLC), we investigated whether onartuzumab added to first-line chemotherapy efficacy in non-squamous NSCLC. MethodsPatients with untreated stage IIIB/IV non-squamous NSCLC, stratified by MET diagnostic status, were randomized to receive onartuzumab (15 mg/kg intravenously every 3 weeks) or placebo in combination with either paclitaxel/platinum/bevacizumab (bevacizumab cohort), or in combination with platinum/pemetrexed (pemetrexed cohort) with maintenance bevacizumab or pemetrexed and onartuzumab/placebo as appropriate. Co-primary endpoints of this phase II study were progression-free survival (PFS) in all patients and in MET+ patients (2+/3+), defined by the Ventana immunohistochemistry assay; secondary endpoints included overall survival (OS), objective response rate (ORR), safety, and pharmacokinetics. ResultsEfficacy data were available for 139 and 120 patients in the bevacizumab and pemetrexed cohorts, respectively. No benefit was seen in the PFS endpoint in the intent-to treat population of either cohort, but was numerically worse in the onartuzumab arm of the MET+ subgroup of the bevacizumab cohort. The onartuzumab and placebo arms had similar ORR and OS results in both cohorts. A higher incidence of some adverse events was observed with onartuzumab versus placebo, including peripheral edema (30% vs. 3%, bevacizumab cohort; 48% vs. 14%, pemetrexed cohort) and venous thromboembolic events (bevacizumab cohort only, 15% vs. 6%). ConclusionOnartuzumab does not appear to provide any additional clinical benefit when given in combination with current first-line standard-of-care chemotherapy for non-squamous NSCLC.

463PD - Clinical factors influencing outcome in metastatic colorectal cancer (mCRC) patients treated with fluoropyrimidine and bevacizumab (FP + Bev) maintenance treatment (Tx) vs observation: A pooled analysis of the phase 3 CAIRO3 and AIO 0207 trials

The CAIRO3 and AIO 0207 studies showed that first-line maintenance Tx with FP + Bev vs observation after FP + oxaliplatin(Ox) + Bev induction Tx in mCRC patients is effective, while quality of life is maintained. We performed a pooled analysis and aimed to identify subgroups with clinical characteristics that benefit most from FP + Bev maintenance Tx. A total of 871 mCRC patients (CAIRO3: n = 557; two arms of AIO 0207: n = 314) that received FP + Bev maintenance Tx vs observation were analyzed. We analyzed whether Tx effect was modified by 12 clinical characteristics: sex; age; performance status; response to induction Tx; stage; primary tumor site and resection status; number of metastatic sites; synchronous vs metachronous mCRC; LDH at randomization; platelet count and CEA at start of induction Tx. We used mixed effects Cox models with study as random intercept and baseline covariables and treatment as fixed effects. Time to 1st progression (PFS1), time to 2nd progression after FP + Ox + Bev reintroduction (PFS2, primary endpoint of both studies) and overall survival (OS) were analyzed. FP + Bev maintenance Tx compared to observation resulted in a highly significant benefit in PFS1 (HR 0.40 [95% CI 0.34 - 0.47]) and PFS2 (HR 0.68 [95% CI 0.59 - 0.80]), which was observed in all investigated subgroups. OS results showed a marked heterogeneity between the two studies, for yet unknown reasons, and remained not significant in the pooled analysis (HR 0.90 [95% CI 0.76 – 1.05]). Patients with elevated platelet count (> 400 x 109/L) at start of induction Tx had significantly more benefit from FP + Bev maintenance Tx vs observation in PFS1 (HR 0.31 [95% CI 0.23 - 0.41] vs HR 0.45 [95% CI 0.37 - 0.55]) and PFS2 (HR 0.53 [95% CI 0.40 - 0.70] vs HR 0.76 [95% CI 0.63 - 0.92]). Tests for interaction were p < 0.05. This pooled analysis confirms the benefit of FP + Bev maintenance Tx compared to observation in the first-line Tx of mCRC. This benefit was observed in all subgroups that were investigated. We identified platelet count at start of induction Tx to be a significant predictive factor for efficacy of FP + Bev maintenance Tx.

