Jacobson, Sawyer

Abstract Sorafenib blocks nonstructural protein 5A (NS5A)-recruited c-Raf–mediated hepatitis C virus (HCV) replication and gene expression. Release of Raf-1-Ask-1 dimer and inhibition of Raf-1 via sorafenib putatively differ in the presence or absence of doxorubicin. Cancer and Leukemia Group B (CALGB) 80802 (Alliance) randomized phase III trial of doxorubicin plus sorafenib versus sorafenib in patients with advanced hepatocellular carcinoma (HCC), showed no improvement in median overall survival (OS). Whether HCV viral load impacts therapy and whether any correlation between HCV titers and outcome based on HCV was studied. In patients with HCV, HCV titer levels were evaluated at baseline and at multiple postbaseline timepoints until disease progression or treatment discontinuation. HCV titer levels were evaluated in relation to OS and progression-free survival (PFS). Among 53 patients with baseline HCV data, 12 patients had undetectable HCV (HCV-UN). Postbaseline HCV titer levels did not significantly differ between treatment arms. One patient in each arm went from detectable to HCV-UN with greater than 2 log-fold titer levels reduction. Aside from these 2 HCV-UN patients, HCV titers remained stable on treatment. Patients who had HCV-UN at baseline were 3.5 times more likely to progress and/or die from HCC compared with HCV detectable (HR = 3.51; 95% confidence interval: 1.58–7.78; P = 0.002). HCV titer levels remained unchanged, negating any sorafenib impact onto HCV titer levels. Although an overall negative phase III study, patients treated with doxorubicin plus sorafenib and sorafenib only, on CALGB 80802 had worse PFS if HCV-UN. Higher levels of HCV titers at baseline were associated with significantly improved PFS. Significance: Sorafenib therapy for HCC may impact HCV replication and viral gene expression. In HCV-positive patients accrued to CLAGB 80802 phase III study evaluating the addition of doxorubicin to sorafenib, HCV titer levels were evaluated at baseline and different timepoints. Sorafenib did not impact HCV titer levels. Despite an improved PFS in patients with detectable higher level HCV titers at baseline, no difference in OS was noted.

Abstract In this secondary analysis of Hispanic adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) treated on Cancer and Leukemia Group B (CALGB) 10403, we evaluated outcomes and geographic enrollment patterns relative to US population data. We used demographic, clinical, and survival data on AYAs enrolled on CALGB 10403 (N = 295, 2007-2012). Surveillance, Epidemiology, and End Results registries provided overall survival (OS) for US AYA ALL by ethnicity/race. North American Association of Cancer Registries provided AYA ALL incidence overall and proportion among Hispanics by US state. Of AYAs enrolled on CALGB 10403, 263 (89%) reported ethnicity/race: 45 (17%) Hispanic, 172 (65%) non-Hispanic White (NHW), 25 (10%) non-Hispanic Black (NHB), and 21 (8%) other. Compared with NHWs, Hispanic and NHB patients had lower household income, and Hispanic patients were more likely to harbor high-risk CRLF2 aberrations. Relative to US estimates, where Hispanic patients represented 46% of newly diagnosed AYA ALL patients and experienced inferior OS compared with NHW (P < .001), Hispanic AYAs on CALGB 10403 did as well as NHW patients (3 year OS, 75% vs 74%; P = NS). Hispanic patients also had higher rates of protocol completion (P = .05). Enrollments on CALGB 10403 differed relative to the distribution of Hispanic AYA ALL in the United States: enrollment was highest in the Midwest; t and only 15% of enrollees were from states with a high proportion of Hispanic AYA ALL patients. In summary, Hispanic patients treated on CALGB 10403 did as well as NHWs and better than population estimates. Geographical misalignment between trial sites and disease epidemiology may partially explain the lower-than-expected enrollment of Hispanic AYA ALL patients.

