Bevacizumab In First-line Treatment Research Articles

TP53 mutations and survival in ovarian carcinoma patients receiving first-line chemotherapy plus bevacizumab: Results of the MITO16A/MaNGO OV-2 study.

To date, there are no biomarkers that define a patient subpopulation responsive to bevacizumab (BEV), an effective treatment option for advanced ovarian carcinoma (OC). In the context of the MITO16A/MaNGO OV-2 trial, a Phase IV study of chemotherapy combined with BEV in first-line treatment of advanced OC, we evaluated TP53 mutations by next-generation sequencing and p53 expression by immunohistochemistry (IHC) on 202 and 311 cases, respectively. We further correlated TP53 mutations in terms of type, function, and site, and IHC data with patients' clinicopathological characteristics and survival. TP53 missense mutations of unknown function (named unclassified) represented the majority of variants in our population (44.4%) and were associated with a significantly improved overall survival (OS) both in univariable (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.20-0.92, p = .03) and multivariable analysis (HR = 0.39, 95% CI = 0.18-0.86, p = .02). Concordance between TP53 mutational analysis and IHC was 91%. We observed an HR of 0.70 for OS in patients with p53 IHC overexpression compared to p53 wild-type, which however did not reach statistical significance (p = .31, 95% CI = 0.36-1.38). Our results indicate that the presence of unclassified TP53 mutations has favorable prognostic significance in patients with OC receiving upfront BEV plus chemotherapy. In particular, unclassified missense TP53 mutations characterize a subpopulation of patients with a significant survival advantage, independently of clinicopathological characteristics. Our findings warrant future investigations to confirm the prognostic impact of TP53 mutations in BEV-treated OC patients and deserve to be assessed for their potential predictive role in future randomized clinical studies.

Efficacy and Safety of Bevacizumab Biosimilar (Encoda) Compared With Reference Bevacizumab (Avastin) in Patients With Metastatic Colorectal Cancer: A Multicenter, Real-World Study.

The bevacizumab biosimilar (Encoda), which was approved by the National Medical Products Administration (NMPA) in China in 2019, is a biosimilar of bevacizumab. Approval of bevacizumab biosimilar (Encoda) for metastatic colorectal cancer (mCRC) was based on the extrapolation principle of biosimilar. However, there is currently no available data regarding the efficacy and safety of both bevacizumab biosimilar (Encoda) and bevacizumab in patients with mCRC. The present real-world study included patients with mCRC who received first-line therapy with either bevacizumab biosimilar (Encoda) or bevacizumab combined with backbone chemotherapy between April 2021 and December 2022. The overall response rate (ORR) was the primary endpoint of the study. Bevacizumab biosimilar (Encoda) would be considered equivalent to bevacizumab if it met any of the following criteria: the 90% CI for ORR risk ratio of bevacizumab biosimilar (Encoda): bevacizumab was included within the predefined equivalence range (0.75 to 1.33) as specified by the NMPA or within the predefined equivalence range (0.73 to 1.36) as specified by US Food and Drug Administration (FDA); the 95% CI for the ORR risk difference of 2 groups was included within the predefined equivalence range (-0.12 to 0.15) as specified by the European Medicines Agency (EMA). The study included a total of 436 patients, with 234 receiving bevacizumab biosimilar (Encoda) and 202 receiving bevacizumab. The ORR was 42.3% (95% CI: 35.9% to 48.9%) in the bevacizumab biosimilar (Encoda) group and 42.1% (95% CI: 35.2% to 49.2%) in the bevacizumab group. The ORR risk ratio and risk difference were 1.005 (90% CI: 0.836 to 1.210) and 0.002 (95% CI: -0.091 to 0.095), respectively, both included within the prespecified equivalence range. The overall safety profile was comparable between the 2 groups. This real-world study is the first to demonstrate the efficacy equivalence of bevacizumab biosimilar (Encoda) and bevacizumab in first-line treatment of mCRC.

FOLFOXIRI Plus Cetuximab or Bevacizumab as First-Line Treatment of BRAFV600E-Mutant Metastatic Colorectal Cancer: The Randomized Phase II FIRE-4.5 (AIO KRK0116) Study.

