Bev Monotherapy Research Articles

CTNI-50. A RANDOMIZED PHASE 2 TRIAL OF CEDIRANIB/OLAPARIB VERSUS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: UPDATED RESULTS

Abstract PURPOSE Hypoxia from inhibition of angiogenesis reduces DNA repair capacity. Targeting homologous recombination pathway also has anti-angiogenic effects. To examine the synergistic effects of disrupting DNA repair pathways and angiogenesis in glioblastoma, we combine cediranib (ced), a pan vascular endothelial growth factor (VEGF) receptor inhibitor with olaparib (ola), a poly-ADP ribose polymerase (PARP) inhibitor compared with bevacizumab (bev), a VEGF-A inhibitor alone. To identify potential biomarkers predicting response to treatments, we also perform whole exome sequencing on archival tissues. METHODS Bevacizumab-naïve adult patients with first or second recurrence of glioblastoma after radiation and temozolomide were randomly assigned to cediranib (30mg PO daily)/olaparib (200mg PO twice daily) or bevacizumab (10mg/kg IV every 2 weeks). The primary end point was progression-free survival (PFS) at 6 months. The secondary end points included safety and overall survival (OS). Whole exome sequencing of formalin-fixed paraffin embedded archival tissue from 23 patients was performed. RESULTS We are presenting the final data from this trial. Between December 2017 and November 2018, a total 70 adult patients with recurrent glioblastoma were randomly assigned to receive ced/ola (n = 35) or bev (n = 35). With a data cut off on 5/30/2022, median PFS was 118 days and 92 days in ced/ola and bev groups, respectively (hazard ratio, 1.099, 95% CI 0.6-2, p = 0.76). Median overall survival was 269.5 days and 192 days in ced/ola and bev groups, respectively (hazard ratio, 0.6892, 95% CI 0.39-1.2, p = 0.2). Whole exome sequencing was performed in total 23 patients (24 samples), 14 patients in the ced/ola group and 9 patients in the bev group. CONCLUSION No significant survival benefit was observed in patients with recurrent glioblastoma treated with ced/ola compared to patients treated with bev monotherapy. Potential biomarkers predicting response to treatment identified from the whole exome sequencing on archival tissues will be presented.

Real-world analysis of outcomes of patients receiving bevacizumab for recurrent glioblastoma in British Columbia.

e14017 Background: Bevacizumab (Bev) has been publicly funded in British Columbia (BC) since 2011 for treatment of recurrent glioblastoma (rGBM). We performed a retrospective outcomes assessment of patients with rGBM treated with Bev to evaluate treatment practices and outcomes. Methods: Patients with rGBM treated at BC Cancer centers with Bev between January 2011 and December 2017 were reviewed. Patient demographics, tumor characteristics, treatment regimens, and dates of radiographic progression and death were collected. Kaplan-Meier method was used to assess survival, and comparisons were made using the log-rank test. Results: 182 patients were reviewed. There were 180 reported deaths with median PFS 3 months (CI95 = 2.5 - 3.5) and OS 7 months (CI95 = 6.2-7.8) from Bev initiation. Higher corticosteroid dose prior to Bev initiation was associated with worse OS on univariate and multivariate analysis ( p = 0.40 and 0.01, respectively). 67% of patients on corticosteroids reduced their dose shortly after Bev initiation. Most patients (68%) were treated with multiple lines of therapy prior to Bev, with a median time from chemoradiation to Bev initiation of 8 months (range 1-67). Patients started on Bev < 6 months from completion of chemoradiation (prior to adjuvant temozolomide completion) had improved PFS ( p = 0.02) and OS compared to those who started Bev later ( p = 0.05), but there was no association between extent of treatment prior to Bev and outcomes ( p = 0.09). Addition of chemotherapy to Bev did not improve survival over Bev monotherapy ( p = 0.10). Conclusions: Bev combinations with chemotherapy did not confer survival advantage over Bev monotherapy. Furthermore, our results show that patients receiving Bev before completion of adjuvant chemotherapy have better outcomes, suggesting pseudoprogression may have prompted the therapeutic switch. Despite limited benefits to overall survival, Bev is associated with reduction in corticosteroid use and likely improvement in quality of life. Therefore, further research is required to optimize patient selection for and administration of Bev. Additional analysis of rGBM patients prescribed Bev until 2020 in BC is currently underway.

NCOG-24. REAL-WORLD ANALYSIS OF OUTCOMES OF PATIENTS RECEIVING BEVACIZUMAB FOR RECURRENT GLIOBLASTOMA IN BRITISH COLUMBIA

Abstract BACKGROUND Bevacizumab (Bev) has been publicly funded in British Columbia (BC) since 2011 for treatment of recurrent glioblastoma (rGBM). We performed a retrospective outcomes assessment of patients with rGBM treated with Bev. METHODS Patients with rGBM treated at BC Cancer centers with Bev between January 2011 and December 2016 were reviewed. Patient demographics, tumor characteristics, treatment regimens, and dates of radiographic progression and death were collected. Kaplan-Meier method was used to assess survival, and comparisons were made using the log-rank test. RESULTS 138 patients were reviewed. There were 136 reported deaths with median PFS 3 months (CI95 = 2.5 - 3.5) and OS 7 months (CI95 = 6.1-8.0) from Bev initiation. 64% of patients on corticosteroids prior to Bev reduced their dose shortly after initiation. The majority of patients (72%) were treated with multiple lines of therapy prior to Bev, with a median time from chemoradiation to Bev initiation of 8 months (range 1-67). Patients started on Bev < 6 months from chemoradiation (prior to completion of adjuvant temozolomide) had improved OS compared to those who started Bev later (p = 0.05), but there was no association between extent of treatment prior to Bev and outcomes (p = 0.182). Addition of chemotherapy to Bev did not improve survival over Bev monotherapy (p = 0.175). CONCLUSIONS Despite limited benefits to overall survival, Bev is associated with reduction in corticosteroid use and likely improvement in quality of life. Bev combinations with chemotherapy did not confer survival advantage over Bev monotherapy. Furthermore, our results show that patients receiving Bev before completion of adjuvant chemotherapy have better outcomes, suggesting pseudoprogression may have prompted the therapeutic switch. Further research is required to optimize patient selection for and administration of Bev. Additional analysis of rGBM patients prescribed Bev until 2020 in BC is currently underway.