PURPOSE Representativeness in acute leukemia clinical research is essential for achieving health equity. The National Cancer Institute's mandate for Comprehensive Cancer Centers (CCCs) to define and assume responsibility for cancer control and treatment across a geographic catchment area provides an enforceable mechanism to target and potentially remediate participatory inequities. METHODS We examined enrollee characteristics across 15 Cancer and Leukemia Group B/Alliance cooperative group adult acute leukemia clinical trials (N = 3,734) from 1998 to 2013, including participation in optional companion biobanks. We determined enrollment odds by race-ethnicity for all participants adjusted for national incidence, and for those enrolled at CCCs adjusted for catchment area incidence. We modeled biobank participation by sociodemographics using logistic regression. RESULTS Non-Hispanic (NH)-White patients were more likely to be enrolled than NH-Black, NH-Asian, or Hispanic patients (odds ratio [OR], 0.75, 0.48, and 0.44, respectively; all P < .001), but less likely than NH-Native American patients (OR, 1.91; P < .001), adjusted for national incidence. Enrollment odds were lower for NH-Black, NH-Asian, and Hispanic patients at CCCs adjusted for catchment area incidence (OR, 0.57, 0.26, and 0.32, respectively; P < .001); differences were driven by overenrollment of NH-White patients from outside self-defined catchment areas (18.1% v 12.3%; χ2 P = .01) and by CCCs with less absolute enrollee diversity (rank sum P = .03). Among all enrollees, NH-White race-ethnicity and lower neighborhood deprivation correlated with biobank participation (OR, 1.81 and 1.45, respectively; P = .01 and .03). For CCC enrollees, the correlation of race-ethnicity with biobank participation was attenuated by a measure accounting for their site's degree of enrollment disparity but not neighborhood deprivation. CONCLUSION Acute leukemia clinical research disparities are substantial and driven by structural trial enrollment barriers at CCCs. Real-time CCC access and enrollment monitoring is needed to better align research participation with local populations.

Abstract Introduction Race-ethnic disparities in clinical trial enrollment have the potential to bias findings, limit generalizability, misdirect drug development, and reduce equitable access to novel therapy. The degree to which such disparities exist within acute myeloid leukemia (AML) North American cooperative group trials, biobanks, and correlative studies remain unclear, as are the factors that influence biobank and correlative study participation among trial enrollees. In addition, the National Cancer Institute's (NCI) mandate for Comprehensive Cancer Centers (CCC) to designate catchment areas has not been explored as a mechanism through which AML enrollment disparities can be addressed. Methods We analyzed enrollment data from the 9 Alliance/CALGB AML treatment trials, 2 biobank protocols, and 2 correlative studies active from 1998-2013 and with published results. Trial enrollees could consent to biobank and/or correlative study participation. We compared participation rates of United States (US) enrollees for the mutually exclusive racial-ethnic groups of non-Hispanic (NH)-white, NH-Black, NH-Asian, NH-Native American, and Hispanic using X 2 testing, with NH-white as the comparator and reporting odds ratios (OR) and 95% confidence intervals (CI). Rates were adjusted by national incidence according to the Surveillance, Epidemiology, and End Results program and the US Census. Testing was repeated for the 55% of participants enrolled at 15 NCI CCCs recruiting ≥10 patients, where incidence was adjusted for catchment area size and demographics. Logistic regression models, clustered by trial, were performed to assess the following predictors for biobank and correlative study participation among trial enrollees: race-ethnicity (NH-white vs non-white), site type (CCC status), age (10-year increments), sex, neighborhood urbanity (urban vs rural) and poverty (&lt;20% vs ≥20% below poverty line) by zip code, and distance from site (10-mile increments). Results There were 3041 trial enrollees at US sites; participant characteristics and demographics by race-ethnicity are shown in Table 1. 93.9% of patients participated in a biobanking study and 60.0% in a correlative study. National incidence adjusted enrollment odds by race-ethnicity are shown in the Figure (top); NH-Black, NH-Asian, and Hispanic persons were enrolled at significantly lower rates than NH-whites; NH-Native American enrollment was significantly higher. Enrollment odds were even lower for NH-Black, NH-Asian, and Hispanic enrollees at CCC sites when adjusted by catchment area incidence (Figure; bottom). Among trial enrollees, there were no univariable predictors of biobank participation, however, male sex (OR 1.12; 95% CI 1.01, 1.37; p=0.04) and NH-white race-ethnicity (OR 1.33; 95% CI 1.12,1.57; p&lt;0.001) were associated with correlative study participation. Multivariable models of correlative study participation, with predictors selected based on univariable significance, are shown in Table 2 for all trial enrollees and when restricted to biobank enrollees; in both cases, NH-white race predicted participation. Conclusions Across 15 years of AML cooperative group studies, there were several enrollment disparities by race-ethnicity, which were more pronounced at CCC sites. Over 90% of trial enrollees participated in biobanking, with no race-ethnic differences seen. However, correlative study participation among trial enrollees was higher for NH-whites. Taken together, these data suggest that efforts should focus on increasing trial and correlative study participant diversity-but not biobanking-within NCI-designated CCC catchment areas. Reasonable next steps include identifying key structural, provider, and patient-based barriers to trial and correlative study participation at CCC sites and developing inclusive, multilevel interventions to address them. Figure 1 Figure 1. Disclosures Eisfeld: Karyopharm (spouse): Current Employment. Stock: Pfizer: Consultancy, Honoraria, Research Funding; amgen: Honoraria; agios: Honoraria; jazz: Honoraria; kura: Honoraria; kite: Honoraria; morphosys: Honoraria; servier: Honoraria; syndax: Consultancy, Honoraria; Pluristeem: Consultancy, Honoraria. Stone: AbbVie Inc, Actinium Pharmaceuticals Inc, Aprea Therapeutics, BerGenBio ASA, ElevateBio, Foghorn Therapeutics, GEMoaB, GlaxoSmithKline, Innate Pharma, Syndax Pharmaceuticals Inc, Syros Pharmaceuticals Inc, Takeda Oncology: Other: Advisory Committee; Agios Pharmaceuticals Inc, Novartis;: Research Funding; ACI Clinical, Syntrix Pharmaceuticals, Takeda Oncology: Other: Data Safety & Monitoring. DeAngelo: Abbvie: Research Funding; Blueprint: Research Funding; Takeda: Consultancy; Autolus: Consultancy; Forty-Seven: Consultancy; Incyte: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Servier: Consultancy; Amgen: Consultancy; Agios: Consultancy; Glycomimetrics: Research Funding. Byrd: Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria.