D11 - A multicentre, randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer (mCRC)

Background: Bevacizumab is a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, approved in combination with chemotherapy in the treatment of mCRC. It is proposed that the schedule of administration might be critical and that giving bevacizumab before chemotherapy might improve treatment efficacy. Methods: mCRC patients, ≤ 75 years old, ECOG PS ≤1, with at least one measurable lesion according to RECIST, having received no more than one line of treatment for metastatic disease, were randomized (1:1) to receive standard concomitant administration of bevacizumab (5mg/kg every 2 weeks) with chemotherapy (mFOLFOX/OXXEL regimen for 12 cycles) vs experimental bevacizumab given 4 days before chemotherapy (same dose), at each cycle. Patients could receive maintenance bevacizumab (7.5 mg/kg every 3 weeks) until disease progression or unacceptable toxicity in both arms. Primary end point was the objective response rate (ORR). With 80% power and 2-tailed alpha 0.05, 230 patients were planned to verify an increase of response rate of 20% between the standard and the experimental arm. With 163 events, the study has 80% power to detect a progression-free survival (PFS) improvement with a hazard ratio (HR) of 0.64. Analyses are based on intention to treat. Results: From May 2012 to Dec 2015, 230 patients were randomised to experimental (n = 115) and standard arm (n = 115). Median age was 62 (IQ range 53-68), 79% were PS 0, 93% were not pretreated, 53% had a single metastatic site. Median numbers of chemotherapy cycles was 12 in both arms, 73% received the FOLFOX regimen. In the experimental arm, the median time between bevacizumab and chemotherapy administration per cycle was 4 (interquartile range 4-4) days. ORR was 57.4% (95% CI 47.8-66.6) in both arms (p = 1.00). With a median follow-up of 21.1 months, 173 PFS events were reported. Median PFS was 12.0 and 10.4 (HR 0.84, 95% CI: 0.63-1.14; log rank p = 0.27) months in the experimental and standard arm, respectively. In a multivariate Cox regression model including PS, previous treatment and number of metastatic sites as covariates, the difference remained not significant (HR 0.83, 95% CI: 0.62-1.12; p = 0.23). Conclusion: the OBELICS trial shows that anticipating bevacizumab to chemotherapy does not improve ORR nor significantly prolongs PFS. Correlative studies on biomarkers and FDG-PET are ongoing. The trial was supported by of the Italian Ministry of Health. ClinicalTrials.gov NCT01718873.

Phase II randomized trial of radiation therapy, cetuximab, and pemetrexed with or without bevacizumab in patients with locally advanced head and neck cancer

We previously reported the safety of concurrent cetuximab, an antibody against epidermal growth factor receptor (EGFR), pemetrexed, and radiation therapy (RT) in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In this non-comparative phase II randomized trial, we evaluated this non-platinum combination with or without bevacizumab, an inhibitor of vascular endothelial growth factor (VEGF). Patients with previously untreated stage III-IVB SCCHN were randomized to receive: conventionally fractionated radiation (70 Gy), concurrent cetuximab, and concurrent pemetrexed (arm A); or the identical regimen plus concurrent bevacizumab followed by bevacizumab maintenance for 24 weeks (arm B). The primary end point was 2-year progression-free survival (PFS), with each arm compared with historical control. Exploratory analyses included the relationship of established prognostic factors to PFS and quality of life (QoL). Seventy-eight patients were randomized: 66 oropharynx (42 HPV-positive, 15 HPV-negative, 9 unknown) and 12 larynx; 38 (49%) had heavy tobacco exposure. Two-year PFS was 79% [90% confidence interval (CI) 0.69-0.92; P < 0.0001] for arm A and 75% (90% CI 0.64-0.88; P < 0.0001) for arm B, both higher than historical control. No differences in PFS were observed for stage, tobacco history, HPV status, or type of center (community versus academic). A significantly increased rate of hemorrhage occurred in arm B. SCCHN-specific QoL declined acutely, with marked improvement but residual symptom burden 1 year post-treatment. RT with a concurrent non-platinum regimen of cetuximab and pemetrexed is feasible in academic and community settings, demonstrating expected toxicities and promising efficacy. Adding bevacizumab increased toxicity without apparent improvement in efficacy, countering the hypothesis that dual EGFR-VEGF targeting would overcome radiation resistance, and enhance clinical benefit. Further development of cetuximab, pemetrexed, and RT will require additional prospective study in defined, high-risk populations where treatment intensification is justified.

