Histologic subtype and response to immune checkpoint inhibitor (ICI) therapy in advanced urothelial cancer (aUC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 495-495
Author(s):  
Natalie J. Miller ◽  
Ali Raza Khaki ◽  
Leonidas Nikolaos Diamantopoulos ◽  
Mehmet Asim Bilen ◽  
Victor Sacristan Santos ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Routine Practice ◽  
Histologic Subtype ◽  
Tract Cancer ◽  
Kaplan Meier ◽  
Urinary Tract Cancer ◽  
Tract Disease ◽  
Histologic Types

495 Background: Urinary tract cancer can be pure urothelial carcinoma (PUC) or variant UC (VUC, defined here as pure non-UC or mixed UC + non-UC); VUC often has a worse prognosis. Little is known about outcomes for patients (pts) with VUC receiving ICI. We hypothesized that VUC does not compromise ICI efficacy in pts with aUC. Methods: We performed a retrospective cohort study across 18 institutions. Demographic, clinicopathologic, treatment and outcomes data was collected for pts with aUC who received ICI. Pts were stratified to PUC vs VUC; VUC was further divided by histologic subtype, i.e. squamous, neuroendocrine (NE), etc. We compared overall response rate (ORR) using logistic regression, progression free survival (PFS) and overall survival (OS) using Kaplan-Meier and Cox proportional hazards; p<0.05 was significant. Results: 519 consecutive pts were identified; 405, 414 and 411 included in ORR, OS and PFS analyses, respectively. Demographics included mean age 69, 27% female, 66% ever smokers, 15% upper tract disease, 54% with extirpative surgery. ORR to ICI between pts with PUC and VUC was comparable (both 28%, p=0.86) without significant differences for individual subtypes vs PUC. Median OS for pts with PUC was 11.0 vs 9.9 mo for VUC (p=0.45), but only 3.7 mo for those with NE features (HR=3.01 [95% CI 1.63-5.57] vs PUC, p<0.001). Median PFS was 4.1 vs 5.2 mo for PUC vs VUC (p=0.46) and 2.8 mo for NE (HR=1.85 [95% CI 0.94-3.61] vs PUC, p=0.07). Conclusions: ORR to ICI and OS were comparable across histologic types; however, OS was shorter for tumors with NE features. VUC should not exclude pts from receiving ICI in routine practice and clinical trials.[Table: see text]

scholarly journals Days gained response discriminates treatment response in patients with recurrent glioblastoma receiving bevacizumab-based therapies

2020 ◽  
Vol 2 (1) ◽  
Author(s):  
Kyle W Singleton ◽  
Alyx B Porter ◽  
Leland S Hu ◽  
Sandra K Johnston ◽  
Kamila M Bond ◽  
...  
Keyword(s):  
Treatment Response ◽  
Proportional Hazards ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Recurrent Glioblastoma ◽  
Response To Therapy ◽  
Cytotoxic Therapy ◽  
Kaplan Meier ◽  
Recurrent Gbm

Abstract Background Accurate assessments of patient response to therapy are a critical component of personalized medicine. In glioblastoma (GBM), the most aggressive form of brain cancer, tumor growth dynamics are heterogenous across patients, complicating assessment of treatment response. This study aimed to analyze days gained (DG), a burgeoning model-based dynamic metric, for response assessment in patients with recurrent GBM who received bevacizumab-based therapies. Methods DG response scores were calculated using volumetric tumor segmentations for patients receiving bevacizumab with and without concurrent cytotoxic therapy (N = 62). Kaplan–Meier and Cox proportional hazards analyses were implemented to examine DG prognostic relationship to overall (OS) and progression-free survival (PFS) from the onset of treatment for recurrent GBM. Results In patients receiving concurrent bevacizumab and cytotoxic therapy, Kaplan–Meier analysis showed significant differences in OS and PFS at DG cutoffs consistent with previously identified values from newly diagnosed GBM using T1-weighted gadolinium-enhanced magnetic resonance imaging (T1Gd). DG scores for bevacizumab monotherapy patients only approached significance for PFS. Cox regression showed that increases of 25 DG on T1Gd imaging were significantly associated with a 12.5% reduction in OS hazard for concurrent therapy patients and a 4.4% reduction in PFS hazard for bevacizumab monotherapy patients. Conclusion DG has significant meaning in recurrent therapy as a metric of treatment response, even in the context of anti-angiogenic therapies. This provides further evidence supporting the use of DG as an adjunct response metric that quantitatively connects treatment response and clinical outcomes.