Olaparib in combination with bevacizumab compared to bevacizumab monotherapy for the first-line maintenance treatment of advanced ovarian cancer: a cost-effectiveness analysis

<h3>Objectives:</h3> The addition of maintenance olaparib to bevacizumab (OLAP+BEV) demonstrated significant progression-free survival (PFS) benefit vs BEV alone in the randomized trial PAOLA-1 in advanced ovarian cancer patients with homologous recombination deficiency (HRD)-positive tumors. We aim to quantify the health and economic impact by evaluating the US cost-effectiveness of OLAP+BEV relative to BEV as a maintenance treatment for women with advanced ovarian cancer who had partial or complete response to first-line platinum-based chemotherapy and whose cancer is associated with HRD-positive status <h3>Methods:</h3> Our economic model was a cohort-level four state partitioned survival model with a lifetime horizon. States were progression-free, post first progression, post second progression, and death, modelled using first PFS (PFS1), second PFS (PFS2) and overall survival (OS) outcomes from the PAOLA-1 trial. This approach captured multiple progressions, and the differing health state utility after each progression. PFS1 was modelled through parametric mixture survival modeling to a landmark survival point at 5 years, beyond which, patients who have not progressed are assumed to experience all-cause mortality as the general population. PFS2 and OS were modelled by fitting standard parametric models, and time on treatment data was used directly from PAOLA-1, with a treatment cap of 24 months for OLAP and 15 months for BEV. The cost of HRD testing was calculated as unit cost divided by prevalence and was included as a one-time cost for OLAP+BEV arm. US-based health state utility values were analyzed by applying the methods developed by Pickard. The analyses were conducted from a US healthcare payer perspective, with an annual discount rate of 3%. We also explored the robustness of results using deterministic (DSA) and probabilistic sensitivity analysis. <h3>Results:</h3> At year 5, 45.1% and 16.9% patients remained PFS from OLAP+BEV and BEV arm, respectively. The results showed that compared with bevacizumab alone, OLAP+BEV led to a gain in quality-adjusted life years (2.89 QALYs gain) and life years (3.43 Lys gain) but resulted in higher costs, leading to a deterministic incremental cost-effectiveness ratio (ICER) of $75,276 per QALY. OLAP+BEV had an 87.5% probability of being cost-effective at a willingness-to-pay threshold of $100,000 per QALY. DSA identified efficacy (PFS and OS parameters), subsequent treatment and utility values as key model drivers. <h3>Conclusions:</h3> OLAP+BEV is associated with LY and QALY gain, and is cost effective for US payers relative to BEV monotherapy for the treatment of women with advanced, HRD-positive ovarian cancer

Targeting the RhoGEF βPIX/COOL-1 in Glioblastoma: Proof of Concept Studies.

Simple SummaryGlioblastoma (GBM) is an incurable disease with a 14-month average life-expectancy following diagnosis, and clinical management has not improved in four decades. GBM mortality is due to rapid tumour growth and invasion into surrounding normal brain. Invasive cells make complete surgical removal of the tumour impossible, and result in disease relapse. Thus, it is imperative that any new treatment strategy takes these invading cells into consideration. Bevacizumab (Bev), which prevents the formation of new blood vessels, is an FDA approved therapy, but it has failed to increase overall survival in GBM and has even been shown to increase tumour invasion in some cases. Complementary anti-invasive therapies are therefore urgently required to enhance bevacizumab efficacy. We have identified βPIX/COOL-1, a RhoGEF protein which plays an important role in GBM cell invasion and angiogenesis and could be a useful target in this setting.Glioblastoma (GBM), a highly invasive and vascular malignancy is shown to rapidly develop resistance and evolve to a more invasive phenotype following bevacizumab (Bev) therapy. Rho Guanine Nucleotide Exchange Factor proteins (RhoGEFs) are mediators of key components in Bev resistance pathways, GBM and Bev-induced invasion. To identify GEFs with enhanced mRNA expression in the leading edge of GBM tumours, a cohort of GEFs was assessed using a clinical dataset. The GEF βPix/COOL-1 was identified, and the functional effect of gene depletion assessed using 3D-boyden chamber, proliferation, and colony formation assays in GBM cells. Anti-angiogenic effects were assessed in endothelial cells using tube formation and wound healing assays. In vivo effects of βPix/COOL-1-siRNA delivered via RGD-Nanoparticle in combination with Bev was studied in an invasive model of GBM. We found that siRNA-mediated knockdown of βPix/COOL-1 in vitro decreased cell invasion, proliferation and increased apoptosis in GBM cell lines. Moreover βPix/COOL-1 mediated endothelial cell migration in vitro. Mice treated with βPix/COOL-1 siRNA-loaded RGD-Nanoparticle and Bev demonstrated a trend towards improved median survival compared with Bev monotherapy. Our hypothesis generating study suggests that the RhoGEF βPix/COOL-1 may represent a target of vulnerability in GBM, in particular to improve Bev efficacy.