Long-term survival in advanced non-squamous NSCLC patients treated with first-line bevacizumab-based therapy.

First-line bevacizumab-based therapies have been shown to improve clinical outcomes in patients with non-squamous non-small-cell lung cancer (NSCLC). We aimed to descriptively analyse patients with non-squamous NSCLC who received a long-term period of maintenance bevacizumab. This retrospective study included 104 patients who had already reached a progression-free survival (PFS) of at least 9months. Median overall survival and PFS were 30.7 and 15.1months, respectively. The overall response rate was 83%. Weight loss ≤5%, ECOG PS=0, or low number of metastatic sites seem to be predictive factors of good evolution. The incidence of bevacizumab-related adverse events appeared to be similar as the previous studies. Our findings show that there is a long-term survivor group whom the administration of bevacizumab resulted in a relevant prolongation of response without new safety signals. Due to the population heterogeneity, it was not possible to identify the standardised predictive factors.

Bevacizumab en association à une première ligne de chimiothérapie chez des patients atteints d’un cancer bronchique non à petites cellules, non épidermoïde, à un stade avancé ou en rechute : résultats de l’étude non interventionnelle EOLE

The EOLE cohort aimed to describe, in routine clinical practice, the characteristics and management of patients receiving bevacizumab in combination with first-line metastatic chemotherapy for advanced metastatic or recurrent non squamous non-small cell lung cancer (nsNSCLC), as well as its efficacy and safety. A total of 423patients were enrolled in this prospective, national, multicenter study. Data were collected every 3months over an 18-month period. Amongst the 407patients analyzed (mean age 60±10years, male 68%, ECOG-PS≤1 88%, smokers or former smokers 87%, cardiovascular comorbidities 40%), all except for 2patients received bevacizumab (7.5 or 15mg/kg/3weeks in 99% of patients) in combination with doublet chemotherapy. A total of 160 (60%) patients who completed induction received bevacizumab maintenance therapy. Median progression-free survival was 6.9months (95% CI=[6.0-7.5]). Median overall survival (12.8 months [10.4-14.7]) was longer in patients with ECOG-PS≤1 (14.4 months [12.3-15.9] versus 4.9 months [3.4-8.3] if ECOG-PS=2). A total of 131 (32%) patients experienced at least one serious adverse event (SAE), and 51 (12%) at least one bevacizumab-related SAE. EOLE confirms the efficacy and safety of bevacizumab in aNSCLC patients, in current medical practice.

Results of a multicenter phase I dose-finding trial of hyperthermic intraperitoneal cisplatin after neoadjuvant chemotherapy and complete cytoreductive surgery and followed by maintenance bevacizumab in initially unresectable ovarian cancer

PurposeHyperthermic intraperitoneal chemotherapy (HIPEC) may improve the outcome of patients with initially unresectable ovarian cancer who are eligible for complete cytoreductive surgery (CCRS) after neoadjuvant chemotherapy. The main objective of this multicenter phase-I study was to identify the recommended dose of cisplatin for HIPEC at CCRS after neoadjuvant carboplatin and paclitaxel (CP). MethodsPatients were treated with 6cycles of CP followed by CCRS and HIPEC using cisplatin heated for one hour at 42°C+/−1°C. Four cisplatin dose-levels were evaluated: 50, 60, 70, 80mg/m2. Dose-limiting toxicities (DLTs) were defined as a grade≥IIIb adverse event (Dindo classification). The Continual Reassessment Method was used for this dose-finding study, with a target percentage of DLT set at 20%. Twenty-two cycles (15mg/kg/cycle) of maintenance bevacizumab therapy were planned after surgery. ResultsBetween June-2011 and September-2012, 30 patients were recruited. No DLT occurred at the first three dose-levels (4, 4 and 5 patients at 50, 60 and 70mg/m2 respectively). At dose-level 4 (80mg/m2, 17 patients), four DLTs occurred: renal failure (n=2), peritonitis (n=1) and hemorrhage (n=1). Eight weeks after surgery, creatinine clearance was reduced to <30mL/min in 3 patients, all treated at 80mg/m2, and between 30 and 60mL/min in 6 patients (2, 1, 1 and 2 at the four dose-levels respectively). Twenty patients started maintenance bevacizumab, and 7 received the 22 courses initially planned. ConclusionsBased on the observed DLTs and prolonged impairment of renal function, we recommend a dose of 70mg/m2 of cisplatin for HIPEC.

A phase III trial of exemestane plus bevacizumab maintenance therapy in patients with metastatic breast cancer after first-line taxane and bevacizumab: a GINECO group study

Maintenance strategies beyond response or tumor stabilization with first-line chemotherapy in metastatic breast cancer (MBC) have not been extensively studied. Endocrine therapy combined with continued bevacizumab may be a helpful option for estrogen receptor (ER)-positive MBC. In this prospective, open-label, phase III study, patients with histologically confirmed ER-positive, HER2-negative MBC and non-progressive disease after 16-24 weeks of taxane plus bevacizumab (T + BEV) were randomized to continuation of T + BEV or maintenance bevacizumab plus exemestane (E + BEV). The primary end point was progression-free survival (PFS) from randomization. To have 80% power to detect an improvement in the 6-month PFS rate (PFS6m) from 50% to 65%, 186 assessable patients were needed for a total of 141 PFS events. An interim analysis was planned after 40% of the required events. The interim analysis with 98 patients showed that the probability of reaching a statistically significant improvement in PFS by the end of the study was only 7%. This led the Independent Data and Monitoring Committee to recommend termination of patient enrollment. After a median of 21-month follow-up of all randomized patients (117 in total), PFS6m from randomization was 67.2% [95% confidence interval (CI) 53.6-77.7] with T + BEV and 55.2% (95% CI 41.5-66.9) with E + BEV [hazard ratio (HR): 1.0, 95% CI 0.7-1.5, P = 0.998]. Median PFS from BEV initiation was 12.5 and 12.3 months in the T + BEV and E + BEV arms, respectively. In the T + BEV arm, taxane was prematurely stopped for the majority of patients (94.9%), mainly due to toxicity (49.2%). Updated data after 35 months' median follow-up showed death rates of 44% and 55% in T + BEV and E + BEV arms, respectively. In this trial, maintenance therapy with E + BEV in ER-positive, HER2-negative MBC patients with no evidence of progression after first-line T + BEV did not achieve longer PFS compared with continuation of T + BEV. NCT01303679.

O-011 Modified FOLFOXIRI (mFOLFOXIRI) plus cetuximab (cet), followed by cet or bevacizumab (bev) maintenance, in RAS/BRAF wt metastatic colorectal cancer (mCRC): results of the phase II randomized MACBETH trial by GONO

O-011 Modified FOLFOXIRI (mFOLFOXIRI) plus cetuximab (cet), followed by cet or bevacizumab (bev) maintenance, in RAS/BRAF wt metastatic colorectal cancer (mCRC): results of the phase II randomized MACBETH trial by GONO

Quantitative measurement of adiposity using CT images to predict the benefit of bevacizumab-based chemotherapy in epithelial ovarian cancer patients.

The present study aims to quantitatively measure adiposity-related image features and to test the feasibility of applying multivariate statistical data analysis-based prediction models to generate a novel clinical marker and predict the benefit of epithelial ovarian cancer (EOC) patients with and without maintenance bevacizumab-based chemotherapy. A dataset involving computed tomography (CT) images acquired from 59 patients diagnosed with advanced EOC was retrospectively collected. Among them, 32 patients received maintenance bevacizumab following primary chemotherapy, while 27 did not. A computer-aided detection scheme was developed to automatically segment visceral and subcutaneous fat areas depicted on CT images of abdominal sections, and 7 adiposity-related image features were computed. Upon combining these features with the measured body mass index, multivariate data analyses were performed using three statistical models (multiple linear, logistic and Cox proportional hazards regressions) to analyze the association between the model-generated prediction results and the treatment outcome, including progression-free survival (PFS) and overall survival (OS) of the patients. The results demonstrated that applying all three prediction models yielded a significant association between the adiposity-related image features and patients' PFS or OS in the group of the patients who received maintenance bevacizumab (P<0.010), while there was no significant difference when these prediction models were applied to predict both PFS and OS in the group of patients that did not receive maintenance bevacizumab. Therefore, the present study demonstrated that the use of a quantitative adiposity-related image feature-based statistical model may generate a novel clinical marker to predict who will benefit among EOC patients receiving maintenance bevacizumab-based chemotherapy.

Predictive value of KRAS mutation status in metastatic colorectal cancer (mCRC) patients treated with capecitabine and bevacizumab (CAP-B) maintenance treatment vs observation in the phase III CAIRO3 study.

3525Background: The impact of KRAS mutation status in mCRC treated with anti-VEGF therapy is controversial. The randomized phase 3 CAIRO3 study showed benefit of first-line CAP-B maintenance treatm...

Final results of PRODIGE 9, a randomized phase III comparing no treatment to bevacizumab maintenance during chemotherapy-free intervals in metastatic colorectal cancer.

3531Background: Conflicting results are reported for maintenance treatment with bevacizumab (bev) during chemotherapy free intervals (CFI) in metastatic colorectal cancer (mCRC). Methods: The objec...

Erlotinib added to bevacizumab as maintenance therapy and health-related quality of life in patients with metastatic colorectal cancer: Results of the GERCOR DREAM phase III trial.

3553Background: The DREAM phase III clinical trial aimed to assess the efficacy and tolerability of maintenance bevacizumab (B) plus erlotinib (E) after a bevacizumab-based induction therapy in pat...

PCN138 - Patient-Reported Symptoms in Ovarian Cancer Before and After Disease Progression in Conjunction with Bevacizumab Maintenance Therapy

PCN138 - Patient-Reported Symptoms in Ovarian Cancer Before and After Disease Progression in Conjunction with Bevacizumab Maintenance Therapy

Bevacizumab plus chemotherapy in elderly patients with previously untreated metastatic colorectal cancer: single center experience.

BackgroundMetastatic colorectal cancer (mCRC) is mainly a disease of elderly, however, geriatric population is underrepresented in clinical trials. Patient registries represent a tool to assess and follow treatment outcomes in this patient population. The aim of the study was with the help of the patients’ register to determine the safety and efficacy of bevacizumab plus chemotherapy in elderly patients who had previously untreated metastatic colorectal cancer.Patients and methodsThe registry of patients with mCRC was designed to prospectively evaluate the safety and efficacy of bevacizumab-containing chemotherapy as well as selection of patients in routine clinical practice. Patient baseline clinical characteristics, pre-specified bevacizumab-related adverse events, and efficacy data were collected, evaluated and compared according to the age categories.ResultsBetween January 2008 and December 2010, 210 patients with mCRC (median age 63, male 61.4%) started bevacizumab-containing therapy in the 1st line setting. Majority of the 210 patients received irinotecan-based chemotherapy (68%) as 1st line treatment and 105 patients (50%) received bevacizumab maintenance therapy. Elderly (≥ 70 years) patients presented 22.9% of all patients and they had worse performance status (PS 1/2, 62.4%) than patients in < 70 years group (PS 1/2, 35.8%). Difference in disease control rate was mainly due to inability to assess response in elderly group (64.6% in elderly and 77.8% in < 70 years group, p = 0.066). The median progression free survival was 10.2 (95% CI, 6.7–16.2) and 11.3 (95% CI, 10.2–12.6) months in elderly and < 70 years group, respectively (p = 0.58). The median overall survival was 18.5 (95% CI, 12.4–28.9) and 27.4 (95% CI, 22.7–31.9) months for elderly and < 70 years group, respectively (p = 0.03). Three-year survival rate was 26% and 37.6% in elderly vs. < 70 years group (p = 0.03). Overall rates of bevacizumab-related adverse events were similar in both groups: proteinuria 21/22 %, hypertension 25/19 %, haemorrhage 2/4 % and thromboembolic events 10/6 %, for elderly and < 70 years group, respectively.ConclusionsIn routine clinical practice, the combination of bevacizumab and chemotherapy is effective and well-tolerated regimen in elderly patients with metastatic colorectal cancer.

Final Results of a Phase II Study of Bevacizumab, Cisplatin and Pemetrexed as First-Line Therapy for Patients with Advanced Non-Squamous Non-Small Cell Lung Cancer

Background: Efficacy and safety data for cisplatin and pemetrexed plus bevacizumabinnon squamousnon non-small cell lung cancer (NSCLC) are still limited. Nevertheless, either bevacizumab plus platinum doublet or pemetrexed plus platinum is approved options for first line therapy. Predictive factors for bevacizumab are needed. KRAS is one of the most common oncogenic drivers in lung cancer. Its prognostic and predictive value in NSCLC is under investigation. Patients and methods: This trial evaluates the addition of bevacizumab 7.5 mg/kg to cisplatin 75 mg/m2 plus pemetrexed 500 mg/m2 as first line treatment in stage IV non-squamous NSCLC patients. Maintenance bevacizumab was received as monotherapy until progressive disease, unacceptable toxicityor consent with drawal. The primary objective was progression free survival (PFS). Secondary objectives included overall survival (OS), safety, global objective responses and the determination of KRAS mutation at baseline. Results: From March 2009 to March 2012, 31 patients were enrolled. Mean age was 59.19 (standard deviation (SD) 8.53). From all the patients included in this trial, 67.70% were men. KRAS was wild type in 19 patients (58.06%); in 7 (22.58%) was mutated and was unknown in 6 patients (19.35%). Median PFS for KRAS mutated patients was 4 months, whereas for the KRAS wild type it was 7.9 months (P = 0.0031). Median OS was 4 months for the KRAS population, and 16.1 months for the KRAS wild type (P = 0.0032). Twenty four patients (77.42%) experienced at least a grade 3 - 4 adverse event. The most common grade 3 - 4 toxicity was asthenia. Conclusions: Both PFS and OS were statistically longer for the KRAS wild type patients compared with the KRAS mutated population (P = 0.0031). Median OS was shorter than the reported in previous trials with bevacizumab. Nevertheless, focussing on the OS for KRAS wild type patients, this achieves a result or 16.1 months. Therefore, this would be a consistent data supporting to qualify this parameter as a predictive factor before starting treatment for NSCLC.

Frontline treatment of epithelial ovarian cancer.

This is a contemporaneous review of the frontline treatment of epithelial ovarian cancer (EOC), specifically on the importance of optimal surgical cytoreductive surgery, the pivotal role of platinum-based adjuvant chemotherapy (which encompasses intraperitoneal and dose-dense regimens) and the emergence of neo-adjuvant chemotherapy. Additionally, the benefit of concurrent and maintenance bevacizumab in the suboptimally debullked stage III and stage IV EOC setting is also reviewed. The article also discusses the increasing importance of prognostic and predictive molecular biomarkers in the future management of EOC.

Bevacizumab with or without erlotinib as maintenance therapy in patients with metastatic colorectal cancer (GERCOR DREAM; OPTIMOX3): a randomised, open-label, phase 3 trial

The combination of an anti-VEGF or an anti-EGFR-targeted monoclonal antibody with chemotherapy has shown clinical activity in patients with metastatic colorectal cancer. However, combining both anti-VEGF and anti-EGFR antibodies with chemotherapy in first-line treatment resulted in adverse outcomes. We assessed whether the combination of erlotinib, an EGFR tyrosine kinase inhibitor, with bevacizumab could increase the efficacy of maintenance therapy in patients with unresectable metastatic colorectal cancer. This randomised, open-label, phase 3 study was undertaken in 49 centres in France, Austria, and Canada. Eligible patients were aged 18-80 years with histologically confirmed, unresectable metastatic colorectal cancer, WHO performance status 0-2, had received no previous therapy for metastatic disease, and had adequate organ function. Patients without disease progression after bevacizumab-based induction therapy were randomly assigned (1:1) by a minimisation technique to bevacizumab (7·5 mg/kg every 3 weeks) or bevacizumab plus erlotinib (150 mg once daily) as maintenance therapy until progression. All patients were stratified by centre, baseline performance status, age, and number of metastatic sites. The primary endpoint was progression-free survival on maintenance therapy analysed by intention to treat. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00265824. Between Jan 1, 2007, and Oct 13, 2011, 700 eligible patients were enrolled; following induction treatment, patients without disease progression were randomly assigned to bevacizumab (n=228) or bevacizumab plus erlotinib (n=224). At the final analysis, median follow-up was 51·0 months (IQR 36·0-60·0) in the bevacizumab group and 48·3 months (31·5-61·0) in the bevacizumab plus erlotinib group. In the primary analysis (after 231 progression-free survival events), median progression-free survival from randomisation was 5·1 months (95% CI 4·1-5·9) in the bevacizumab plus erlotinib group compared with 6·0 months (4·6-7·9) in the bevacizumab group (stratified hazard ratio [HR] 0·79 [95% CI 0·60-1·06]; p=0·11; unstratified HR 0·76 [0·59-0·99]; p=0·043). In the final analysis, median progression-free survival from randomisation was 5·4 months (95% CI 4·3-6·2) in the bevacizumab plus erlotinib group compared with 4·9 months (4·1-5·7) in the bevacizumab group (stratified HR 0·81 [95% CI 0·66-1·01], p=0·059; unstratified HR 0·78 [0·68-0·96], p=0·019). At the final analysis, median overall survival from maintenance was 24·9 months (95% CI 21·4-28·9) in the bevacizumab plus erlotinib group and 22·1 months (19·6-26·7) in the bevacizumab group (stratified HR 0·79 [95% CI 0·63-0·99], p=0·036; unstratified HR 0·79 [0·64-0·98], p=0·035). The most frequent grade 3-4 adverse events were skin rash (47 [21%] of 220 patients in the bevacizumab plus erlotinib group vs none of 224 patients in the bevacizumab alone group), diarrhoea (21 [10%] vs two [<1%]), and asthenia (12 [5%] vs two [<1%]). Maintenance bevacizumab plus erlotinib might be a new non-chemotherapy-based maintenance option for the first-line treatment of patients with unresectable metastatic colorectal cancer after bevacizumab-based induction therapy. GERCOR and F Hoffmann-La Roche.