Thromboembolism (TE) in patients (pts) with bladder cancer treated with checkpoint inhibitors (CPIs).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5042-5042
Author(s):  
Iris Yeong- Fung Sheng ◽  
Shilpa Gupta ◽  
Chandana A. Reddy ◽  
Dana E Angelini ◽  
Pauline Funchain ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Upper Limb ◽  
Proportional Hazards ◽  
Checkpoint Inhibitors ◽  
Cleveland Clinic ◽  
Cox Proportional Hazards ◽  
High Risk Population ◽  
Kaplan Meier ◽  
Tract Disease ◽  
The Impact

5042 Background: Most pts with bladder cancer will be treated with immunotherapy. There is concern for increased TE risk with CPIs in this already high risk population. We present the first analysis of the incidence and outcomes of venous (VTE) and arterial (ATE) thromboembolism in pts with bladder cancer treated with CPIs. Methods: Consecutive pts with bladder cancer treated with CPIs at the Cleveland Clinic from 1/2015 to 12/2019 were identified and TE events noted. Overall survival (OS) was estimated using Kaplan-Meier method and the impact of VTE on OS was evaluated using Cox proportional hazards regression. Results: Of 274 pts, 72% were men (median age 73.3 years, 89% white), 82% had pure UC, 92% had lower tract disease, and 67% had a Bajorin score ≥1 (median KPS 90, 61% visceral metastases), 59% had prior systemic therapy (median 1, range 0-4) and 36% had prior TE (14% ATE, 19% VTE, 0.4% both). At CPI initiation, 24% were on antiplatelet therapy, and 15% on therapeutic anticoagulation. CPI (median doses 5, range 8.5-59) included: 40% atezolizumab, 3% nivolumab, 57% pembrolizumab. VTE occurred in 14% (n = 37), including 8% DVT, 4% PE, 2% both. DVT locations were 56% lower limb, 26% upper limb, 15% visceral vein, 4% visceral+upper limb. 2% (n = 5) had ATE (1% CVA, 0.4% visceral, 0.4% left subclavian). 92% of VTE and all ATE occurred within 6 months of CPI initiation. The incidence of TE was 10.9% (95%CI 6.6%—15.1%) at 6 months and 19.8% (95%CI 13.3%-26.4%) at 12 months. 82% of VTE (mean 6 days) and all ATE (mean 5 days) resulted in hospitalization. Multivariate analysis showed TE (HR 2.296, 95%CI 1.451-3.632, p = 0.0004), Bajorin score 1 (HR 1.490, 95%CI 1.036-2.142, p = 0.0315), and Bajorin score 2 (HR 3.50, 95%CI 2.14-5.74, p < 0.0001) were independently associated with worse OS. Conclusions: CPIs in bladder cancer pts are associated with a high TE risk, especially within six months of initiation. TE is associated with worsened survival. Further investigation into the risk factors for CPI-associated TE is needed to identify if benefits exist from thromboprophylaxis.

