Bevacizumab Combination Therapy Research Articles

Copy number load predicts outcome of metastatic colorectal cancer patients receiving bevacizumab combination therapy

Increased copy number alterations (CNAs) indicative of chromosomal instability (CIN) have been associated with poor cancer outcome. Here, we study CNAs as potential biomarkers of bevacizumab (BVZ) response in metastatic colorectal cancer (mCRC). We cluster 409 mCRCs in three subclusters characterized by different degrees of CIN. Tumors belonging to intermediate-to-high instability clusters have improved outcome following chemotherapy plus BVZ versus chemotherapy alone. In contrast, low instability tumors, which amongst others consist of POLE-mutated and microsatellite-instable tumors, derive no further benefit from BVZ. This is confirmed in 81 mCRC tumors from the phase 2 MoMa study involving BVZ. CNA clusters overlap with CRC consensus molecular subtypes (CMS); CMS2/4 xenografts correspond to intermediate-to-high instability clusters and respond to FOLFOX chemotherapy plus mouse avastin (B20), while CMS1/3 xenografts match with low instability clusters and fail to respond. Overall, we identify copy number load as a novel potential predictive biomarker of BVZ combination therapy.

Does afatinib plus bevacizumab combination therapy induce positive conversion of T790M in previously-negative patients?

Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are markedly effective for T790M-positive patients. To confer their clinical benefit to more patients, a novel therapy to induce positive conversion in T790M-negative patients may be possible. We retrospectively reviewed medical records of patients who had received rebiopsy after completion of ABC-study: a prospective phase II study of Afatinib plus Bevacizumab Combination (ABC)-therapy after acquired resistance to EGFR-TKI. Between October 2014 and September 2016, 32 eligible patients were enrolled in ABC-study at our institutes. Eighteen patients were T790M-negative and 14 were T790M-positive before ABC-therapy. Rebiopsy was performed on 13 T790M-negative and 5 T790M-positive patients after progression of ABC-therapy. In 8 (62%) of 13 T790M-negative patients, T790M status changed from negative to positive after ABC-therapy. Seven of these 8 patients underwent osimertinib therapy. The response rate and median time to treatment failure were 86% and 12.2 months, respectively. There were no adverse events ≥grade 3, nor any treatment-related deaths. On the other hand, T790M remained positive after ABC-therapy in all 5 previous T790M-positive patients. ABC-therapy could induce positive conversion of T790M even in previously-negative patients. We hypothesize that ABC-therapy could provoke “clonal selection”, which purifies T790M-positive cancer cells in heterogeneous tumors. Further studies are warranted to confirm this phenomena.

P2-099 - How should we exploit TAS-102?

Background: In salvage line chemotherapy to colorectal cancer, TAS-102 is one of useful agents. We have experienced three colorectal cancer cases with TAS-102 plus bevacizumab. Cases: The first case is a 68-year-old male with recurrence of rectal cancer. The first case is a 68-year-old man who had relapsed after resection of the primary lesion for rectal cancer with metastasis to the liver and lung. Because of toxicity of l-OHP, he did not want postoperative chemotherapy. After 18 months residual tumor recurred, we treated with TAS-102 and bevacizumab after TAS-102 monotherapy. He got good clinical control up to 12 courses. The second case is a 66-year-old female with recurrent rectal cancer and ovarian cancer. Due to the toxicity of XELOX therapy, she chose to treat with TAS-102. TAS-102 monotherapy showed severe neutropenia and poor compliance with her treatment. Therefore, we changed to treatment with TAS-102 and bevacizumab. From the viewpoint of compliance with treatment, we changed the administration of TAS-102 to day 1-5, 15-19. The third case is a 69-year-old male who had recurrence of rectal cancer after excisional surgery for rectal cancer with liver metastasis and left kidney cell carcinoma. Because of interstitial pneumonia due to treatment with CPT-11 plus cetuximab, we changed to TAS-102 and bevacizumab combination therapy. While he is in remission now, during the course of treatment he developed a rectourethral fistula. Conclusion: Through these cases, we would like to discuss the rationale of combination therapy with TAS-102 and its issues.