Comparative Efficacy of Different Therapies for Recurrent Glioblastoma: A Systematic Review and Bayesian Network Meta-Analysis

Background: The optimal treatment of recurrent glioblastoma remains controversial. Therefore, our study aimed to compare and rank active therapies in recurrent glioblastoma. Methods: We performed a systematic review and a Bayesian network meta-analysis. We obtained a treatment hierarchy using the surface under the cumulative ranking curve and mean ranks. A cluster analysis was conducted to aggregate the separated results of 3 outcomes. The protocol of this network meta-analysis was registered in PROSPERO (CRD42019146794). Findings: A total of 1667 citations were identified, and 12 eligible articles remained in the final network meta-analysis. None of the treatment regimens showed a significant increase or decrease in ORR, 6-m PFS rate or OS. Among the reports, cediranib plus lomustine corresponded to the highest rates of grade 3-4 adverse events. Cluster analysis indicated that BEV plus low-dose CCNU (90 mg/m2) had a higher efficacy on the 6-m PFS rate and OS and a moderate effect on ORR and that BEV monotherapy or combined with active drug therapies were advantageous for ORR and 6-m PFS rate. Cediranib plus CCNU and low-dose BEV plus low-dose CCNU showed moderate efficacy on all 3 outcomes. Interpretation: No significant difference was found in ORR, 6-m PFS rate and OS among any of the therapies included in our study. BEV plus low-dose CCNU (90 mg/m 2 ) is recommended firstly. BEV monotherapy alone or combined with active drug therapies are recommended in patients with severe neurological symptoms, and low-dose BEV plus low-dose CCNU can be used as an alternative therapy. Funding Statement: 1. Beijing Municipal Science & Technology Commission, China. 2. Chinese Academy of Medical Sciences. 3. Peking Union Medical College Hospital, Beijing, China Declaration of Interests: The authors declare no competing interests.

Abstract P1-03-04: Zebrafish xenografts as a fast screening platform for bevacizumab impact on tumor growth, angiogenesis and micrometastasis in breast cancer

Abstract Background: VEGF-A is the most potent pro-angiogenic factor and is upregulated in a variety of tumors. Therapies were developed to neutralize VEGF signalling, such as Bevacizumab (Bev). Despite promising pre-clinical results, the average response rate to Bev is reduced for most cancers, with significant side effects. In breast cancer (BC) several studies and a meta-analysis have also confirmed a limited i efficacy in unselected populations. Lack of predictive biomarkers prevents a good patient selection. As such guidelines consider Bev only in a minority of cases. Additionally, depending on the individual tumor, VEGF-A can either block or promote metastasis. In this context, an assay able to predict individual responses to Bev, including its impact on metastasis would prove of great value. Methods: We developed an assay, using zebrafish xenografts(zX), where tumor response and the impact on angiogenesis and metastasis (mets) can be readily analysed. By using Triple negative BC (TNBC) cell line models (Hs578T and MDA-MB-468) and zebrafish patient derived xenografts(zPDX) we evaluated the impact of Bev on proliferation, apoptotis, tumor size, angiogenesis and metastasis. Results: a) Human TNBC cell lines display different tumoral features in zX: Hs578T presented the most vascularized tumors (vessel density ~32.4%) and the lowest metastatic capacity (2.6% of xenografts presented mets, n=77). In contrast, MDA-MB-468 that only recruits blood vessels to the base of the tumor, showed a higher metastatic potential (42.5%, n=87). No direct correlation between vessel density and metastasis could be seen. b) zX were able to reveal different individual tumor responses to Bev in 4 days. Analysis of cell death revealed higher apoptosis rate in Hs578T xenografts (1.6-fold, p&amp;lt;0.0001) with a reduction in tumor size (40% tumor reduction, p&amp;lt;0.0001). MDA-MB-468 displayed resistance to Bev with no changes in the analysed parameters. c) zX can reveal different impact of Bev in tumor micro-environment in 4 days. Hs578T tumors had the highest angiogenic potential being the most affected by Bev treatment (vessel density reduction, [20% p=0.0023] and vessel infiltration [32% reduction, P=0.0027]. In MDA-MB-468 tumors no significant impact on vessel network was observed. d) We identified the previously reported paradoxical responses of antiangiogenic therapies in metastasis in this fast time window of 4 days assay. In Hs578T tumors Bev monotherapy resulted in a 2-fold increase in the frequency of mets(p=0.03). In contrast MDA-MB-468 tumors, that exhibited the highest metastasis potential, showed a reduced frequency of mets upon Bev treatment (42,5% vs 19,7% in control vs Bev group; p=0.0013). e) Differential responses to Bev in zPDX were seen. We processed primary TNBC resected samples and treated the resulting zPDX with Bev. A variety of phenotypes were observed. zPDX1 and zPDX3 had a profile reminiscent to MDA-MB468, with Bev having no anti-tumor effect (p=1.0, p=0.42,respectively), but reducing the micrometastasis incidence (zPDX1-from 42% to 0%, p=0.072; zPDX3- from 20% to 0%, p=0.167). zPDX2 exhibited a profile like Hs578T, where we could detect a significant increase in apoptosis upon Bev treatment (6.5% to 18.7%, p=0.01), accompanied by a trend to tumor shrinkage (21% reduction, p=0.42) but increase mets frequency (12% to 53%, p=0.26). Conclusions: Our results show that the zebrafish larvae xenografts have enough resolution to display differential tumor responses to Bev in TNBC models and zPDX in just 4 days. We propose zebrafish cancer xenografts as a promising fast in vivo platform for Bev screening, allowing analysis of personalized responses. Citation Format: Cátia Almeida, Raquel Mendes, Joana Mourato Ribeiro, Maria João Cardoso, Fátima Cardoso, Miguel Godinho Ferreira, Rita Fior. Zebrafish xenografts as a fast screening platform for bevacizumab impact on tumor growth, angiogenesis and micrometastasis in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-03-04.