Prognostic Impact of Laterality in Malignant Ovarian Germ Cell Tumors

2011 ◽  
Vol 21 (2) ◽  
pp. 257-262 ◽  
Author(s):  
Haider Mahdi ◽  
Sanjeev Kumar ◽  
Shelly Seward ◽  
Assaad Semaan ◽  
Ramesh Batchu ◽  
...  
Keyword(s):  
Germ Cell ◽  
Proportional Hazards ◽  
Germ Cell Tumors ◽  
Cox Proportional Hazards ◽  
Prognostic Impact ◽  
Advanced Stage ◽  
Kaplan Meier ◽  
Stage Disease ◽  
Histologic Types ◽  
Mixed Germ Cell Tumors

Objective:To compare the survival of patients with bilateral versus unilateral malignant ovarian germ cell tumors (OGCT).Methods:Patients with a diagnosis of OGCT were identified from the Surveillance, Epidemiology, and End Results Program for the period 1988 to 2006 and were divided into bilateral and unilateral subgroups. Only surgically treated patients were included. Histologic types were grouped into dysgerminoma, malignant teratoma, and mixed germ cell tumors with pure nondysgerminoma cell tumors. Statistical analysis using Wilcoxon rank sum test, Kaplan-Meier survival methods, and Cox proportional hazards regression model were performed.Results:In 1529 patients with OGCT, 1463 (95.7%) were unilateral and 66 (4.3%) were bilateral. Bilaterality was more common with dysgerminomas (6.5%) and mixed germ cell tumors with pure nondysgerminoma cell tumors (6.25%) than with immature teratomas (1.7%),P< 0.001. Most OGCT (67.3%) were stage I. Bilateral OGCT were more likely than unilateral tumors to be associated with advanced-stage disease (FIGO III and IV, 41% vs 20%,P< 0.04). Overall 5-year survival was 93.6% for unilateral OGCT and 80.7% in bilateral OGCT,P< 0.001. In multivariate analysis, bilaterality was not an independent predictor of survival when controlling for age, histology, stage, and surgical staging (hazard ratio, 1.3; 95% confidence interval, 0.7-2.5;P= 0.40).Conclusions:Compared with unilateral tumors, bilateral OGCT are more often associated with advanced-stage disease, high-risk histology, and poor survival. When other prognostic factors are accounted for, bilaterality was not an independent prognostic predictor of survival.

scholarly journals Does Very Poor Performance Status Systematically Preclude Single Agent Anti-PD-1 Immunotherapy? A Multicenter Study of 35 Consecutive Patients

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1040
Author(s):  
Valérie Gounant ◽  
Michael Duruisseaux ◽  
Ghassen Soussi ◽  
Sylvie Van Hulst ◽  
Olivier Bylicki ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Poor Performance ◽  
Cox Proportional Hazards ◽  
Poor Performance Status ◽  
Low Grade ◽  
Kaplan Meier ◽  
Cox Proportional Hazards Models

Anti-PD-1 antibodies prolong survival of performance status (PS) 0–1 advanced non-small-cell lung cancer (aNSCLC) patients. Their efficacy in PS 3–4 patients is unknown. Conse- cutive PS 3–4 aNSCLC patients receiving compassionate nivolumab were accrued by 12 French thoracic oncology departments, over 24 months. Overall survival (OS) was calculated using the Kaplan-Meier method. Prognostic variables were assessed using Cox proportional hazards models. Overall, 35 PS 3–4 aNSCLC patients (median age 65 years) received a median of 4 nivolumab infusions (interquartile range [IQR], 1–7) as first- (n = 6) or second-line (n = 29) therapy. At a median of 52-month follow-up (95%CI, 41–63), 32 (91%) patients had died. Median progression-free survival was 2.1 months (95%CI, 1.1–3.2). Median OS was 4.4 months (95%CI, 0.5–8.2). Overall, 20% of patients were alive at 1 year, and 14% at 2 years. Treatment-related adverse events occurred in 8/35 patients (23%), mostly of low-grade. After adjustment, brain metastases (HR = 5.2; 95%CI, 9–14.3, p = 0.001) and <20 pack-years (HR = 4.8; 95%CI, 1.7–13.8, p = 0.003) predicted worse survival. PS improvement from 3–4 to 0–1 (n = 9) led to a median 43-month (95%CI, 0–102) OS. Certain patients with very poor general condition could derive long-term benefit from nivolumab salvage therapy.

