Bevacizumab In First-line Setting Research Articles

Identification of patients with ovarian cancer who are experiencing the highest benefit from bevacizumab in first-line setting based on their tumor intrinsic chemosensitivity (KELIM): GOG-0218 validation study.

5553 Background: In patients with high-grade ovarian cancer in first-line setting, predictive factors of bevacizumab efficacy are needed, for selecting patients. In ICON-7 trial, a poor tumor intrisic chemosensitivity (defined by unfavorable modeled CA-125 kinetic ELIMination rate constant KELIM) was a predictive biomarker. Among patients with high-risk diseases, only those with unfavorable KELIM had survival benefit from bevacizumab (mOS: 29.7 vs 20.6 months, HR = 0.78)(Colomban. JNCI CS 2020). The objective was to perform an external validation in GOG-0218 trial (NCT00262847). Methods: In GOG-0218, 1,873 patients were treated with carboplatin-paclitaxel +/- concurrent bevacizumab/placebo followed by a 15 month maintenance. Patient KELIM values were estimated with longitudinal CA-125 kinetics during the first 100 chemotherapy days. The association between KELIM score (categorized as favorable ≥ 1, or unfavorable < 1) and efficacy of bevacizumab (bevacizumab-concurrent + maintenance, vs placebo) for PFS and OS was assessed using univariate/multivariate analyses, in a Training set with 2/3 patients managed the investigators, and then a Validation set with all patients, managed by NGR-GOG. Results: KELIM was assessable in 1,662 patients with ≥ 3 CA-125 available values. In both sets, the patients with unfavorable KELIM derived benefit from bevacizumab compared to placebo (Training: PFS, HR = 0.65 [0.54-0.80]; OS, HR = 0.80 [0.65-0.99]; Validation: PFS, HR = 0.69 [0.59-0.82]; OS, HR = 0.87 [0.73-1.03]), whilst those with favorable KELIM had no benefit from bevacizumab (Training: PFS, HR = 0.96 [0.75-1.23]; OS, HR = 1.05 [0.80-1.37]; Validation, PFS, HR = 0.96 [0.79-1.17]; OS HR = 1.11 [0.89-1.84]). The highest benefit was observed in patients with high-risk diseases (stage IV or sub-optimally resected stage III) characterized by unfavorable KELIM, for PFS (Learning (n = 276): mPFS: 9.0 vs 5.2 months, HR = 0.61 [0.48-0.78]; Validation (n = 433): mPFS: 9.1 vs 5.6 months, HR = 0.64 [0.53-0.78]), and for OS (Learning (n = 278): mOS: 38.9 vs 27.9 months, HR = 0.72 [0.56-0.93], Validation set (n = 438): mOS: 35.1 vs 29.1 months, HR = 0.79 [0.65-0.97]). Conclusions: This validation analysis of GOG-0218 trial confirms the outcomes of ICON-7 trial about the association between poor tumor chemosensitivity and benefit from concurrent + maintenance bevacizumab, suggesting that bevacizumab is mainly effective in patients with poorly chemosensitive diseases. No benefit was found in patients with favorable KELIM. The patients who derived the highest benefit from bevacizumab in PFS and OS (OS absolute benefit ̃ 6 to 9 months) were those with high-risk diseases (stage IV, or incompletely resected stage III) associated with an unfavorable KELIM score (calculator on https://www.biomarker-kinetics.org/CA-125).

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

11564 Background: Early VEGF-A reduction by targeting abundant VEGF-A is a potential predictive marker of bevacizumab (BV). CCL5/CCR5 axis modulates VEGF-A production via endothelial progenitor cells migration. We tested whether genetic polymorphisms in CCL5/CCR5 pathway will predict outcomes in metastatic colorectal cancer (mCRC) patients (pts) receiving BV in first-line setting. Methods: Genomic DNA was extracted from 215 samples of three independent cohorts: 61 pts receiving FOLFOX+BV (median age 60 yrs, median follow-up 39.2 mos); 83 pts receiving FOLFOX (median age 61 yrs, median follow-up 57.6 mos); 71 pts receiving FOLFOX/XELOX+BV as exploratory for serum biochemistry assay (median age 60 yrs, median follow-up 28.9 mos). Single nucleotide polymorphisms of genes in CCL5/CCR5 pathway were analyzed by PCR-based direct sequencing. Serum VEGF-A levels at baseline and day 14 were measured using ELISA. Results: In univariate analysis for the FOLFOX cohort, pts with the CCL5 rs2280789 G/G variant or any CCR5 rs1799988 T allele had shorter overall survival (OS) compared to the those with any A allele or the C/C variant (18.7 vs. 29.4 mos, HR 1.93, 95%CI: 1.05−3.53 P= 0.025; 22.0 vs. 31.2 mos, HR 1.74, 95%CI: 0.98-3.90, P= 0.055). The trend remained in multivariable analysis ( P= 0.090 and P= 0.026). The differences were not confirmed in the FOLFOX+BV cohort. Pts with any CCL5 rs2280789 G allele had longer progression-free survival (PFS) and OS when receiving FOLFOX+BV than FOLFOX (PFS: 19.8 vs. 11.0 mos, HR: 0.44, 95%CI: 0.25-0.78, P= 0.002; OS: 41.8 vs. 21.1 mos, HR: 0.43, 95%CI: 0.24-0.77, P= 0.002); pts carrying any CCR5 rs1799988 T allele had longer PFS and OS ( P= 0.025 and P= 0.008, respectively). No significant difference was shown in pts with either A/A or C/C variant. In the exploratory cohort, any CCL5 rs2280789 G allele was associated with higher VEGF-A levels at baseline and greater decrease of VEGF-A levels at day 14 compared with the A/A variant. Conclusions: CCL5 and CCR5 impact the angiogenic environment. Our data suggest the genotypes may identify specific populations who benefit from BV-based chemotherapy in first-line treatment for mCRC.

Assessment of chemotherapy strategy using bevacizumab for non-squamous non-small cell lung cancer in a real-world setting: A multi-institutional observational study

Abstract Micro-abstract We retrospectively analyzed 162 patients with non-squamous non-small cell lung cancer (NSCLC) who underwent first-line chemotherapy with bevacizumab (BEV); 127 patients without driver oncogenes, 17 patients with EGFR major mutations, 12 patients with ALK rearrangements, 4 patients with EGFR minor mutations and 2 patients with rare types of histology. Background BEV has been approved for treatment of non-squamous NSCLC and is authenticated as one of the key drugs in the treatment of advanced non-squamous NSCLC. Patients and methods We retrospectively analyzed patients with stage IIIB/IV non-squamous NSCLC who underwent chemotherapy with BEV in first-line setting. Results In 162 patients who underwent chemotherapy combined with BEV as first-line treatment, the median overall survival (OS) and progression-free survival (PFS) were 23.5 months and 6.8 months, respectively. The PFS did not differ significantly by the presence of driver oncogenes. In patients without driver oncogenes, more patients who received carboplatin plus pemetrexed with BEV could complete at least 4 cycles of induction therapy and more of these patients proceeded to maintenance therapy than those who received carboplatin plus paclitaxel with BEV, which resulted in better outcome associated with carboplatin plus pemetrexed with BEV. Continuation of BEV beyond first progression did not show any survival benefit. In EGFR mutation-positive patients, the order of BEV-containing regimen and TKI did not influence on OS. None of 18 patients with brain metastases detected at diagnosis developed intracranial hemorrhage. Conclusions PFS of first-line chemotherapy using BEV was not influenced by the existence of driver oncogenes. In patients without driver mutations in real clinical practice, as the first-line partner regimen with BEV, carboplatin plus pemetrexed may be more feasible as compared to carboplatin plus paclitaxel. BEV use beyond first progression did not deliver significant survival benefit. BEV was safe for brain metastases.