BRAFV600E mutation is associated with a poor outcome in metastatic colorectal cancer (mCRC). This clinical trial investigated the efficacy of triplet chemotherapy (fluorouracil, folinic acid, oxaliplatin, and irinotecan) combined with either cetuximab or bevacizumab in patients with previously untreated BRAFV600E-mutant mCRC. In this controlled, randomized, open-label phase II trial, 109 patients were randomly assigned, 107 of whom were included into the full analysis set (FAS). Patients were randomly assigned in a 2:1 ratio to receive either FOLFOXIRI plus cetuximab in the experimental arm (n = 72) or FOLFOXIRI plus bevacizumab in the control arm (n = 35). The primary end point was objective response rate (ORR) according to RECIST 1.1., evaluated in patients treated according to protocol (ATP population). Progression-free survival (PFS), overall survival (OS), toxicity, and feasibility were analyzed as secondary end points. Eighteen patients discontinued study treatment before the first tumor assessment, thus resulting in the ATP population of 89 patients. In these patients, ORR was 51% (30/59) in the cetuximab-based experimental arm and 67% (20/30) in the bevacizumab-based control arm (odds ratio, 1.93; 80% CI, 1.06 to 3.52; P = .92 [one-sided]). In the full analysis set, median PFS was significantly inferior in the experimental arm (6.7 months v 10.7 months; hazard ratio [HR], 1.89; P = .006). Median OS analyzed at an event rate of 64.5% showed a trend toward shorter survival in cetuximab-treated patients (12.9 months v 17.1 months; HR, 1.4; P = .20). To our knowledge, FIRE-4.5 is the first prospective and randomized study investigating first-line treatment of BRAFV600E-mutant mCRC. FOLFOXIRI plus cetuximab does not induce a higher ORR when compared with FOLFOXIRI plus bevacizumab in first-line treatment of BRAFV600E-mutant mCRC. Bevacizumab-based chemotherapy remains the preferable first-line treatment of patients with BRAFV600E-mutant mCRC.

P-243 Impact of relative dose intensity of bevacizumab in first-line treatment of hepatocellular cancer

Atezolizumab-Bevacizumab (AB) is the current standard of care for treatment of unresectable hepatocellular cancer (HCC), with the recommended dosage of bevacizumab at 15mg/kg. Notable adverse events with an incidence of >20% in the AB group include hypertension and proteinuria, consistent with bevacizumab’s distinctive toxicity profile. In the real-world, many physicians choose to use a lower dose of bevacizumab upfront based on patients' comorbidities, anticipated toxicities, and cost considerations. Early phase II data comparing 5mg/kg versus 10mg/kg of bevacizumab in advanced HCC suggested no difference in outcomes, though they were not powered to examine this. In other tumour types like colon cancer, the standard dose of bevacizumab is lower, though there is some data describing higher dose intensity of bevacizumab and improved survival on progression. A relative dose intensity (RDI) of ≥70% is correlated with better overall survival (OS) and radiological responses for other first-line therapies for HCC like Lenvatinib. We sought to examine the dose effect of bevacizumab in the use of AB for HCC treatment. We retrospectively analysed data on patients treated at a single-centre in Singapore who received at least one dose of AB for unresectable HCC between September 2020 and December 2021. RDI over the 1st two doses was calculated as the cumulative dose for those two cycles divided by the weight-based standard dose of bevacizumab. We evaluated the association of RDI ≥70% compared to RDI < 70%, with OS, progression free survival (PFS), and response rate (by RECIST v1.1). 57 patients were included, with a mean age of 65 years. All were ECOG 0 and majority were male (96.49%), Chinese (85.69%), had underlying viral hepatitis (56.14%) and were Child’s-Pugh A (98%) on treatment initiation. 65.91% had BCLC C disease, while the rest had BCLC B disease. Majority used AB as 1st line of systemic therapy (82.46%), and 42.11% achieved a relative dose intensity ≥70%. Patients who had RDI ≥70% were not significantly different from those with RDI < 70% in terms of baseline characteristics such as age, gender, race, cirrhosis etiology, BCLC status, or line of usage of AB (1st or later). Response rates (25.0% vs 18.2%, p = 0.742) and disease control rates (43.8% vs 54.6%, p = 0.435) did not differ between those with RDI ≥70% or < 70%. Median OS was 10.99 months (95% CI, 5.83-NR) in the RDI ≥70% group and did not differ significantly from 10.76 months (95% CI, 8.45-NR) in the RDI < 70% group (HR 0.94; 95% CI, 0.404-2.215). Median PFS was likewise similar in both groups, at 4.04 months (95% CI, 1.01-7.76) in RDI ≥70% and 3.09 months (95% CI, 1.55-NR) in RDI < 70% (HR 0.83; 95% CI, 0.45-1.70). Both OS and PFS remained not significantly different on adjustment for age, gender, BCLC status, viral/non-viral etiologies, and line of usage of AB. Frequency of common adverse events were similar between both groups. We demonstrated that a lower dose of bevacizumab at < 70% RDI achieved similar radiological and survival outcomes as ≥70% when given in combination with atezolizumab for advanced HCC. Use of reduced dose bevacizumab can be considered to reduce cost and toxicity without significantly affecting treatment outcomes. This should be explored further in a prospective setting.

Patterns of first-line systemic therapy delivery and adoption of bevacizumab in advanced ovarian cancer in Ontario, Canada.

292 Background: Initial treatment of epithelial ovarian cancer (EOC) consists of combination of cytoreductive surgery (CSR) and/or chemotherapy. Targeted therapies such as bevacizumab have shown to improve outcomes in a subset population with high-risk features. Real-world patterns of systemic therapy delivery in EOC in the modern era are not well understood. Our objective is to evaluate the patterns of first-line systemic treatment of advanced EOC in Ontario, focusing on adoption of bevacizumab, which was approved for use in 2016. Methods: We conducted a retrospective, population cohort study using administrative databases held at the ICES in Ontario, Canada. Patients diagnosed with non-mucinous EOC between 2014 and 2018 were identified from the Ontario Cancer Registry; early-stage disease was excluded. Information on systemic therapy was obtained from Activity Level Reporting and New Drug Funding Program databases. Provider of care (gynecologic oncologist vs medical oncologist) information was obtained from billing codes. Academic cancer centers were identified using validated systemic facility codes from Cancer Care Ontario. Statistical analyses include descriptive statistics, t-tests, and multivariable logistic regression using SAS. Results: Out of 4,680 cases diagnosed with EOC during the study period, 3,632 (77.6%) were considered advanced stage. Median age of cohort was between 65-70, and the majority had Charlson score of 1-2 (97%) and are urban (91.8%). A total of 3,181 (87.6%) patients underwent CRS and 2,722(74.9%) patients underwent chemotherapy. Of those who received chemotherapy, 1,259 (46.2%) received neoadjuvant chemotherapy, 1,012 (37.2%) received upfront CRS, and 451(16.5%) received chemotherapy only. The majority of chemotherapy was delivered by gynecologic oncologists (60.6%) and in academic cancer centres (61.7%). There was no significant difference in use of neoadjuvant chemotherapy between medical oncologists and gynecologic oncologists (p = 0.67). Only 53 chemotherapy patients (1.9%) received bevacizumab containing-regimen in the first-line setting. Medical oncologists were 4 times more likely to administer bevacizumab-containing regimen compared to gynecologic oncologists (OR 4.03, 95% CI.29 – 7.36) after adjusting for age, stage, Charlson score and rurality score on logistic regression. Delivery of bevacizumab is relatively higher in non-academic cancer centres (OR 2.61, 95% CI 2.32- 2.94) while 83% of intraperitoneal chemotherapy is delivered in academic cancer centres. Conclusions: Patterns of care of EOC in Ontario remain heterogenous between care providers and institutions, while uptake of bevacizumab for first-line treatment of EOC remains low. Factors leading to low uptake and real-world outcomes should be explored.

The use of bevacizumab is correlated with improved post-progression survival in advanced recurrent ovarian cancer.

The recent improvements in anti-cancer therapy following first-line treatment can potentially impact post-progression survival. We evaluated the factors that influence post-progression survival in advanced recurrent ovarian cancer. Eighty-nine patients who underwent first-line treatment between June 2005 and December 2017 were included. The post-progression survival was defined as the difference between overall survival and initial progression-free survival. The effects of age, histology, stage, optimal surgery, secondary debulking surgery, bevacizumab administration, platinum sensitivity, and olaparib maintenance in recurrence were compared and independent risk factors were determined. The median follow-up duration was 60.0months (range: 2-181). Platinum-sensitive recurrence had longer post-progression survival than platinum-resistant (P<0.001). Inclusion of bevacizumab in first-line treatment did not produce a significant difference in post-progression survival (P=0.462). Secondary debulking surgery (P=0.013), bevacizumab administration (P<0.001), and olaparib maintenance (P=0.001) during recurrence increased post-progression survival. In multivariate analysis, histologies other than serous or endometrioid (hazard ratio=2.389; 95% confidence interval=1.200-4.754; P=0.013) and non-bevacizumab usage in recurrence (hazard ratio=4.484; 95% confidence interval=1.939-10.370; P<0.001) were independently correlated with poorer prognosis. Bevacizumab administration beyond progressive disease elicited improved post-progression survival (P<0.001). In patients receiving bevacizumab in first-line treatment, exclusion of bevacizumab in the recurrent therapy (hazard ratio=5.507; 95% confidence interval=2.301-12.124; P<0.001) was independently correlated with poorer prognosis. The continuous use of bevacizumab beyond progressive disease improves post-progression survival suggesting its important role in first-line and recurrence treatment for ovarian cancer.

Safety and efficacy of lenvatinib in HCC beyond second-line treatment.

e16592 Background: Until 2018 sorafenib was the only first-line systemic treatment option for advanced hepatocellular carcinoma (HCC). Ten years later a new agent, called lenvatinib, showed equal efficiency in comparison to sorafenib. Currently sorafenib and lenvatinib are options for first line treatment with regorafenib, cabozantinib and ramucirumab (if alpha fetoprotein &gt; 400 ng / ml) as second-line treatment choices. The first published results from Imbrave150-trial shows promising effects regarding the combination of atezolizumab and bevacizumab for first line treatment in advanced HCC. This highlights the question for reasonable sequence therapies. Yet, it has so not been demonstrated, if lenvatinib is an option for a treatment line beyond the second. Methods: We identified 5 patients with advanced HCC from our hospital, who had been treated with local ablative procedures as well as at least three different systemic therapies with still excellent clinical performance status before receiving lenvatinib. Retrospective analysis was performed to examine clinical and radiologicresponse rates as well as side effects. Results: 3/5 patients achieved regression in at least third treatment lines. One patient showed stable disease, and only one of these five patients showed a mixed response. The toxicity profile was heterogeneous. One patient developed a mild hand-foot syndrome. Another one evolved hypertension. Developing of proteinuria led to stop treatment in one patient. One patient showed psychiatric disorder, which was possibly associated with lenvatinib. Response was independent of the underlying cause of HCC. Conclusions: Lenvatinib is a promising agent for treating advanced HCC in a later treatment line and revealed a tolerable toxicity profile.

Health economic analysis of doublet chemotherapy with and without bevacizumab for first-line treatment of RAS mutant metastatic colorectal cancer based on real-world data.

e16048 Background: Bevacizumab remains the dominant biologic treatment option for RAS mutant (RASmt) metastatic colorectal cancer (mCRC). While the health economic impact of bevacizumab in the RASmt subpopulation may deviate from its use in the general mCRC population, this has never been investigated. This study uses the power of real-world data to assess the cost-effectiveness of doublet chemotherapy with compared to without bevacizumab (ChemBev and ChemOnly, respectively) for first-line treatment of RASmt mCRC, while accounting for subsequent treatment in second and third line. Methods: Data from the Treatment of Recurrent and Advanced Colorectal Cancer (TRACC) registry was analyzed to populate a discrete event simulation of three treatment lines, surgery of primary tumor and metastases, hospitalizations following serious adverse events, and best supportive care. Imbalance in baseline patient and disease characteristics was corrected for in all analyses using inverse probability weights. Costs were included from an Australian public payer perspective in Australian dollars (AUD). All health and economic outcomes were discounted at 5% per year. Results: Of the 507 included RASmt mCRC patients that started first-line treatment in the 2010 – 2017 time period, 345 received ChemBev and 162 ChemOnly. The corrected median time on first-line treatment was 7.1 months (95% confidence interval: 6.4 – 8.0) for ChemBev and 4.1 months (3.5 – 5.1) for ChemOnly. Time on second- and third-line treatment was comparable between the groups. Corrected overall survival was 22.6 months (21.7 – 24.0) for ChemBev and 14.3 months (12.1 – 21.7) for ChemOnly. In terms of the health economic impact, mean life years were 1.9 for ChemBev and 1.5 for ChemOnly, and mean costs were AUD 93,025 and AUD 44,929 per patient, respectively. The resulting incremental cost-effectiveness ratio (ICER) of ChemBev compared to ChemOnly was AUD 149,317 per life-year gained (LYG). Conclusions: In contrast to results from clinical trials, overall survival was substantially longer for patients who received bevacizumab, which can possibly be attributed to an imbalance between groups despite correction for known prognostic factors. At an ICER of AUD 149,317 per LYG, the economic burden of upfront treatment with bevacizumab was found to be substantial and consistent with estimates for the general mCRC population. This is mainly caused by the duration of first-line treatment, which was significantly longer for ChemBev.

Addition of Bevacizumab to First-Line Palliative Chemotherapy in Patients with Metastatic Small Bowel Adenocarcinoma: A Population-Based Study.