P3-027 - Liver cirrhosis associated with paclitaxel and bevacizumab combination therapy in a metastatic breast cancer patient

P3-027 - Liver cirrhosis associated with paclitaxel and bevacizumab combination therapy in a metastatic breast cancer patient

P1.15-33 Real-World Data on Prognostic Factors for Overall Survival in NSCLC Patients Treated with Bevacizumab Combination Therapy

Bevacizumab is used as combination with chemotherapy as 1st-line treatment for non-squamous cell carcinoma. In order to understand the influence of bevacizumab on different combination medication response, this study aimed to identify independent prognostic factors for overall survival (OS) of NSCLC patients receiving bevacizumab treatment in real-world practice. We performed retrospective collected non-squamous cell carcinoma patients undergoing bevacizumab treatment and analyzed their response and overall survival to bevacizumab. Demographic data, TTF-1 stain status, EGFR mutation status, and survival data were collected. Survival data analysis were plotted by the Kaplan–Meier method and compared by the log-rank test. From November 2009 to October 2015, 114 non-squamous cell carcinoma patients treated with bevacizumab were enrolled for analysis. The median overall survival was 21.9 months. There were 11 patients who received continuous bevacizumab beyond disease progress of 1st-line treatment and in all treatment courses. They had longer overall survival than those (N = 103) who did not received bevacizumab in all treatment courses (p = 0.003). The patients harboring positive TTF-1 tumor also had a longer overall survival than those harboring negative TTF-1 tumors (p = 0.025). Multivariate analysis revealed that patients harboring tumor with positive staining of TTF-1 (p < 0.001) and those received bevacizumab in all treatment course (p = 0.013) had a longer median OS. Non-squamous cell carcinoma patients receiving bevacizumab beyond 1st-line treatment failure, as all treatment course, had a longer median OS than those received bevacizumab in partial course.

A novel approach to monitoring the efficacy of anti-tumor treatments in animal models: combining functional MRI and texture analysis

BackgroundThe aim of this study was to evaluate the early anti-tumor efficiency of different therapeutic agents with a combination of multi-b-value DWI, DCE-MRI and texture analysis.MethodsEighteen 4 T1 homograft tumor models were divided into control, paclitaxel monotherapy and paclitaxel and bevacizumab combination therapy groups (n = 6) that underwent multi-b-value DWI, DCE-MRI and texture analysis before and 15 days after treatment.ResultsAfter treatment, the tumors in the control group were significantly larger than those in the combination group (P = 0.018). In multi-b-value DWI, the ADCslow obviously increased in the combination group compared to that in the others (P < 0.01). The f increased in the control and paclitaxel groups, but the combination group showed a significant decrease versus the others (P < 0.02). Additionally, in DCE-MRI, the decreasing Ktrans showed an evident difference between the combination and control groups (P = 0.003) due to the latter’s increasing Ktrans. The intra-group comparisons of tumor texture in pre-, mid- and post-treatments showed that the entropy had all significantly increased in all groups (P < 0.01, SSF = 0–6), though the MPP, mean and SD increased only in the combination group (PMPP,mean,SD < 0.05, SSF = 4–6). Moreover, the inter-group comparisons revealed that the mean and MPP exhibited significant differences after treatment (Pmean,MPP < 0.05, SSF = 0–3).ConclusionAll these results suggest some strong correlations among DWI, DCE and texture analysis, which are beneficial for further study and clinical research.

Biweekly Administration of TAS-102 for Neutropenia Prevention in Patients with Colorectal Cancer.

TAS-102 has led to a significant improvement in overall survival (OS) and progression-free survival (PFS) of patients with metastatic colorectal cancer (mCRC). Neutropenia is the most common adverse event and an important factor impacting chemotherapy continuation. In this retrospective study, factors associated with grade ≥3 neutropenia, that is frequently observed in TAS-102-treated patients, were examined. The medical records of 41 patients with CRC who received TAS-102 between October 2014 and June 2017 at the Fukuoka University Hospital were retrospectively reviewed. Response rate, PFS, OS, and adverse events were analyzed using KRAS mutation, administration method, concomitant drug administration, neutrophil-to-lymphocyte ratio (NLR), and Onodera's prognostic nutritional index (Onodera's index) as a stratification factors. Both PFS and OS were significantly higher with TAS-102 plus bevacizumab combination therapy. Biweekly administration (7.1%) was associated with significantly less neutropenia compared to normal administration (44.4%). DCR with biweekly administration was better than that with normal administration, although without statistical significance. No significant difference was observed in OS rates between the biweekly and normal administration regimens; however, the biweekly regimen was associated with significantly prolonged PFS. By multivariate analysis, a significant difference was noted in the Onodera's index for OS and in the administration method and NLR for PFS. Biweekly administration without a change in the drug dose intensity was associated with reduced neutropenia in patients with mCRC. The effects and adverse events of TAS-102 were associated with concomitant drug administration, administration method, and nutritional status.