ACT-10 TREATMENT FOR GLIOBLASTOMA RECURRED AFTER CONCOMITANT CHEMORADIATION THERAPY WITH TEMOZOLOMIDE AND THEIR PROGNOSIS

There are few data about treatment for glioblastoma recurred after concomitant chemoradiation therapy with temozolomide (TMZ). We retrospectively examined treatment and prognosis of recurred glioblastoma patients who registered Kansai molecular diagnosis network for central nervous system tumors, and whose clinical information were available. One hundred and fifty-seven patients that were clinically diagnosed as recurrence between November 2007 and April 2019 were included. Their median age at primary diagnosis was 52 years old and median KPS was 80%. Proportion of methylated MGMT promoter was 43.3% (65 patients), and mutated IDH was 5.4% (8 patients). Median overall survival after recurrence (mSAR) was 8.2 months. One hundred and sixteen patients (73.9%) were received any anticancer treatment and their mSAR was 10.5m. Combination of TMZ and bevacizumab (Bev) were most frequently used for 33 patients, followed by Bev monotherapy for 17 patients, surgery + TMZ + Bev for 15 patients, surgery + TMZ for 12 patients, and TMZ monotherapy for ten. Their mSAR were 8.0m, 7.5m, 10.5m, 13.0m, and 8.0m, respectively. Using univariate analysis, MGMT promoter methylation (p=0.0007), TMZ (p=0.00933), surgery (p=0.0126), re-radiation (p=0.0367), and surgery+TMZ+Bev (p=0.0493) significantly affected prognosis. By multivariate analysis, MGMT promoter methylation, TMZ, and re-radiation were statistically significant (p=0.000138, 0.00161, 0.00403, respectively). These data showed that relatively young patients with good performance status would receive anti-cancer treatment beyond progression and MGMT promoter methylation might be one of prognostic factor for longer survival. In this cohort, re-radiation was performed for few patients and nitrosourea such as nimustine was almost not used. Further study would be needed whether these treatments have any positive effect or not.

P14.28 First report on the combination of axitinib and Tumor Treating Fields (TTFields) in three patients with recurrent glioblastoma

Abstract BACKGROUND Adding Tumor Treating Fields (TTFields) to first-line therapy in glioblastoma (GBM) demonstrated significantly improved survival in the EF-14 trial. Furthermore, in a post-hoc analysis of the EF-14 trial, median overall survival increased significantly upon recurrence (rGBM) for patients treated with bevacizumab (Bev) and TTFields compared to Bev monotherapy. Axitinib (Axi) is an orally available tyrosine kinase inhibitor which is approved for the treatment of metastatic renal cell carcinoma. It has a high affinity and specificity for vascular endothelial growth factor receptors, thereby acting similar to Bev. In phase 2 trials, Axi improved response rate and progression free survival in rGBM patients compared to historical controls with a manageable toxicity profile. We report on three rGBM patients treated with TTFields and Axi (AxiTTFields). METHODS A 53-year-old male patient (#1) presented with a multifocal and consistently progressing GBM after initial surgery, radiochemotherapy (RCT) and after 4 cycles of temozolomide (TMZ), combined with TTFields. To meet the urgent need of an alternative treatment, Axi (5mg twice a day) was added to the treatment regimen. In a 46-year-old male patient (#2), an early progress occurred after surgery, RCT and 3 cycles of TMZ combined with TTFields. Similarly to #1, Axi was added to the treatment regimen. In a 61-year-old male patient (#3) with a rGBM after surgery and RCT at the time of the 6th cycle of TMZ, TTFields therapy was initiated at recurrence and treatment regimen was adapted to AxiTTFields. RESULTS In these three patients, AxiTTFields was safe and feasible. #1 and #2 were on AxiTTFields therapy for more than 8 months, presenting an improved neurological status with a partial response in the MRI 3 months initiating the combined treatment of AxiTTFields. #3 declined in his neurological status without any change in the MRI monitoring and died 2.4 months after initiating AxiTTFields. Although, Axi as well as TTFields may cause skin irritations, none were observed in this case series. With an average of 77 % in these three patients, the TTFields usage rate was above the independent prognostic threshold of 75 %, underlining the feasibility of this approach. There were no additional adverse events due to the combined therapy of AxiTTFields. CONCLUSION In summary, AxiTTFields was feasible and safe in three rGBM patients. As the addition of Axi to TTFields therapy is a promising approach, we plan to investigate the safety and feasibility of this combination in a pilot trial. Further studies might explore effects on outcome and survival of AxiTTFields in rGBM.

Liposomal 64Cu-PET Imaging of Anti-VEGF Drug Effects on Liposomal Delivery to Colon Cancer Xenografts.

Liposomes (LP) deliver drug to tumors due to enhanced permeability and retention (EPR). LP were labeled with 64Cu for positron emission tomography (PET) to image tumor localization. Bevacizumab (bev), a VEGF targeted antibody, may modify LP delivery by altering tumor EPR and this change can also be imaged.Objective: Assess the utility of 64Cu-labeled LP for PET in measuring altered LP delivery early after treatment with bev.Methods: HT-29 human colorectal adenocarcinoma tumors were grown subcutaneously in SCID mice. Empty LP MM-DX-929 (Merrimack Pharmaceuticals, Inc. Cambridge, MA) were labeled with 64CuCl2 chelated with 4-DEAP-ATSC. Tumor-bearing mice received ~200-300 μCi of 64Cu-MM-DX-929 and imaged with microPET. All mice were scanned before and after the treatment period, in which half of the mice received bev for one week. Scans were compared for changes in LP accumulation during this time. Initially, tissues were collected after the second PET for biodistribution measurements and histological analysis. Subsequent groups were divided for further treatment. Tumor growth following bev treatment, with or without LP-I, was assessed compared to untreated controls.Results: PET scans of untreated mice showed increased uptake of 64Cu-MM-DX-929, with a mean change in tumor SUVmax of 43.9%±6.6% (n=10) after 7 days. Conversely, images of treated mice showed that liposome delivery did not increase, with changes in SUVmax of 7.6%±4.8% (n=12). Changes in tumor SUVmax were significantly different between both groups (p=0.0003). Histology of tumor tissues indicated that short-term bev was able to alter vessel size. Therapeutically, while bev monotherapy, LP-I monotherapy, and treatment with bev followed by LP-I all slowed HT-29 tumor growth compared to controls, combination provided no therapeutic benefit.Conclusions: PET with tracer LP 64Cu-MM-DX-929 can detect significant differences in LP delivery to colon tumors treated with bev when compared to untreated controls. Imaging with 64Cu-MM-DX-929 is sensitive enough to measure drug-induced changes in LP localization which can have an effect on outcomes of treatment with LP.