Data about the use and effectiveness of targeted therapy in metastatic small bowel adenocarcinoma (SBA) are scarce. The aim of this population-based study was to obtain insights into the use and effectiveness of targeted therapy in patients with synchronous metastases of SBA. Data were retrieved from the Netherlands Cancer Registry. Patients treated with palliative chemotherapy and/or targeted therapy for synchronous metastatic SBA between 2007 and 2016 were included (n = 187). Differences in treatment and the subsequent effects on overall survival (OS) were evaluated. In first-line treatment, 25 patients (13%) received additional targeted therapy, exclusively bevacizumab, and mostly in combination with CAPOX/FOLFOX (n = 24). A primary ileal tumour was predictive for receiving bevacizumab in first-line treatment (odds ratio 3.2, 95% confidence interval (CI) 1.06-9.93). Median OS for patients in whom bevacizumab was added to first-line chemotherapy was 9.3months, compared to 9.1months with chemotherapy only (p = 0.85). Median OS for patients receiving first-line treatment only was 8.5months with and 6.4months without the addition of bevacizumab, respectively (p = 0.54). In multivariable survival analyses, the addition of bevacizumab was no prognostic factor (hazard ratio 1.01, 95% CI 0.65-1.59). Bevacizumab was the only prescribed targeted therapy in first-line treatment. Considering the limited number of patients receiving first-line bevacizumab and the unknown reasons to prescribe additional targeted therapy, the corresponding survival rates of patients treated with and without additional bevacizumab in first-line treatment might suggest a limited clinical effect of bevacizumab in addition to first-line palliative chemotherapy on OS. Future research should focus on identifying the subgroup of patients who might benefit from anti-VEGF therapy in metastatic SBA.

Genetic variants in CCL5 and CCR5 genes and serum VEGF-A levels predict efficacy of bevacizumab in metastatic colorectal cancer patients.

Early VEGF-A reduction (EVR) by targeting abundant VEGF-A is a potential predictive marker of bevacizumab (BEV). The CCL5/CCR5 axis modulates VEGF-A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in the CCL5/CCR5 pathway could predict efficacy of BEV in patients with metastatic colorectal cancer (mCRC) in a first-line setting. Genomic DNA was extracted from 215 samples from three independent cohorts: 61 patients receiving FOLFOX+BEV (evaluation cohort); 83 patients receiving FOLFOX (control cohort); 71 patients receiving FOLFOX/XELOX+BEV (exploratory cohort) for validation and serum biochemistry assay (n = 48). Single nucleotide polymorphisms of genes in the CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Considering the unbalanced distribution of patient baseline characteristics between the evaluation and control cohorts, propensity score matching analysis was performed. Serum VEGF-A levels during treatment were measured using ELISA. Among the evaluation and control cohorts, patients with any CCL5 rs2280789 G allele had longer progression-free survival (PFS) and overall survival (OS) when receiving FOLFOX+BEV than FOLFOX (PFS: 19.8 vs. 11.0 months, HR 0.44, 95%CI: 0.24-0.83, p = 0.004; OS: 41.8 vs. 24.5 months, HR: 0.50, 95%CI: 0.26-0.95, p = 0.024). No significant difference was shown in patients with the A/A variant. In the exploratory cohort, CCL5 rs2280789 G alleles were associated with higher VEGF-A levels at baseline and a greater decrease in VEGF-A levels at day 14 compared to the A/A variant. CCL5 and CCR5 impact the angiogenic environment, and the genotypes in CCL5/CCR5 genes may identify specific populations who will benefit from BEV in first-line treatment for mCRC.

FDA approves atezolizumab with chemotherapy and bevacizumab for first-line treatment of metastatic non-squamous NSCLC

FDA approves atezolizumab with chemotherapy and bevacizumab for first-line treatment of metastatic non-squamous NSCLC

Efficacy of bevacizumab in first-line treatment of metastatic colorectal cancer: A systematic review and meta-analysis

BackgroundThis systematic review and meta-analysis aims to evaluate the additive effect of bevacizumab when combined with first-line chemotherapy in metastatic colorectal cancer (mCRC). MethodsWe searched EMBASE, MEDLINE, the Cochrane Library in April 2018. When possible, data were pooled to estimate summary effects. The present analysis evaluated treatment related efficacy based on progression-free survival (PFS) and overall survival (OS). The analysis was performed to define the overall effect and the effect observed in currently used chemotherapy regimens. ResultsSeven randomised studies were included. In the analysis of the overall effect, PFS (hazard ratio [HR] 0.71, p < 0.00001) and OS (HR 0.85, p = 0.0008) clearly favoured bevacizumab plus chemotherapy versus chemotherapy alone. When the analysis was focused on currently used chemotherapy excluding 5-FU bolus regimens and including only infusional 5-FU plus irinotecan or oxaliplatin, the addition of bevacizumab prolonged PFS (HR 0.79, p < 0.0001) but not OS (HR 0.92, p = 0.18). However, addition of bevacizumab to fluoropyrimidine monotherapy lead to a significant prolongation of PFS (HR 0.57, p < 0.00001) and OS (HR 0.83, p = 0.03). ConclusionThe present meta-analysis demonstrates that the effect of bevacizumab on survival is not consistent throughout the included regimens. Considering only presently used regimens, a significant effect on PFS and OS was only observed when bevacizumab was added to fluoropyrimidine monotherapy.

479O - Consensus molecular subtypes (cms) as predictors of benefit from bevacizumab in first line treatment of metastatic colorectal cancer: Retrospective analysis of the MAX clinical trial

Background: CMS is a transcriptome-based classification of colorectal cancer (CRC) with prognostic implications, but its association with treatment outcomes, especially in the metastatic setting, remains unknown. We investigated whether CMS classification was predictive of bevacizumab treatment benefit using data from the phase 3 MAX trial. MAX previously reported progression-free survival (PFS) benefit for the addition of bevacizumab (B) to chemotherapy (capecitabine (C) +/- mitomycin (M)) in first line treatment of metastatic CRC. Methods: Archival tumours from 256 patients (54% of trial population) were available for gene expression profiling using Almac Xcel microarray. Tumours were classified into CMS groups 1 to 4 using previously published methods. We correlated CMS groups with PFS in the MAX trial. The predictive value of CMS was demonstrated as the interaction between CMS and bevacizumab treatment, assessed by Cox proportional hazards model. Results: After data quality control, primary tumours from 239 patients (51% of trial population) were suitable for survival analysis. Distribution of CMS groups were CMS1 18%, CMS2 48%, CMS3 12%, CMS4 23%. Hazard ratios (HR)(95% CI) of PFS in C vs CB+CBM arms for CMS 1,2,3 and 4 were 0.83 (0.43-1.62), 0.50 (0.33-0.76), 0.31 (0.13-0.75) and 1.24 (0.68-2.25) respectively (test for interaction between CMS and treatment, p = 0.03). CMS remained a significant independent predictor of PFS after adjustment for prognostic factors in a multivariate analysis (p = 0.04). Conclusions: In metastatic CRC, CMS 2 and 3 subtypes preferentially benefit from the addition of bevacizumab to chemotherapy, compared to CMS 1 and 4. Validation of these findings in independent cohorts is required. Once validated, CMS classification could be used to guide patient selection for bevacizumab therapy. Legal entity responsible for the study: Olivia Newton-John Cancer Research Institute, Australia Funding: Olivia Newton-John Cancer Research Institute, Australia and Australian Gastrointestinal Trials Group (AGITG) Disclosure: P. Wirapati: Funding: Roche, Bayer and Sanofi for research in predictive biomarker for colorectal cancer. T.J. Price, N. Tebbutt: Advisory boards: Roche All other authors have declared no conflicts of interest.

Cost-utility of erlotinib combined with bevacizumab versus bevacizumab alone after completion of chemotherapy with bevacizumab for first-line treatment of advanced non-small-cell lung cancer

Cost-utility of erlotinib combined with bevacizumab versus bevacizumab alone after completion of chemotherapy with bevacizumab for first-line treatment of advanced non-small-cell lung cancer

MINI01.19: Cost Analysis of Pemetrexed-Platinum with Maintenance vs. Paclitaxel-Carboplatin-Bevacizumab with Maintenance in Patients with Lung Cancer

Given minimal differences in efficacy between pemetrexed and bevacizumab in first-line treatment to progression, based on the PRONOUNCE and POINTBREAK Phase III studies, evidence-based decision making regarding optimum treatment strategy may be driven by potential differences in healthcare resource utilization (HCRU) and costs. Real-world data from commercial and Medicare supplemental insurance claims in the U.S. were used to compare HCRU and costs associated with continuation maintenance with bevacizumab and pemetrexed. Insurance claims data from Truven Health Analytics Marketscan Databases were used to identify lung cancer patients who initiated treatment with pemetrexed-platinum or paclitaxel-carboplatin-bevacizumab between March 2009 and June 2013 and continued monotherapy following ≥4 administrations of first-line treatment. Patients were followed up to 12 months from treatment initiation to identify subsequent claims for healthcare services. HCRU and costs were evaluated from initiation of first-line treatment to end of 12-month follow-up (or death or disenrollment) and from initiation of first-line treatment through end of maintenance. Propensity score bin bootstrapping methods were used to adjust for demographic and clinical differences between treatment cohorts. The pemetrexed-platinum maintenance cohort included 509 patients (104 cisplatin, 405 carboplatin), and the paclitaxel-carboplatin-bevacizumab maintenance cohort included 177 patients. Pemetrexed-platinum patients were older (62.7 vs. 60.5, p<0.009), more likely to live in the Northeast (21.6% vs 9.04%, p<0.003), and had higher comorbidity burden (mean Charlson Comorbidity Index 2 vs. 1.7, p<0.014). Pemetrexed-platinum patients were more likely to have pulmonary heart disease (11.0% vs. 4.52%, p=0.038), chronic pulmonary disease (47.0% vs. 35.0%, p=0.023), and brain metastasis (23.0% vs. 13.6%, p=0.028). In the 6 months prior to treatment initiation, pemetrexed-platinum patients were more likely to have had an emergency room visit (34.4% vs. 21.5% and inpatient stay (48.7% vs. 33.9%), and had higher total costs ($38,796 vs. $31,161, p=0.014). During the period from treatment initiation to end of maintenance, mean total costs per patient per month were $2,600 (95% CI [$2560, 2640]) lower for pemetrexed-platinum patients compared to paclitaxel-carboplatin-bevacizumab patients, primarily due to lower outpatient costs. In the 12-month period following initiation of first-line treatment, mean total costs per patient per month were $1,653 (95% CI, [$1617, $1688]) lower for pemetrexed-platinum patients, again due to lower outpatient costs. Mean total costs per patient per month were significantly lower for pemetrexed-platinum patients compared to paclitaxel-carboplatin-bevacizumab patients in the setting of first-line treatment to progression in lung cancer patients with commercial or Medicare supplemental health insurance.

Colorectal cancer trial endpoints: time for dynamic thinking?

Assessment of early tumour shrinkage and depth of response in relation to survival outcomes has recently emerged as a topical research topic. Initial results of the FIRE-3 study 1 Heinemann V von Weikersthal LF Decker T et al. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol. 2014; 15: 1065-1075 Summary Full Text Full Text PDF PubMed Scopus (1273) Google Scholar in 2014 caused much debate: a benefit in overall survival was noted with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus cetuximab as compared with FOLFIRI plus bevacizumab in first-line treatment of metastatic colorectal cancer in the absence of significant differences in either the proportion of patients who achieved an objective response or progression-free survival. The original trial was powered to detect an improvement in the proportion of patients who had an objective response in a population of 592 patients whose tumours were wild-type for KRAS exon 2 mutations, with progression-free survival and overall survival as secondary outcomes. Further controversy arose as the overall survival benefit was not confirmed in the much larger CALGB 80405 study, 2 Venook A Niedzwiecki D Lenz H-J et al. CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). Proc Am Soc Clin Oncol. 2014; 32 (abstr LBA3.) Google Scholar in which overall survival was used as the primary endpoint, although most patients were treated with a FOLFOX (fluorouracil, leucovorin, and oxaliplatin) backbone. The secondary analysis 3 Stintzing S Modest DP Rossius L et al. on behalf of the FIRE-3 investigatorsFOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol. 2016; 17: 1426-1434 Summary Full Text Full Text PDF PubMed Scopus (275) Google Scholar reported by Sebastian Stintzing and colleagues in The Lancet Oncology involves a subgroup of 330 patients whose tumours were wild-type for RAS (including both KRAS and NRAS) mutations with imaging available for independent external review and evaluates early tumour shrinkage (defined as a ≥20% reduction in the diameter sum of target lesions at the first 6 week tumour assessment timepoint), depth of response (defined as the smallest sum of target lesion diameters compared with baseline), and survival outcomes. In the group treated with FOLFIRI plus cetuximab, early tumour shrinkage occurred significantly more frequently than in the FOLFIRI plus bevacizumab group (107 [68·2%; 95% CI 60·3–75·4] of 157 patients in the FOLFIRI plus cetuximab group vs 85 [49·1%; 41·5–56·8] of 173 patients in the FOLFIRI plus bevacizumab group; p=0·0005). Median depth of response was also greater in the FOLFIRI plus cetuximab group compared with the FOLFIRI plus bevacizumab group (−48·9% [–54·3 to −42·0] tumour shrinkage vs −32·3% [–38·2 to −29·2]; p<0·0001), with patients in the FOLFIRI plus cetuximab showing a greater depth of response at all assessed timepoints. Early tumour shrinkage and depth of response were highly correlated with each other, and both were associated with improved post progression survival and overall survival irrespective of treatment arm. FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trialThis analysis provides a new framework that connects alternative metrics of response to overall survival. Superior response-related outcome parameters, such as early tumour shrinkage and depth of response, obtained by centralised radiological review correlated with the overall survival benefit conferred by FOLFIRI plus cetuximab compared with FOLFIRI plus bevacizumab in the extended RAS wild-type subgroup. Full-Text PDF

E02* - Anti-EGFR or Bevacizumab in first line treatment of RAS wild type metastatic colorectal neoplasm (RwtMCRC): meta-analysis of randomized clincal trials

E02* - Anti-EGFR or Bevacizumab in first line treatment of RAS wild type metastatic colorectal neoplasm (RwtMCRC): meta-analysis of randomized clincal trials

2109 Anti-EGFR or Bevacizumab in first line treatment of RAS wild type metastatic colorectal neoplasm (RwtMCRC): pooled analysis of randomized clincal trials

2109 Anti-EGFR or Bevacizumab in first line treatment of RAS wild type metastatic colorectal neoplasm (RwtMCRC): pooled analysis of randomized clincal trials

The impact of early tumor shrinkage on survival in WJOG4407G trial, a randomized phase III trial of mFOLFOX6 plus bevacizumab versus FOLFIRI plus bevacizumab in first-line treatment for metastatic colorectal cancer.

679 Background: Early tumor shrinkage (ETS) has been reported as an important predictor of favorable outcomes in patients with metastatic colorectal cancer (mCRC) receiving first-line chemotherapy. We investigated the impact of ETS on survival in a randomized phase III study (WJOG4407G), which directly compared mFOLFOX6+bevacizumab (Bev) with FOLFIRI+Bev as first-line treatment. Methods: The subjects of this study were patients with measurable lesions whose tumor responses at 8 weeks were evaluated. ETS was defined as 20% or more decrease in the sum of the longest diameters of target lesions (RECIST ver.1.0) at 8 weeks. Progression-free survival (PFS) and overall survival (OS) were compared between patients with ETS and without ETS in each treatment. Results: Of 402 patients enrolled in the WJOG4407G trial, 354 (mFOLFOX6+Bev/FOLFIRI+Bev 175/179) patients were evaluated for this analysis. In this population, response rate, median PFS, and median OS of mFOLFOX+Bev/FOLFIRI+Bev were 65.7/68.2%, 10.7/12.1 months (HR 0.916, 95%CI 0.725-1.157, p=0.281), and 28.9/31.9 months (HR 0.870, 95%CI 0.653-1.159, p=0.272), respectively. One hundred (57.1%)/113 (63.1%) patients in the FOLFOX+Bev/FOLFIRI+Bev groups achieved ETS. No significant difference of the ratio of the patients with ETS between both groups was observed (p=0.099). In the FOLFIRI+Bev group, both PFS and OS were significantly longer in patients with ETS than those without ETS while there were no remarkable differences in the mFOLFOX6+Bev group (see Table). Conclusions: There were substantial differences in PFS and OS between the patients with and without ETS in the FOLFIRI+Bev group, but not in the FOLFOX+Bev group. The impact of ETS on survival is suggested to be different according to chemotherapy regimens. Clinical trial information: UMIN000001396. [Table: see text]

The ‘real-life’ impact of adding bevacizumab to first-line therapy in metastatic colorectal cancer patients: A large Israeli retrospective cohort study

Background. After a decade of extensive use, the actual contribution of bevacizumab in first-line treatment of metastatic colorectal cancer (mCRC) is still unclear.Objective. To evaluate ‘real-life’ outcomes of patients with mCRC before and after the introduction of bevacizumab to standard mCRC first-line practice.Methods. Using the computerized administrative database of Clalit Health Services’ (CHS), Israel's largest health care provider, we retrospectively compared two cohorts (n = 1739): (A) all CHS’ patients diagnosed with mCRC between January 2000 and December 2004 that received first-line irinotecan or oxaliplatin-based combination chemotherapy (before bevacizumab was introduced) (n = 1052), and (B) all patients that started first-line irinotecan or oxaliplatin combination chemotherapy together with bevacizumab between September 2006 and December 2009 (after bevacizumab was fully reimbursed in Israel for mCRC first-line therapy) (n = 687). The primary endpoint was overall survival (OS) and secondary endpoints were first-line progression-free survival (PFS) and metastatectomy rates.Results. Median OS was longer in Cohort B than in Cohort A [23.0 months vs.15.0, adjusted hazard ratio (HR), 0.75]. Secondary outcomes were also better; PFS of 14.0 months vs. 9.8 in the earlier period (HR, 0.75) and metastatectomy rate of 8.1% versus 3.9%. The longer OS in Cohort B was preserved even after controlling for latter-line epidermal growth factor receptor (EGFR) inhibitor use (HR = 0.77).Conclusion. In this analysis, OS, PFS and metastatectomy rates of first-line treatment of mCRC were significantly higher in the later period of the study. These results, derived from ‘real-life’ practice, suggest that the use of bevacizumab, among other alterations in the clinical management of mCRC between the two periods, might have had a significant contribution to these outcomes, and may therefore support the current practice of adding bevacizumab to first-line treatment of mCRC.