The prognosis for patients with newly diagnosed glioblastoma receiving bevacizumab combination therapy: a meta-analysis

BackgroundA combination of temozolomide (TMZ) and radiotherapy and subsequent adjuvant chemotherapy is the gold standard of treatment for glioblastoma (GB). Bevacizumab (BEV), a humanized monoclonal antibody that blocks the effects of vascular endothelial growth factor A, has produced impressive response rates for recurrent GB and has been approved as second-line therapy. The efficacy and safety of BEV in newly diagnosed GB are not known.AimThis systematic meta-analysis was undertaken to evaluate the value of combination therapy involving BEV in newly diagnosed GB.MethodsElectronic databases were searched for eligible literature up to October 2017. Randomized controlled trials assessing the efficacy and safety of BEV in patients with newly diagnosed GB were included, of which the main outcomes were progression-free survival (PFS), overall survival (OS), and adverse events (AEs). All the data were pooled with the corresponding 95% confidence intervals (CIs) using RevMan software. Sensitivity analyses and heterogeneity were quantitatively evaluated.ResultsA total of six randomized controlled trials were included in this analysis. The experimental BEV group had significantly improved the overall PFS (OR =0.46, 95% CI =0.26–0.81, P=0.007), as well as PFS at 6 months (OR =3.47, 95% CI =2.85–4.22, P<0.00001) and PFS at 12 months (OR =2.02, 95% CI =1.66–2.46, P<0.00001), respectively. However, there were no significant differences in PFS at 24 months with BEV (OR =0.95, 95% CI =0.61–1.48, P=0.82). OS at 6 months (P=0.07) and 24 months (P=0.07) was not significantly improved with BEV in patients with newly diagnosed GB. However, the meta-analysis on the OS at 12 months showed differences with BEV (OR =1.24, 95% CI =1.03–1.50, P=0.02).ConclusionOur study indicates that addition of BEV for newly diagnosed GB resulted in a superior PFS rate. However, the combination therapy involving BEV did not improve OS. Future investigations are needed to analyze whether BEV helps improve OS efficacy.

Phase II study of a combination therapy of nivolumab, bevacizumab and paclitaxel in patients with HER2-negative metastatic breast cancer as a first-line treatment (WJOG9917B, NEWBEAT trial).

TPS1110Background: In recent years, an immune checkpoint inhibitor, anti-PD-1 antibody, has been developed for various cancer types including breast cancer. The synergic effect of combination of ni...

Gastrointestinal perforation during treatment with erlotinib plus bevacizumab in two patients with non-small cell lung cancer exhibiting epidermal growth factor receptor mutations: A case report.

A previous randomized phase II study in patients with non-small cell lung cancer (NSCLC) identified that combination treatment with erlotinib plus bevacizumab prolonged progression-free survival compared with erlotinib alone. However, combination bevacizumab and erlotinib treatment generally increased the risk of severe adverse events, including hemorrhage, thrombosis, fistula formation and gastrointestinal perforation. The present report describes two patients with NSCLC harboring epidermal growth factor receptor (EGFR) mutations, who experienced gastrointestinal perforation associated with erlotinib plus bevacizumab combination therapy. The first patient, a 67-year-old male with stage IIIB lung adenocarcinoma harboring a L858R point mutation in EGFR exon 21, received concurrent chemoradiotherapy. However, seven months later, the patient experienced a relapse and was administered erlotinib plus bevacizumab treatment. A total of two months subsequent to commencing treatment, the patient developed a perforated duodenal ulcer. The second patient, a 66-year-old male with lung adenocarcinoma harboring a deletion in EGFR exon 19 and multiple pulmonary metastases, demonstrated a partial response to erlotinib plus bevacizumab treatment. A total of seven months subsequent to starting treatment, the patient experienced lower abdominal pain, and abdominal computed tomography confirmed a diagnosis of colocutaneous fistula complicating sigmoid diverticulitis. Following repair of the perforation, both patients were restarted on erlotinib treatment alone. Gastrointestinal perforation may be a potentially severe adverse event of erlotinib plus bevacizumab combination therapy, even in the absence of tumor metastasis in the abdomen.

Bevacizumab Reduces S100A9-Positive MDSCs Linked to Intracranial Control in Patients with EGFR-Mutant Lung Adenocarcinoma.

Invitro models have demonstrated immune-modulating effects of bevacizumab (BEV). Combinations of an EGFR tyrosine kinase inhibitor (TKI) with BEV improve progression-free survival (PFS) in patients with EGFR-mutated lung adenocarcinoma. How BEV confers this clinical effect andthe underlying mechanisms of its effect are not clear. A total of 55 patients with stage 4 EGFR-mutated lung adenocarcinoma were enrolled. Myeloid-derived suppressor cells (MDSCs), type 1 and type 2 helper T cells, and cytotoxic T lymphocytes were analyzed by flow cytometry. Clinical data were collected for analysis. In all, 25 patients received EGFR TKI and BEV combination therapy (the BEV/TKI group) and 30 patients received EGFR TKI monotherapy (the TKI-only group). The BEV/TKI group had longer PFS (23.0 versus 8.6 months [p= 0.001]) and, in particular, better intracranial control rates (80.0% versus 43.0% [p= 0.03]), a longer time to intracranial progression (49.1 versus 12.9 months [p= 0.002]), and fewer new brain metastases (38.0% versus 71.0% [p= 0.03]) than the TKI-only group did. The BEV/TKI group had a lower percentage of circulating MDSCs (20.4% ± 6.5% before treatment versus 12.8% ± 6.6% after treatment, respectively [p= 0.02]), and higher percentages of type 1 helper T cells (22.9% ± 15.3% versus 33.2% ± 15.6% [p < 0.01]) and cytotoxic T lymphocytes (15.5% ± 7.2% versus 21.2% ± 5.6% [p < 0.01]) after treatment, changes that were not seen in the TKI-only group. Pretreatment percentage of MDSCs was correlated with PFS, with this correlation attenuated after BEV/TKI treatment. Percentage of MDSCs was also associated with shorter time to intracranial progression. Combining a EGFR TKI with BEV extended PFS and protected against brain metastasis. Those effects were probably due to the reduction of circulating S100A9-positive MDSCs by BEV, which leads to restoration of effective antitumor immunity. Our data also support the rationale for a BEV-immune checkpoint inhibitor combination.

Phase II study of bevacizumab, cisplatin, and docetaxel plus maintenance bevacizumab as first-line treatment for patients with advanced non-squamous non-small-cell lung cancer combined with exploratory analysis of circulating endothelial cells: Thoracic Oncology Research Group (TORG)1016

BackgroundPreclinical studies have demonstrated that docetaxel and bevacizumab may act synergistically by decreasing endothelial cell proliferation and preventing circulating endothelial progenitor mobilization. The objective of this study was to assess the efficacy and safety of a combination therapy of bevacizumab, cisplatin, and docetaxel in chemotherapy-naive Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC).MethodsEligible patients were chemotherapy-naive and had advanced/recurrent non-squamous NSCLC. The patients received 4 cycles of docetaxel (60 mg/m2), cisplatin (80 mg/m2), and bevacizumab (15 mg/kg) once every 3 weeks, followed by bevacizumab as maintenance therapy, every 3 weeks until disease progression or attainment of unacceptable toxicity level. The primary endpoint was objective response rate (ORR). The numbers of circulating endothelial cells (CEC) were also estimated on days 1 and 8 of the first cycle for the exploratory analysis of efficacy prediction.ResultsA total of 47 patients were enrolled from October 2010 to April 2012. Bevacizumab as maintenance therapy was administered to 41 patients (87.2%), and the median number of total treatment cycles was 9 (range: 1–36). ORR, median progression-free survival (PFS), and median overall survival of the patients were 74.5%, 9.0 months, and 27.5 months, respectively. The most common grade 3/4 adverse event was neutropenia (95.7%), followed by leukopenia (59.6%) and hypertension (46.8%). PFS was longer in patients with ≥10 count increase in CECs than that in patients with < 10 count increase in CECs (respective median PFS of 11.0 months versus 6.90 months) although the difference was not statistically significant (p = 0.074).ConclusionsA combination therapy of bevacizumab, cisplatin, and docetaxel, followed by bevacizumab as maintenance was highly effective in patients with non-squamous NSCLC despite the high incidence of grade 3/4 neutropenia. The increase in CEC count between days 1 and 8 may predict the efficacy of our bevacizumab-contained treatment regimen.Trial registrationUMIN Clinical Trial Registry; UMIN000004368. Registered date; October 11, 2010 (Retrospectively registered).

Abstract OT2-06-02: A randomized phase II study of maintenance hormone therapy with or without capecitabine after induction therapy with bevacizumab plus paclitaxel in hormone receptor positive and HER2 negative metastatic breast cancer (KBCSG-TR1214)

Abstract Background: The combination therapy of Bevacizumab (B) and Paclitaxel (P) has proved to prolong progression free survival (PFS) in E2100 and MERiDiAN study for advanced and metastatic breast cancer(AMBC). Because of its longer PFS, developing optimal therapeutic strategy of B+P to improve survival, including management of toxicity is crucial. From the International Consensus Conference for Advanced Breast Cancer, most experts agreed the maintenance endocrine therapy after effective induction chemotherapy in AMBC. In KBCSG-TR 1214 study, we planned to examine the following clinical questions. 1. As a maintenance therapy, which is more effective either endocrine therapy alone (E) or endocrine therapy with capecitabine (E+C)? 2. Can maintenance therapy reduce toxicity of B+P and restore patient's QOL.? 3. How effective is B+P re-challenge after failure of maintenance therapy? Methods: KBCSG-TR 1214 study is multicenter open-labeled randomized phase II trial for hormone receptor (HR)-positive and HER2-nagative patientswho have experienced none or one prior chemotherapy for AMBC. Patients will receive B (10mg/kg q2w) in combination with P (90mg/m2 on day 1, 8, and 15 q4w) as an induction therapy. Patients without progression after 6 cycles of B+P will be randomized to E or E+C. Endocrine treatment has been administrated by their physician's choice. Patients in E+C will receive endocrine therapy with capecitabine 1657mg/m2 on day1 to 21 q4w. Stratification factors for randomization are menopausal status, presence of target lesion, number of prior endocrine therapies for AMBC, with or without 1st line chemotherapy for AMBC. After progression of maintenance therapy (E or E+C), B+P will be started again as a re-challenge therapy. Primary end point is PFS of maintenance therapy. Secondary end points include time to failure of strategy from randomization, efficacy of re-challenge therapy, overall survival and safety of induction therapy. Translational research is also planned. VEGF, angiopoetin-1, and apelin in plasma will be measured at four points (before induction therapy, at the beginning of the maintenance therapy and the re-induction therapy, and at the end of the trial). The sample size was calculated by typeIerror (1-sided) of 0.05 and 80% power to estimate median PFS of each maintenance therapy 9 months with a threshold of 6 months. The target number of patients enrolled and randomized after induction therapy was 120 and 90, respectively. Enrollment has been completed with 116 patients as of April, 2016 and 90 patients had been successful to shift to the maintenance phase with randomization. The last patient had been randomized on October, 2016. The first analysis will be planned during the second quarter of 2018 (UMIN000008662). Citation Format: Yamaguchi M, Nakayama T, Yoshinami T, Ikeda M, Iwamoto M, Komoike Y, Takashima T, Tsurutani J, Yoshidome K, Yamada T, Morita S, Masuda N. A randomized phase II study of maintenance hormone therapy with or without capecitabine after induction therapy with bevacizumab plus paclitaxel in hormone receptor positive and HER2 negative metastatic breast cancer (KBCSG-TR1214) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT2-06-02.

MALDI mass spectrometry imaging of erlotinib administered in combination with bevacizumab in xenograft mice bearing B901L, EGFR-mutated NSCLC cells

Combination therapy of erlotinib plus bevacizumab improves progression-free survival of patients with epidermal growth factor receptor–mutated (EGFR-mutated) advanced non–small-cell lung cancer (NSCLC) compared with erlotinib alone. Although improved delivery and distribution of erlotinib to tumours as a result of the normalization of microvessels by bevacizumab is thought to be one of the underlying mechanisms, there is insufficient supporting evidence. B901L cells derived from EGFR-mutated NSCLC were subcutaneously implanted into mice, and mice were treated with bevacizumab or human IgG followed by treatment with erlotinib. The distribution of erlotinib in their tumours at different times after erlotinib administration was analysed by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI). We also analysed the distribution of erlotinib metabolites and the distribution of erlotinib in tumours refractory to erlotinib, which were established by long-term treatment with erlotinib. We found that erlotinib was broadly diffused in the tumours from B901L-implanted xenograft mice, independently of bevacizumab treatment. We also found that erlotinib metabolites were co-localized with erlotinib and that erlotinib in erlotinib-refractory tumours was broadly distributed throughout the tumour tissue. Multivariate imaging approaches using MALDI MSI as applied in this study are of great value for pharmacokinetic studies in drug development.

P1.03-049 Phase II Study of S-1 plus Bevacizumab Combination Therapy for Patients Previously Treated for Non-Squamous Non–Small Cell Lung Cancer

P1.03-049 Phase II Study of S-1 plus Bevacizumab Combination Therapy for Patients Previously Treated for Non-Squamous Non–Small Cell Lung Cancer

424P - Does afatinib plus bevacizumab combination therapy induce positive conversion of T790M in previously T790M-negative patients?

Background: Third-generation EGFR-TKIs are markedly effective and safe for T790M+ patients (pts). To confer their clinical benefit to more pts, a novel therapy to induce positive conversion in T790M-negative pts may be possible. Methods: We retrospectively reviewed medical records of patients who had received rebiopsy after completion of the ABC-study: a prospective phase II study of Afatinib (Afa)+Bevacizumab (Bev) after acquired resistance to EGFR-TKI. Results: Between October 2014 and September 2016, 21 pts were enrolled to the ABC-study at our institute. 15 pts were T790M-negative and 6 pts were T790M-positive before Afa+Bev therapy. Rebiopsy was performed on 11 of 15 T790M-negative and 4 of 6 T790M-positive pts after progression of Afa+Bev therapy. In 7 (64%) of 11 T790M-negative pts, T790M status changed from negative to positive after Afa+Bev therapy. Six of these 7 patients underwent osimertinib therapy. The response rate and median PFS were 83% and 11.5 months, respectively. There were no adverse events ≥grade 3 and no treatment-related deaths. On the other hand, T790M remained positive after Afa+Bev therapy in all 4 previously T790M-positive pts. Conclusions: Afa+Bev combination therapy could induce positive conversion of T790M even in previously T790M-negative pts. We hypothesize that Afa+Bev could provoke “clonal evolution” which selects and purifies T790M+ cancer cells in heterogeneous tumors. Further studies are warranted to confirm this phenomenon. Legal entity responsible for the study: Institute of Biomedical Research and Innovation Funding: None Disclosure: A. Hata: Speaker fee from Boehringer Ingelheim, Astrazeneca, Chugai, and Eli Lilly Trial financial support from Boehlinger Ingerheim and Astrazeneca Consultant fee from Boehringer Ingelheim, Astrazeneca, Chugai, and Eli Lilly, N. Katakami: Trial financial support from Boehringer Ingelheim and Astrazeneca All other authors have declared no conflicts of interest.

Aberrant glioblastoma neovascularization patterns and their correlation with DCE-MRI-derived parameters following temozolomide and bevacizumab treatment

Glioblastoma (GBM) is a highly angiogenic malignancy, and its abundant, aberrant neovascularization is closely related to the proliferation and invasion of tumor cells. However, anti-angiogenesis combined with standard radio-/chemo-therapy produces little improvement in treatment outcomes. Determining the reason for treatment failure is pivotal for GBM treatment. Here, histopathological analysis and dynamic contrast-enhanced MRI (DCE-MRI) were used to explore the effects of temozolomide (TMZ) and bevacizumab (BEV) on GBM neovascularization patterns in an orthotopic U87MG mouse model at 1, 3 and 6 days after treatment. We found that the amount of vascular mimicry (VM) significantly increased 6 days after BEV treatment. TMZ inhibited neovascularization at an early stage, but the microvessel density (MVD) and transfer coefficient (Ktrans) derived from DCE-MRI increased 6 days after treatment. TMZ and BEV combination therapy slightly prolonged the inhibitory effect on tumor microvessels. Sprouting angiogenesis was positively correlated with Ktrans in all treatment groups. The increase in VM after BEV administration and the increase in MVD and Ktrans after TMZ administration may be responsible for treatment resistance. Ktrans holds great potential as an imaging biomarker for indicating the variation in sprouting angiogenesis during drug treatment for GBM.

474O - Treatment outcome according to tumor RAS mutation status in TRICOLORE trial: A randomized phase 3 trial of S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment for metastatic colorectal cancer

Background: Combination therapy with oral fluoropyrimidine and irinotecan (CPT-11) has not yet been established as first-line treatment for metastatic colorectal cancer (mCRC). However, several studies of S-1 and CPT-11 plus bevacizumab (Bmab) combination therapy have shown promising efficacy in mCRC, suggesting the potential to replace mFOLFOX6 or CapeOX plus Bmab. We performed a randomized phase 3 trial to determine whether S-1 and CPT-11 plus Bmab is non-inferior or superior to mFOLFOX6 or CapeOX plus Bmab in terms of progression-free survival (PFS). Methods: The TRICOLORE trial was a randomized, open-label, phase 3 trial. Chemotherapy-naïve patients with mCRC were randomized to receive either mFOLFOX6 or CapeOX plus Bmab (group A) or S-1 and CPT-11 plus Bmab (group B; 3-week regimen: 7.5 mg/kg Bmab, 150 mg/m2 CPT-11 on day 1, and 40 − 60 mg S-1 twice daily for 2 weeks, followed by a 1-week rest; or 4-week regimen: 5 mg/kg Bmab, 100 mg/m2 CPT-11 on days 1 and 15, and 40 − 60 mg S-1 twice daily for 2 weeks, followed by a 2-week rest). The primary endpoint was PFS. The non-inferiority margin was a hazard ratio (HR) of 1.25 based on the assumption of a median PFS of 11/12 months in group A/group B (power 0.85, 1-sided alpha 0.025). The primary tumor RAS status of patients consented to submit tissue sample were centrally analyzed. Results: A total of 487 patients were enrolled from June 2012 to September 2014. Data were analyzed after confirming >374 events as planned. All demographic factors were well balanced. Median PFS was 10.8 months in group A and 14.0 months in group B (HR 0.85, 95% CI: 0.70–1.03, p < 0.001 for non-inferiority, p = 0.087 for superiority). The RAS mutation status was evaluable in 67.6%. In the RAS wild-type subgroup, median PFS was 11.6 months in group A and 15.9 months in group B. In the RAS mutant-type subgroup, median PFS was 9.3 months in group A and 11.3 months in group B. Conclusions: S-1 and CPT-11 plus Bmab was non-inferior to mFOLFOX6 or CapeOX plus Bmab with respect to PFS and has now become a recommended 1st-line treatment for mCRC irrespective of RAS status. Clinical trial identification: UMIN000007834 2012/05/11 Legal entity responsible for the study: The Tokyo Cooprative Oncology Group Funding: The Tokyo Cooprative Oncology Group (with funding from Taiho) Disclosure: Y. Komatsu: Other substantive relationships: Taiho Pharmaceutical, Lilly, MSD, Ono Pharmaceutical, Novartis, Chugai Pharma, Yakult, Merck Serono, Pfizer, Bayer. A. Takashima: Corporate-sponsored research: Taiho Pharmaceutical, Gilead Sciences, Merck Serono. M. Gamoh: Corporate-sponsored research: Taiho Pharmaceutical, Gilead Sciences, Merck Serono. H. Shimodaira: Corporate-sponsored research: Taiho, Eisai, Bayer. H. Baba: Advisory board or Board of directors: Taiho Pharmaceutical Co., Ltd.; corporate-sponsored research: Taiho Pharmaceutical Co., Ltd. C. Ishioka: Mochida, Kyowa-K, Eisai, Chugai, Tsumura, Novartis, Merck Serono, Daiichi Sankyo, Takeda, Nihon-Kayaku, Yakult, Taiho, Ono, Astellas, Asahi Kasei, Kissei, Bristol-Myers Squibb, Mochida, Chugai, Novartis, Lilly, Bayer. A. Sato: Advisory board or Board of directors: Taiho Pharmaceutical Co., Ltd. Chugai Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.; corporate-sponsored research: Taiho Pharmaceutical Co., Ltd.Chugai Pharma Co., Ltd. S. Yuki: Speakers’ bureau: Chugai Pharmaceutical, Eli Lilly Japan, Bayer Yakuhin, Takeda Pharmaceutical, Taiho Pharmaceutical, Merck Serono. S. Morita: Corporate-sponsored research: Taiho; honorarium: Taiho. All other authors have declared no conflicts of interest.

The potential of gemcitabine, cisplatin, and bevacizumab combination therapy for patients with ovarian clear cell carcinoma.

e17065 Background: Patients with advanced ovarian clear cell carcinoma (OCC) have poor prognosis, and response rate of chemotherapy for relapsed OCC is less than 10%. The effective standard treatment has not been established yet. The synergic effect between gemcitabine and cisplatin in ovarian cancer patients has been reported. And bevacizumab added on chemotherapy has some evidences of progression-free survival improvement at primary, platinum sensitive relapse and platinum resistant relapse situation than chemotherapy only. Therefore, we conducted a retrospective charts review to examine the safety and efficacy of gemcitabine, cisplatin, and bevacizumab combination (GPB) therapy in OCC patients treated in our hospital. Methods: Intravenous gemcitabine (1,000 mg/m2, day 1, 15), cisplatin (40 mg/m2, day 1, 15), and bevacizumab (15 mg/kg, day 1) were administrated every 28 days. This combination therapy was continued until disease progression or appearance of intolerable toxicity. This retrospective study was approved by our institutional ethics board. Results: Eight patients were treated with this GPB therapy in our institution between April 2013 and August 2015. Six patients received this therapy due to presence of relapse, and 2 patients were administered GPB as post-operative adjuvant therapy. Four patients were not treated with bevacizumab due to their medical conditions. The median treatment cycle was 5.5 (range: 1-15). Six patients were evaluable and their responses were partial response (PR) 1, stable disease (SD) 2, and progressive disease (PD) 3. The overall response rate was 13% and the disease control rate was 50%. Four patients needed dose reduction or treatment delay. Grade 3 adverse events observed were anemia (25%), nausea (13%), and elevation of G-GTP (13%). Conclusions: GPB therapy is feasible and moderately effective for patients with OCC. We are currently conducting the prospective multi-institutional phase II trial (UMIN 000023097) and expect that GPB therapy will be used as the standard treatment regimen for OCC, in future.

Bevacizumab for ramucirumab refractory malignant pleural effusion in non-small cell lung cancer: a case report and review of the literature

Malignant pleural effusion (MPE) is a major problem associated with advanced non-small cell lung cancer for which an optimum treatment strategy has yet to be determined. Notably, vascular endothelial growth factor (VEGF) signaling has been found to influence MPE, and bevacizumab, a VEGF ligand inhibitor, can effectively control MPE. Ramucirumab, a human monoclonal antibody specific for VEGF receptor-2, has recently been approved for advanced non-small cell lung cancer. However, it remains unclear which of these agents more effectively control MPE.We describe a case of a 68-year-old man with advanced non-small cell lung cancer in whom ramucirumab plus docetaxel-refractory MPE was responsive to bevacizumab plus docetaxel combination therapy. The patient’s MPE progressed after two cycles of ramucirumab plus docetaxel second-line chemotherapy. After switching to bevacizumab plus docetaxel, a computed tomography scan revealed a decreased MPE after two cycles of treatment.Bevacizumab may be more effective for treating MPE. However, further investigations are still warranted to determine the optimal VEGF-targeted agent for this condition.