AT-19 * SINGLE INSTITUTION RETROSPECTIVE COMPARISON OF GLIOBLASTOMA (GBM) PATIENTS (PTS) INITIATED ON BEVACIZUMAB (BEV) BEFORE VERSUS AFTER RECURRENCE IN CLINICAL PRACTICE

BACKGROUND: BEV monotherapy received accelerated approval in May 2009 for the treatment of progressive GBM pts. We performed a retrospective chart review of GBM pts initiated on BEV at Duke before first disease progression (BEV-early) versus after the time of recurrence (BEV-late) to understand outcomes of BEV-treated pts in the community. METHODS: Adult GBM pts treated at Duke were identified through our Primary and Recurrent Glioblastoma Registry. We conducted a retrospective chart review of pts who initiated BEV off clinical trial between 1/1/2009 and 5/14/2012. Pts alive on 5/15/2012 consented to prospective data collection. Demographic, clinical, and outcome data were analyzed. RESULTS: 188 pts treated on BEV-early and 80 pts on BEV-late were identified. Demographics were similar for BEV-early and BEV-late pts; median age of 57 and 55 years, respectively, and the majority are male (64.4% and 51.3%, respectively). At a median follow-up of 38.5 months, median OS from the time of GBM diagnosis was 25.8 months (95% Confidence Interval [CI], 23.1-29 months) for BEV-early pts and 20.5 months (95%CI, 17.1-27.9 months) for BEV-late pts. Median PFS from the time of BEV initiation was 14.8 months (95%CI, 12.2-17.9 months) and 8.8 months (95%CI, 6.6-11.7 months), respectively. 83% and 91% of BEV-early and BEV-late patients who received salvage treatment after initial failure continued with BEV. Grade ≥3 proteinuria occurred in 4% of pts in both groups; grade ≥3 thromboembolic events occurred in 6.9% of BEV-early versus 4% of BEV-late pts. No intracranial hemorrhage was observed. CONCLUSION: This single institution retrospective review suggests a survival advantage for pts initiated on BEV-early compared to BEV-late group, with a median survival difference from GBM diagnosis of at least 5.3 months. Further analyses to identify subgroups of pts benefitting from the addition of BEV early or late will be presented.

P2-18-2 - Safety and Efficacy of Bevacizumab-Containing Chemotherapy in Nsclc Patients with Brain Metastases

Background: Prior to 2012, bevacizumab was contraindicated for patients with brain metastases in Japan due to concerns about cerebral hemorrhage. The package insert changed in 2012 to allow careful administration of bevacizumab; however, we still have insufficient data describing the safety and efficacy of bevacizumab-containing chemotherapy. Because bevacizumab may be effective in the treatment of edema associated with brain metastases and radiation necrosis, it may have additional clinical uses.Methods: We retrospectively evaluated non-small cell lung cancer (NSCLC) patients with brain metastases who had received chemotherapy containing bevacizumab at Chiba Cancer Center between April 2012 and December 2013.Results: Thirty patients were eligible for participation in this study. Of the patients in this study, 15 were men, and 15 were women; patients had a median age of 62.5 years, and all except one had histological adenocarcinoma. Surgery, stereotactic radiosurgery, whole brain radiation, and other therapies were performed in 9, 13, 2, and 1 patients, respectively; 5 patients were not treated. Additionally, 26, 1, 2, and 1 patients received the following chemotherapies: CBDCA + PTX + BEV, CDDP + PEM + BEV, PEM + BEV, or BEV monotherapy, respectively. RECIST classifications of brain metastases were complete response in 2 patients, partial response in 7 patients, stable disease in 11 patients, progressive disease in 1 patients, and NE in 9 patients. Grade 3 adverse events included sensory neuropathy in 1 patient, epileptic seizure in 1 patient, dysbasia in 1 patient, viral encephalitis in 1 patient, febril neutropenia in 1 patient, and subcutaneous abscess of the buttocks in 1 patient. Grade 4 epileptic seizure was occurred in 1 patient. There were no cerebral hemorrhage.Conclusion: Bevacizumab did not increase toxicities in patients with brain metastases and appeared to be effective in the treatment of NSCLC patients with brain metastases.

Adjuvant bevacizumab as treatment for melanoma patients at high risk of recurrence: Preplanned interim results for the AVAST-M trial.

LBA9000 Background: Bevacizumab (Bev) is a recombinant humanized monoclonal antibody to vascular endothelial growth factor (VEGF) shown to improve survival in several advanced solid tumors. Multiple adjuvant trials are underway, but trials that have reported in colon and triple-negative breast cancer did not meet their primary end points. Since VEGF is a relevant target in melanoma, AVAST-M aimed to evaluate the role of Bev in patients (pts) with resected melanoma at high risk of recurrence. Methods: AVAST-M is a randomized phase III trial evaluating single agent Bev (7.5mg/kg IV 3 weekly for 1 year) as adjuvant therapy following resection of AJCC stage IIB, IIC, and III cutaneous melanoma compared to standard observation (Obs). 1,320 pts were required to detect 8% differences in 5-year overall survival (OS) rate from 40% to 48%; 85% power, 5% alpha level. Primary endpoint is OS; secondary endpoints are disease free interval (DFI), distant-metastasis free interval (DMFI), safety, and quality of life (QoL). An associated translational study is ongoing. Results of the first pre-planned interim analysis (agreed by the IDSMC) are reported here. Results: Between July 2007 and March 2012, 1,343 pts were recruited. 56% were male; median age 56 years (range 18-88 years), 16% were stage IIB, 11% IIC, 15% IIIA, 36% IIIB, 20% IIIC, and 2% unknown stage. Ulceration status of the primary melanoma was: 38% present, 45% absent, 17% unknown. At the time of the interim analysis, 286 (21%) patients had died. Median follow-up for survival was 25 months. Median duration of Bev treatment in 671 treated pts was 51 weeks (dose intensity 86%). Main outcomes are shown in the table. Grade 3/4 adverse events were experienced in 101 (15%) Bev pts and 36 (5%) Obs pts. Conclusions: Interim analysis of this large, multicenter trial of melanoma patients at high risk of recurrence has shown that adjuvant Bev monotherapy is well tolerated and improved DFI. Longer follow-up is required to determine an impact on the primary endpoint of 5-year OS. Clinical trial information: 81261306. [Table: see text]