Abstract Introduction According to population-based Surveillance, Epidemiology and End Results (SEER) cancer registry data, approximately 40% of adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) in the United States (U.S.) are Hispanic and 7% are Black and both Hispanic and Black patients have significantly inferior outcomes relative to non-Hispanic Whites (NHW). CALGB 10403, a prospective Phase II clinical trial conducted by the U.S. Intergroup, demonstrated the feasibility of delivering a pediatric-inspired ALL regimen to newly diagnosed AYA ALL patients and found this approach to be superior to historical adult regimens (Stock et al. Blood 2019). In the current analysis, we evaluate enrollment patterns of Hispanic and Black AYAs on CALGB 10403 and compare survival relative to SEER estimates. Methods Demographics on AYAs (18-40 yrs) enrolled on CALGB 10403 (N=295 from 2007-2012) were supplemented with patient-reported education and socioeconomic status (SES) information. Data from the North American Association of Cancer Registries (NAACCR; 2013-2017) were used to evaluate U.S. country-wide ALL incidence (20-49 yrs) overall and among Hispanics, reported per U.S. state. SEER registries (2008-2012) provided racial/ethnic distribution and overall survival (OS) of AYA ALL (15-39 yrs). The distribution of OS was estimated using the Kaplan-Meier method and compared across racial/ethnic groups using log-rank tests. Results Relative to the U.S. AYA ALL population, CALGB 10403 included proportionally fewer Hispanics (41.7% vs. 16.3%, P &lt; 0.001); the distribution of blacks was similar (6.4% vs. 8.5%, P = 0.174). Demographics and ALL characteristics among CALGB 10403 enrollees demonstrated no significant differences in age, sex, cytogenetics, or BMI by race/ethnicity; however, Black AYAs were more likely to have T-ALL, and Hispanic patients were more likely to have Ph-like B-ALL and rearrangements in CRLF2. Hispanic and Black patients reported lower household yearly income, and Black patients had less educational attainment. In order to explore reasons for disproportionately low Hispanic enrollment on CALGB 10403, we calculated the proportion of Hispanic AYAs with ALL relative to the AYA ALL incidence across U.S. states using NAACCR data and compared this with the geographical distribution of CALGB 10403 enrollments. The incidence of AYA ALL across U.S. states is represented in Fig 1A and the proportion of Hispanic AYA ALL patients in Fig 1B. The states with highest proportion of Hispanic patients included CA, TX, and NM, followed by AZ, CO, FL, and NJ. Although CALGB 10403 enrolled patients in 31 U.S. states, the trial did not open in TX or FL. The enrollments numbers were highest across the Mid-Western U.S., with only 47/295 (15.9%) of enrollments coming from the seven states with a high proportion of Hispanic AYA ALL patients (Fig 1C). The 3-yr event-free survival (EFS) and OS for the total CALGB 10403 cohort were 59.1% (53.1%, 65.75%) and 73.5% (68.1%, 79.4%), respectively. Per protocol completion of therapy was highest in Hispanics (75%), relative to Black (64%) and NHW patients (56%), P=0.049. Overall survival among CALGB 10403 participants differed significantly across race/ethnicity (Fig 2), with superior OS experienced by Hispanic patients and inferior OS by Black patients (P= 0.021). These clinical trial results differ from SEER estimates, where both Hispanic and Black patients experience worse OS relative to NHW (Fig 2). Conclusions This in-depth analysis of racial/ethnic enrollments and outcomes on CALGB 10403 uncovered findings that may translate across clinical trials beyond AYA ALL. Importantly, our data suggest that closer matching of trial site selection to geographical racial/ethnic disease incidence may improve minority enrollments on multi-center clinical trials. Relative to NHW, Hispanic patients had superior survival despite having higher rates of Ph-like ALL, indicating that clinical trial participation may mitigate racial/ethnic survival disparities seen in population-based data. Finally, we saw no improvement in trial outcomes among Black AYAs; a deeper understanding of the biological leukemia underpinnings and barriers to successful outcomes would aid future efforts at improving survival across racial/ethnic groups. Figure 1 Figure 1. Disclosures Muffly: Pfizer, Amgen, Jazz, Medexus, Pfizer: Consultancy; Astellas, Jasper, Adaptive, Baxalta: Research Funding; Adaptive: Honoraria, Other: fees for non-CME/CE services: , Research Funding. Advani: Abbvie: Research Funding; Macrogenics: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunogen: Research Funding; Pfizer: Honoraria, Research Funding; OBI: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Tallman: NYU Grand Rounds: Honoraria; Syros: Membership on an entity's Board of Directors or advisory committees; Kura: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Litzow: Omeros: Other: Advisory Board; Jazz: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Foster: Macrogenics: Research Funding; Rafael Pharmaceuticals: Research Funding; Macrogenics: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Bellicum Pharmaceuticals: Research Funding. Larson: Gilead: Research Funding; Epizyme: Consultancy; Astellas: Consultancy, Research Funding; Rafael Pharmaceuticals: Research Funding; CVS/Caremark: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Cellectis: Research Funding.

AbstractBackgroundAdipocyte-derived adiponectin may play a role in the host inflammatory response to cancer. We examined the association of plasma adiponectin with the density of tumor-infiltrating lymphocytes (TILs) in colon cancers and with vitamin D, clinicopathological features, and patient survival.MethodsPlasma adiponectin and 25-hydroxyvitamin D [25(OH)D] were analyzed by radioimmunoassay in 600 patients with stage III colon cancer who received FOLFOX-based adjuvant chemotherapy (NCCTG N0147 [Alliance]). TIL densities were determined in histopathological sections. Associations with disease-free survival (DFS), time to recurrence, and overall survival were evaluated by multivariable Cox regression adjusting for potential confounders (ie, body mass index, race, TILs, and N stage). All statistical tests were 2-sided.ResultsWe found a statistically significant reduction in adiponectin, but not 25(OH)D, levels in tumors with high vs low TIL densities (median = 6845 vs 8984 ng/mL; P = .04). A statistically significant reduction in adiponectin was also observed in obese (body mass index &gt;30 kg/m2) vs nonobese patients (median = 6608 vs 12 351 ng/mL; P &lt; .001), in men vs women (median = 8185 vs 11 567 ng/mL; P &lt; .001), in Blacks vs Whites or Asians (median = 6412 vs 8847 vs 7858 ng/mL; P &lt; .03), and in those with fewer lymph node metastases (N1 vs N2: median = 7768 vs 9253 ng/mL; P = .01). Insufficiency of 25(OH)D (&lt;30 ng/mL) was detected in 291 (48.5%) patients. In multivariable analyses, neither adiponectin nor 25(OH)D were associated with a statistically significant difference in DFS, overall survival , or time to recurrence in models adjusted for potential confounders. We found a statistically significant association of TILs with prognosis, yet no such interaction was observed for the association of adiponectin with TILs for DFS.ConclusionsLower circulating adiponectin levels were associated with a statistically significant increase in TIL densities in colon cancers, indicating an enhanced antitumor immune response. In contrast to TILs, neither adiponectin nor 25(OH)D was independently prognostic.

Abstract Overexpression of B-cell leukemia/lymphoma 2 (BCL2) renders acute myeloid leukemia (AML) cells resistant to chemotherapy and has been associated with unfavorable outcomes. Oblimersen (G3139) is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 BCL2 codons. In a phase 1 study of AML patients treated with G3139, cytarabine, and daunorubicin induction with cytarabine consolidation, no antisense-related toxicity was reported, and BCL2 downregulation occurred in patients achieving complete remission. In this phase 3 trial, untreated older AML patients were randomized to cytarabine (100 mg/m2 per day on days 4-10) and daunorubicin (60 mg/m2 per day on days 4-6) followed by cytarabine consolidation (2000 mg/m2 per day on days 4-8) with (arm A) or without (arm B) G3139 (7 mg/m2 per day on days 1-10 [induction] or days 1-8 [consolidation]). A total of 506 patients were enrolled. No differences in toxicity were observed between arms. Estimated overall survival (OS) at 1 year was 43% for arm A and 40% for arm B (1-sided log rank P = .13), with no differences in disease-free (DFS; P = .26) or event-free survival (P = .80). Subgroup analyses showed patients age &lt;70 years in arm A had improved OS by 1 month vs those in arm B (P = .04), and patients with secondary AML in arm A had better DFS vs those in arm B (P = .04). We conclude that addition of G3139 to chemotherapy failed to improve outcomes of older AML patients. However, more effective means of inhibiting BCL2 are showing promising results in combination with chemotherapy in AML. This trial was registered at www.clinicaltrials.gov as #NCT00085124.

3591 Background: Adiponectin is a peptide hormone exclusively secreted by adipocytes that plays a role in immune regulation and in the host inflammatory response to cancer. We examined postsurgical adiponectin levels in relationship to tumor infiltrating lymphocytes (TILs), clinicopathological features, vitamin D status, and patient survival in participants in a phase 3 trial of adjuvant chemotherapy. Methods: Plasma adiponectin and 25-hydroxyvitamin D [25(OH)D] were analyzed by radioimmunoassay in 600 patients with stage III colon carcinoma who received adjuvant FOLFOX +/- cetuximab. TIL densities were determined at light microscopy in routine histopathological sections. The associations between adiponectin and 25(OH)D, TILs, other factors were evaluated by Fisher’s Exact, Chi-squared, t-test, and Kruskal-Wallis tests where appropriate. The association between adiponectin or 25(OH)D with disease-free survival (DFS), time to recurrence (TTR) and overall survival (OS) were evaluated by multivariable Cox regression, adjusting for body mass index (BMI), race, T, N stage, performance status, tumor location, TILs, BRAF/KRAS, and mismatch repair status. Results: A statistically significant and inverse association between adiponectin level and BMI was observed with lower levels found with obesity (BMI > 30 kg/m2) [p < 0.001]. The level of adiponectin was significantly lower in men vs women (p < 0.001), in blacks vs whites or Asians (p < 0.032), and in patients with fewer regional lymph node metastases (N1 vs N2 stage, p = 0.011). A significantly lower level of adiponectin was found in patients whose tumors had high vs low TIL densities (p = 0.040), but was unrelated to 25(OH)D. Insufficiency of 25(OH)D ( < 30 ng/ml) was detected in 291 (49%) of patients and was not associated with TILs. By multivariable analysis, adiponectin was not associated significantly with patient DFS (HRadj= 0.98, 95% CI 0.74-1.29, padj= 0.88) nor with OS nor time-to-recurrence (TTR). TIL densities were significantly prognostic, but 25(OH)D was not (DFS: HRadj= 1.12, 95% CI 0.85-1.47, padj= 0.44). No significant interaction was observed for adiponectin with TILs for the association with DFS. Conclusions: Lower adiponectin levels were associated with significantly increased TIL densities in colon cancers, indicating an enhanced anti-tumor immune response. In contrast to TILs, adiponectin was not independently associated with patient outcome. Nearly one-half of stage III patients were vitamin D insufficient, although 25(OH)D was not prognostic.

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.