Evaluation of brain metastasis in JAVELIN Renal 101: Efficacy of avelumab + axitinib (A+Ax) versus sunitinib (S).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 687-687 ◽  
Author(s):  
Eric Jonasch ◽  
Elshad Hasanov ◽  
Robert J. Motzer ◽  
Subramanian Hariharan ◽  
Toni K. Choueiri ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Brain Metastases ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Hazards Model ◽  
Kaplan Meier ◽  
Disease Site

687 Background: Patients (pts) with brain metastasis from renal cell carcinoma (RCC) have poor prognosis and are often excluded from randomized registrational trials. The phase 3 JAVELIN Renal 101 trial (NCT02684006) demonstrated significantly improved progression-free survival (PFS) for A+Ax vs S in pts with advanced RCC (Motzer NEJM 2019). The activity of A+Ax in pts with brain metastasis enrolled in JAVELIN Renal 101 is presented. Methods: PFS was compared between treatment arms for the subgroup of pts randomized in JAVELIN Renal 101 with brain metastases at enrollment (pts with brain disease site prior to randomization by blinded independent central review [BICR] or by investigator assessment). PFS time was summarized per BICR assessment by treatment arm using the Kaplan-Meier method. The Cox proportional hazards model was fitted to compute the hazard ratio (HR) and the corresponding CI. In addition, time to brain metastasis was assessed for pts without brain metastasis by BICR at enrollment after treating death as a competing risk. Results: Of all randomized pts (A+Ax arm, N=442; S, N=444), 23 in each arm (5.2%) had asymptomatic brain metastasis at enrollment; of these, pts assigned to A+Ax had a PFS of 4.9 mo (95% CI: 1.6, 5.7) vs 2.8 mo (95% CI: 2.3, 5.6) for pts assigned to S (HR: 0.90; 95% CI: 0.43, 1.88). Among pts without brain metastasis at enrollment, 8 pts on the A+Ax arm and 10 on the S arm developed brain metastasis during the trial, based on BICR assessment; 17/18 occurred ≤12 mo from randomization. The cumulative incidence rate of brain metastasis at 18 mo was 2% (95% CI: 0.6, 3.3) for the A+Ax arm and 3% (95% CI: 1.1, 4.8) for the S arm. Conclusions: In this post hoc exploratory analysis of JAVELIN Renal 101, the observed PFS among pts with brain metastasis at enrollment was similar between the two arms, with HR and median PFS numerically favoring A+Ax. Pts on the S arm had a numerically higher incidence of new brain metastases on trial. Outcomes are poor in pts with advanced RCC and brain metastasis; more effective treatments are needed. Clinical trial information: NCT02684006.

Stereotactic Radiosurgery for Neurofibromatosis 2—Associated Vestibular Schwannomas

Neurosurgery ◽  
2013 ◽  
Vol 74 (3) ◽  
pp. 292-301 ◽  
Author(s):  
Grant W. Mallory ◽  
Bruce E. Pollock ◽  
Robert L. Foote ◽  
Matthew L. Carlson ◽  
Colin L. Driscoll ◽  
...  
Keyword(s):  
Tumor Volume ◽  
Proportional Hazards ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Nerve Function ◽  
Facial Nerve Function ◽  
Free Survival ◽  
Kaplan Meier

Abstract BACKGROUND: Management of neurofibromatosis type 2 (NF2)—associated vestibular schwannomas (VSs) remains controversial. Stereotactic radiosurgery (SRS) with conventional dosing is less effective for NF2-related VS compared with sporadic lesions. OBJECTIVE: To evaluate optimal SRS dose parameters for NF2-related VS and to report long-term outcomes. METHODS: A prospective database was reviewed and outcome measures, including radiographic progression, American Academy of Otolaryngology—Head and Neck Surgery hearing class, and facial nerve function, were analyzed. Progression-free survival was estimated with Kaplan-Meier methods. Associations between tumor progression and radiosurgical treatment parameters, tumor volume, and patient age were explored with the use of Cox proportional hazards regression. RESULTS: Between 1990 and 2010, 26 patients with 32 NF2-related VSs underwent SRS. Median marginal dose and tumor volume were 14 Gy and 2.7 cm3, respectively. Twenty-seven tumors (84%) showed no growth (median follow-up, 7.6 years). Kaplan-Meier estimates for 5- and 10-year progression-free survival were 85% and 80%, respectively. Cox proportional hazards demonstrated a significant inverse association between higher marginal doses and tumor progression (hazard ratio, 0.49; 95% confidence interval, 0.17-0.92; P = .02). Audiometric data were available in 30 ears, with 12 having class A/B hearing before SRS. Only 3 maintained serviceable hearing at the last follow-up. Four underwent cochlear implantation. Initially, 3 achieved open-set speech recognition, although only 1 experienced long-term benefit. Facial nerve function remained stable in 50% of cases. CONCLUSION: Higher marginal doses than commonly prescribed for sporadic VS were associated with improved tumor control in patients with NF2. Hearing outcomes were poor even when contemporary reduced marginal doses were used. However, SRS allows an anatomically preserved cochlear nerve and may permit hearing rehabilitation with cochlear implantation. Further consideration should be given to optimum dosing to achieve long-term control while maximizing functional outcomes.

Biomarker analysis from a phase III trial (GOLD) of dovitinib (Dov) versus sorafenib (Sor) in patients with metastatic renal cell carcinoma after one prior VEGF pathway–targeted therapy and one prior mTOR inhibitor therapy.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 473-473 ◽  
Author(s):  
Bernard J. Escudier ◽  
Camillo Porta ◽  
Matthew Squires ◽  
Cezary Szczylik ◽  
Christian K. Kollmannsberger ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Phase Iii ◽  
Plasma Samples ◽  
Plasma Biomarkers ◽  
Kaplan Meier ◽  
Cox Proportional Hazards Models ◽  
Biomarker Analysis ◽  
Line Setting

473 Background: In the GOLD trial, Dov did not improve progression-free survival (PFS) or overall survival (OS) over Sor. An exploratory objective of the study was to investigate plasma and tumor biomarkers to predict outcome. Methods: Plasma samples were obtained longitudinally throughout the study, and biomarkers were assessed by immunoassay. Primary archival tumor samples were assessed by immunohistochemistry. Log-rank tests, stratified by baseline MSKCC risk group, for difference in Kaplan-Meier curves between biomarker category (low/high based on </≥ median baseline values) within treatment arm were performed. Hazard ratios (HRs) were estimated from Cox proportional hazards models. Results: Plasma samples were available from 561 patients (Dov, n = 281; Sor, n = 280), and tumor samples were available from 341 patients (Dov, n = 181; Sor, n = 160). Baseline plasma biomarker levels were not predictive of Dov or Sor PFS or OS. However, strong prognostic effects, particularly for OS, were observed. High baseline cKIT and low baseline FGF2, HGF, PlGF, sVEGFR1, VEGFA, and VEGFD were associated with better OS for both Dov and Sor (Table). Changes from baseline in a number of plasma biomarkers were observed following treatment with Dov and Sor, consistent with VEGFR/FGFR inhibitory effects. Prognostic effects were also observed for low FGFR2 (PFS) and low FGF2 (OS) expression in archival tumors. Conclusions: Baseline plasma biomarkers are prognostic but not predictive in the third-line setting. Clinical trial information: NCT01223027. [Table: see text]

Association of early bone metastases and outcomes of the bone predominant metastatic urothelial carcinoma (BP mUC) phenotype.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16016-e16016
Author(s):  
Ariel Ann Nelson ◽  
Matthew David Wright ◽  
Ali Raza Khaki ◽  
Leonidas Nikolaos Diamantopoulos ◽  
Ravi Kumar Kyasaram ◽  
...  
Keyword(s):  
Bone Metastases ◽  
Proportional Hazards ