◥Regorafenib is a tyrosine kinase inhibitor approved by the FDA for the treatment of patients with chemotherapy refractory metastatic colorectal cancer (mCRC). Regorafenib inhibits signaling through multiple receptors associated with angiogenesis, metastasis, and tumor immunity. Here, we report biomarker results from LCCC1029, a randomized, placebo-controlled, phase II trial of chemotherapy AE regorafenib in patients with second-line mCRC. A panel of 20 soluble protein biomarkers (termed the Angiome) was assessed in the plasma of 149 patients from the LCCC1029 trial both at baseline and along the treatment continuum. Baseline protein levels were analyzed for prognostic and predictive value for progression-free survival (PFS) and overall survival (OS). Changes in protein levels during treatment were analyzed for potential pharmacodynamic effects. Six markers (HGF, IL6, PlGF, VEGF-R1, OPN, and IL6R) were found to be prognostic for PFS. Nine markers (IL6, TIMP-1, PlGF, VCAM-1, ICAM-1, OPN, TSP-2, HGF, and VEGF-R1) were prognostic for OS. Higher baseline levels of OPN (P intx ¼ 0.0167), VCAM-1 (P intx ¼ 0.0216), and PDGF-AA (P intx ¼ 0.0435) appeared to predict for PFS benefit from regorafenib compared with placebo. VCAM-1 was also potentially predictive of OS benefit from regorafenib compared with placebo (P intx ¼ 0.0124). On-treatment changes of six markers reflected potential on-target effect of regorafenib. Consistent results were observed in an Italian cohort where 105 patients with late-stage mCRC received regorafenib monotherapy. The key findings of this study suggest that VCAM-1 may be a predictive biomarker for regorafenib benefit, while multiple protein markers may be prognostic of outcome in patients with mCRC.
597 Background: LCCC1029 was a 2:1 randomized phase II trial of second-line FOLFIRI plus either regorafenib or placebo in mCRC that showed no statistically significant difference in PFS or OS. CMS, defined using gene expression, is prognostic for PFS and OS in previously untreated mCRC, but the impact of CMS in second-line treatment is unclear, as well as its impact on regorafenib efficacy. Methods: RNAseq on archival tumor tissue was successfully performed in 68 LCCC1029 patients (49 on regorafenib, 19 on placebo). A multinomial elastic net CMS classifier was trained using 6 CRC gene expression data sets with known CMS classification. We built our model with only CMS1-4 classified samples and then applied it to normalized and median adjusted RNASeq from LCCC1029 to classify all samples into CMS1-4. TTP, PFS, and OS were compared using Kaplan-Meier method and log-rank tests, and hazard ratios were estimated using Cox proportional hazards method. Results: Our model had > 93% sensitivity and specificity for CMS1-4 in the training data set; the 17% of non-consensus samples in the training data were predominantly labeled CMS2. We classified the LCCC1029 samples as CMS1 (12%), CMS2 (63%), CMS3 (4%), and CMS4 (21%). CMS was prognostic for TTP (log-rank p=0.03), with median for CMS1 of 2.0 months (95% CI 0.0-4.8) versus 5.6 months (5.3-5.9) for CMS2 and 7.8 months (5.5-10.1) for CMS4. There was a trend toward association between CMS and either PFS (log-rank p = 0.11) or OS (log-rank p = 0.085). CMS2 had superior OS compared to CMS1 (HR 0.39, 95% CI 0.17-0.87, p = 0.02). With our limited sample size, we found no significant interaction between CMS and treatment arm for TTP, PFS, or OS. Conclusions: CMS is associated with significant differences in TTP in second-line treatment of mCRC in LCCC1029, and specific CMS types also have differences in OS. Thus, the prognostic impact of CMS extends to second-line treatment in mCRC, meriting further study of CMS classification in additional non-first-line studies.
Hypertension is a common toxicity induced by vascular endothelial growth factor (VEGF) pathway inhibitors. There are no validated markers of hypertension induced by these drugs.Methods: We previously discovered that cancer patients with lower plasma levels of angiopoietin-2, VCAM-1 and VEGF-A are at high risk of developing severe hypertension when treated with bevacizumab. This study aimed to validate the predictive value of these markers in pretreatment plasma samples of an additional cohort of 101 colorectal cancer patients treated with regorafenib. The levels of angiopoietin-2, VCAM-1 and VEGF-A were measured by enzyme-linked immunosorbent assay (ELISA). The association between proteins and grade ≥2 regorafenib-induced hypertension was performed by calculating the odds ratio (OR) from logistic regression.Using the optimal cut-point of each protein, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for hypertension were estimated.
3030 Background: Diarrhea, HFS, and hypertension are common toxicities of sorafenib. No markers are validated to predict patients at risk of these toxicities. This study aimed to identify genetic predictors of sorafenib-induced toxicities. Methods: A two-step, discovery-validation approach was used. The discovery set included 140 renal cell carcinoma patients from the TARGET study treated with sorafenib (400 mg twice daily) and genotyped for 1040 single-nucleotide polymorphisms (SNPs) in 56 genes. The three most statistically significant SNPs associated with grade ≥2 composite toxicity (either hypertension, diarrhea, HFS, or other skin toxicities, CTCAE v.3.0) were tested for association with grade 3 composite toxicity (either hypertension, diarrhea, or HFS, CTCAE v.4.0) in a validation set of 240 hepatocellular carcinoma patients from Alliance/CALGB 80802 treated with sorafenib (400 mg twice daily) alone or with doxorubicin. Associations between SNPs and composite toxicity was performed by logistic regression, with adjusting covariates (age, gender, race, and treatment arm, the latter two covariates for the validation set only). A meta-analysis odds ratio (OR) of each SNP-grade 3 toxicity association between the discovery and validation sets was obtained by inverse variance to point toward effects specific to a type of toxicity. Results: In the discovery set, the top three SNPs associated with grade ≥2 composite toxicity were rs12366035 (C>T, minor allele frequency, MAF 0.34) in VEGFB (p 0.0007), rs4035887 (G>A, MAF 0.49) in EPAS1 (p 0.0021), and rs4864950 (T>A, MAF 0.23) in KDR (p 0.0058). These SNPs were genotyped in the validation set and only rs4864950 in KDR was replicated. No grade 4 toxicities were reported. Similar to the discovery set (OR 2.41, 95% CI 1.29-4.51), the A allele of rs4864950 increased the risk of grade 3 composite toxicity (p 0.032, OR 2.12, 95% CI 1.70-4.27) in the validation set. Grade 3 toxicity prevalence in the discovery and validation sets were 3.6% and 7.4% diarrhea, 8.6% and 12.3% HFS, 3.6% and 8.8% hypertension, respectively. The meta-analysis of the two datasets showed that the A allele of rs4864950 increased the risk of grade 3 diarrhea (p 0.045, OR 3.09, 95% CI 1.03-9.29), grade 3 HFS (p 0.012, OR 2.57, 95% CI 1.24-5.37), but not grade 3 hypertension (p 0.207, OR 0.51, 95% CI 0.18-1.45). Conclusions: We provide the first evidence of clinical validity of a marker of sorafenib-induced diarrhea and HFS. Sorafenib inhibits VEGFR2 (coded by KDR), leading to epithelial hypoxia and causing diarrhea and HFS. Variant rs4864950 might affect the function VEGFR2, which, during VEGFR2 inhibition, increases the risk of diarrhea and HFS. This SNP is common and can be genotyped in patients before receiving sorafenib for a better risk assessment. Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ClinicalTrials.gov Id: NCT01015833.
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