Bevacizumab-based therapy in patients with heavily pretreated ovarian and other Mullerian tract cancers.

e16533 Background: Bevacizumab (Bev) is approved for the therapy (Tx) of primary and platinum-sensitive recurrent Mullerian tract cancers (MTC) such as ovarian (OC), fallopian tube (FTC), type II endometrial (EC-II), and peritoneal papillary-serous carcinomas (PPSC). However, the role of Bev in the ≥ 3rd line Tx of MTCs is still unclear.This retrospective study summarizes our long-term experiences with Bev in patients (pts) with heavily pretreated MTC who did not qualify for recruitment into a controlled clinical trial. Methods: A total of 74 intensively pretreated MTC pts (OC, n = 65; FTC, n = 2; EC-II, n = 4; PPSC, n = 3) were included in this study with 43 (58.1%) being platinum-resistant. Pts had failed a median of 4 (range 1-10) prior chemotherapies (CTx ). Tx included Bev monotherapy (group A, n = 17), Bev + metronomic CTx (group B, n = 37), and Bev + conventionally dosed CTx (Group C, n=20). Bev was administered at either 10 mg/kg BW q2w or 15 mg/kg BW q3w. Adverse effects were classified according to CTCAE Vs 4.03. TTP was calculated from the start of Bev until progression, OS was calculated from the start of Bev until death or loss to follow up. Results: Most common Tx related toxicities were hypertension, proteinuria, headache, inflammation/infection, epistaxis, and subileus. Hypertension which often required adequate treatment was limiting in only one case as also were renal toxicity and infection. Median TTP was 27.8 wks and median OS was 53.6 wks with no significant difference between platinum-resistant and –sensitive pts. In regard to both TTP and OS, there was a non-significant trend favoring groups A (33.4/63.0 wks) and B (29.9/61.6 wks) vs group C (19.2/35.4 wks). Conclusions: Bev based Tx was active and generally well tolerated in this hard-to-treat population of pts with recurrent MTC. Both TTP and OS were equal or even superior to any conventional CTx used in this setting. Moreover, clinical platinum-resistance did not predict a worse clinical outcome. Although this is not a randomized trial, our results argue in favor that Bev should be preferably given either as single agent or combined with metronomic CTx in pts with heavily pretreated MTCs. Further clinical trials of Bev in recurrent MTCs may prove useful.

A randomized phase II study of carboplatin and bevacizumab in recurrent glioblastoma multiforme (CABARET).

2017 Background: The optimal use of bevacizumab (bev) in recurrent glioblastoma (GBM) remains uncertain including the choice between monotherapy or combination therapy as well as the role of continuing bev beyond disease progression. Methods: This was a sequential stratified two part randomized phase II study. Eligibility criteria included: recurrent GBM after radiotherapy and temozolomide, no other chemotherapy for GBM, ECOG PS 0-2. The primary objective (Part 1) was to determine the effect of bev plus carboplatin versus bev alone on 6 month progression-free survival (6PFS) using modified RANO criteria. Bev was given 2-weekly 10mg/kg, carboplatin 4-weekly AUC5. On progression, patients (pts) able to continue treatment were randomized to continue or cease bev (Part 2). Secondary endpoints included response rate (RR); cognitive function; quality of life; toxicity and overall survival (OS). Results: 122 pts (median age 55) were enrolled from 18 Australian sites. 87 (71.3%) were PS 0-1. The current median follow up is 14.7 months with median on-treatment time 3.7 months. 6PFS was 26% (combination) versus 24% (monotherapy) (HR 0.96, 95%CI (0.66, 1.39), p = 0.82). RR (CR+PR) was 15% versus 13%. Median OS was 6.9 versus 6.4 months (HR 1.08, 95%CI (0.74, 1.59), p = 0.68). There were 2 treatment (bev) related deaths in the combination arm (one GI perforation, one CNS hemorrhage). To date, overall incidence of bev-related AEs is similar to prior literature with 10 (8.3%) venous thromboembolic events and 5 (4.2%) hemorrhages (all grades) reported. There were 3 episodes of G3-4 neutropenia, all in the combination arm (5%) and 9 episodes of G3-4 thrombocytopenia. As of January 14, 2013, 47 pts have continued on to Part 2. Data for bev beyond progression is not yet available. Conclusions: In this study of patients with recurrent GBM, the addition of carboplatin to bev did not result in additional clinical benefit compared to bev monotherapy. This large multicentre population-based study demonstrated that clinical outcomes in patients with recurrent GBM treated with bev were inferior to previously reported studies. Ongoing follow-up of patients on bev beyond progression, and novel secondary and exploratory endpoints continues. Clinical trial information: ACTRN12610000915055.

The Addition of Bevacizumab to Standard Therapy with R-CHOP in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Is Associated with an Increased Rate of Cardiac Adverse Events: Final Analysis of Safety and Efficacy Outcomes From the Placebo-Controlled Phase 3 MAIN Study

Abstract 58 Vascular endothelial growth factor (VEGF) is involved in lymphoma growth, suggesting a potential therapeutic role for anti-VEGF therapies. This randomized, placebo (PBO)-controlled, double-blind, multicenter, phase 3 trial (MAIN study) evaluated if adding the anti-VEGF antibody bevacizumab (Bev) to standard R-CHOP therapy improves outcomes for patients (pts) with previously untreated CD20+ diffuse large B-cell lymphoma (DLBCL). The study was designed to detect a 27% reduction in the risk of a progression-free survival (PFS) event (Hazard ratio [HR] = 0.73, R-CHOP + Bev vs R-CHOP). Pts with DLBCL (IPI score ≥2 or bulky disease, ≥7.5 cm irrespective of IPI) and normal cardiac function were randomized (1:1) to receive Bev or PBO + site pre-specified immunochemotherapy (8 cycles R-CHOP-21 or 6 cycles R-CHOP-14 followed by 2 cycles R). R-CHOP-21 & R-CHOP-14 cohorts received Bev at 15 mg/kg q21d & 10 mg/kg q14d, respectively. Response was assessed at the end of induction; pts achieving complete remission continued Bev monotherapy (15 mg/kg q21d, up to 1y from study start, Bev arm) or observation (PBO arm). To observe the required 326 events the planned sample size was 1060 pts followed for 60 mo. The protocol specified strict cardiac monitoring; left ventricular ejection fraction (LVEF) was measured at baseline (bl), after 4 & 8 cycles of therapy, and at 1y. LVEF adverse events (AEs) were defined as a ≥20% absolute decline from bl and/or a decline of ≥10% from bl to As part of ongoing serial safety monitoring, in May 2010 the independent Data and Safety Monitoring Board (DSMB) observed an increased number of LVEF AEs in the Bev arm. Given a low probability of the study meeting the primary efficacy endpoint, the DSMB concluded an unfavorable benefit–risk profile for pts treated with R-CHOP + Bev. Therefore, Bev treatment was immediately discontinued and further enrollment stopped. The study was revised and completed as a safety-oriented follow-up of the enrolled pts. The final analysis included 787 pts (enrolled 7/07 to 6/10) who were followed until 12 mo after the last pt had received the last dose of chemotherapy. Study arms were balanced for age, gender, planned chest irradiation, history of hypertension, cardiac risk factors, and bl LVEF. Efficacy of R-CHOP was not significantly affected by the addition of Bev; median PFS was 42.9 (PBO) vs 40.2 mo (Bev) (HR = 1.09, P =.49). While survival data are immature, no difference was evident (deaths 83/397 [20.9%] PBO vs 82/390 [21%] Bev). Pts in the Bev arm vs the PBO arm had higher rates of LVEF (18.0 vs 8.0%; OR 2.51, 95% CI [1.60;3.93], respectively) and CHF AEs (16.2 vs 6.5%; OR 2.79; 95% CI [1.72;4.54], respectively). Further analysis of CHF AEs by treatment and age group indicated that pts ≥65y had a higher rate than younger pts; both in the Bev arm (20.0 vs 14.0%) and PBO (9.3% vs 4.7%). Incidence of CHF AEs varied according to backbone regimen and in the Bev arm was 16.8% (R-CHOP-21) and 13.8% (R-CHOP-14), and in the PBO arm was 4.6% (R-CHOP-21) and 13.8% (R-CHOP-14). As this was an unplanned analysis on a non-randomized pt population an imbalance of relevant bl features was observed (e.g. age and race composition). CHF events began to increase (determined by Kaplan–Meier analysis) at a cumulative doxorubicin dose of 200 mg/m2 and above in both treatment arms, and increased further at a cumulative doxorubicin dose ≥300 mg/m2 in the Bev arm vs. the PBO arm. Pts in the PBO arm were more likely to resolve their CHF events without sequelae (by investigators reporting, 77.8% in PBO arm vs 63.2% in Bev arm), and also had fewer unresolved CHF events (14.8% vs 20.6%). Fatal CHF AEs were comparable in both arms (1/386 vs 2/395). In conclusion, this study demonstrates that the addition of Bev to R-CHOP is associated with an increased risk of LVEF/CHF events in pts with DLBCL. Following the DSMB recommendation, recruitment was stopped and Bev was discontinued. Data suggest that, regardless of randomization CHF risk is increased for pts ≥65 y of age, and the addition of Bev increases the cardiac toxicity rate of doxorubicin. The current data do not support further evaluation of Bev with R-CHOP in DLBCL. Disclosures: Seymour:Roche/Genetech: Honoraria. Off Label Use: The addition of bevacizumab to standard therapy with R-CHOP in patients with previously untreated diffuse large B-cell lymphoma. Pfreundshuh:Roche: Consultancy, Research Funding; Celgene: Consultancy; Pfizer: Consultancy; Mundi Pharma: Consultancy; Onyx: Consultancy; Amgen: Research Funding. Coiffier:Roche: Consultancy. Trneny:Roche: Consultancy, Honoraria, Research Funding. Sehn:Roche: Consultancy, Honoraria, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Csinady:Roche: Employment.

437TiP - A Randomised Phase II Study of Carboplatin and Bevacizumab in Recurrent Glioblastoma Multiforme (CABARET STUDY). Cooperative Trials Group For Neuro-Oncology (COGNO)

ABSTRACT Background Glioblastoma (GBM) is the most aggressive malignant glial tumor. There is no accepted standard management after disease progression. Much remains unknown about the optimal use of bevacizumab (bev), including the role of continuing beyond progression, and patterns of radiological progression during and after use. In addition, the new Response Assessment in Neuro-Oncology (RANO) criteria have yet to be validated prospectively. Methods This study is a multi-centre, stratified randomised phase II trial. Patients have recurrent GBM after radiotherapy and temozolomide, have had no other chemotherapy for GBM, and have ECOG performance status 0–2. At least three months have elapsed since radiotherapy. In Part 1, patients are randomised 1:1 to intravenous bev 10 mg/kg 2-weekly and carboplatin AUC5 4-weekly or bev monotherapy. On progression, eligible patients are randomised to continue or cease bev (Part 2). The primary objective is to determine the effect of bev plus carboplatin versus bev alone on progression-free survival according to modified RANO criteria. Secondary endpoints are response rates, cognitive function, quality of life, steroid dose, toxicity, and overall survival. CogState, a validated neurocognitive testing system, is being used prospectively for the first time in this population and compared with mini-mental state examination. Exploratory endpoints include biomarker analyses, comparison of modified RANO and modified MacDonald criteria, predictive value of early MRI after 2 doses of bev, steroid dosing, and location and type of radiological progression during and after therapy. Results Enrolment commenced in Nov 2010, completing Part 1 accrual in Mar 2012 with 122 patients randomised from 17 Australian sites. Randomisation to Part 2 continues. Feasibility and safety data will be presented; efficacy outcome results are not expected until 2013. Conclusions The study results will significantly improve knowledge regarding the use of bevacizumab in the setting of recurrent GBM, as well as providing for the first time a prospective analysis of CogState neurocognitive testing for patients with brain tumours. Disclosure M.A. Rosenthal: Roche Advisory Board member. H. Wheeler: Roche Advisory Board member. E. Hovey: Roche Advisory Board member. A.K. Nowak: Roche Advisory Board member and has received research funding through Roche Australia. R.J. Simes: Roche Advisory Board Member. All other authors have declared no conflicts of interest.

Treatment of Unresectable Adult Pilocytic Astrocytoma with Bevacizumab with or without Temozolomide (P04.183)

Objective: We hypothesized that bevacizumab (bev) with or without temozolomide (TMZ) might be effective in treating unresectable pilocytic astrocytoma (PA) in adults. Background PA is a WHO Grade I tumor that is often not completely resectable. TMZ, an alkylating agent, and bev, a blocker of vascular endothelial growth factor (VEGF), are both approved for treatment of glioblastoma. Pathological studies have shown VEGF expression in PA. Design/Methods: We reviewed cases of unresectable PA treated with bev with or without TMZ. We identified 9 patients, 5 male and 4 female, with a median age of 40 years. Six tumors were in the hypothalamus, and 1 each in the thalamus, pineal region, and cerebral peduncle. Two patients were treated in the up-front setting, and 7 were treated for progression after radiation therapy. Three patients had received prior chemotherapy, 1 each PCV, carboplatin, or TMZ. Treatment consisted of bev 5 mg/kg every 14 days, with or without TMZ 150-200 mg/sq m every 5 of 28 days. MR scans were graded according to Macdonald criteria. Results: Seven patients were treated with TMZ plus bev and 2 with bev monotherapy. Median duration of therapy was 351 days for bev and 308 days for TMZ. Seven patients (78%) achieved a partial response, 1 a minor response, and 1 no response. Cyst volumes were decreased in 3 of 4 tumors (75%) with multicystic change. Both patients treated with bev monotherapy achieved a partial response, as did both patients treated in the up-front setting. Visual field or extraocular movement deficits improved significantly in 4 patients. One patient experienced symptomatic intratumoral hemorrhage. One patient died after craniotomy for hemorrhagic tumor progression. Median time to progression on bev was 593 days. Conclusions: Bev when administered with or without TMZ is effective in unresectable adult PA and deserves a Phase II study. Disclosure: Dr. Green has nothing to disclose. Dr. Woyshner has nothing to disclose. Dr. Quan has nothing to disclose. Dr. Cloughesy has received personal compensation for activities with Genentech, Inc., and Roche Diagnostics Corporation.

Phase I trial of bevacizumab combined with concurrent chemoradiation for squamous cell carcinoma of the head and neck: Preliminary outcome results.

5518 Background: A Phase I trial has been completed to examine the safety and feasibility of combining bevacizumab (bev) with radiation and cisplatin in patients with locoregionally advanced head and neck squamous cell carcinoma (LA-HNSCC). We assessed the capacity of bev monotherapy to induce tumor response as measured by functional imaging and biomarker evaluation. We report preliminary clinical outcome as well as correlative imaging and biomarker results. Methods: All patients underwent experimental imaging [FLT-PET (proliferation), CuATSM-PET (hypoxia), DCE-CT scans (flow/perfusion)] and biomarker evaluation prior to bev monotherapy. At three weeks, repeat tumor biopsy and imaging/serum studies were performed. Comprehensive H&N chemoradiation (CRT) was then delivered to 70 Gy in 33 fractions with concurrent weekly cisplatin at 30 mg/m2 and Q3 week bev (wks 1, 4, 7) with dose escalation from 5 to 10 to 15 mg/kg. Results: Between 2007-2010, ten LA-HNSCC pts were enrolled. All had stage IV HNSCC and remain alive (9 NED) with a mean survival of 22.4 months. There have been two recurrences at 15 and 16 months respectively. Nine patients experienced grade 3 toxicity (dysphagia-9, mucositis-7, tumor pain-3, weight loss-4, nausea/vomiting-2), with two cases of grade 4 lymphopenia. No significant bleeding was observed. Tumor proliferation (FLT) following bev monotherapy and at mid-course showed significant reduction (p<0.05). Tumor hypoxia (Cu-ATSM) showed minimal change following bev alone, but showed reduction during CRT. AQUA histology confirmed reduction in VEGFR2 expression from tumor biopsies following bev therapy. Conclusions: The incorporation of bev with comprehensive CRT for LA-HNSCC appears safe and feasible. Several patients manifested tumor regression following administration of bev alone. Three patients experienced pronounced tumor pain early in the treatment course. Experimental imaging and biomarker evaluation demonstrated clear changes following bev alone and during CRT. These findings may afford opportunities to forecast clinical outcome for individual patients and thereby tailor therapy approaches in future clinical trials.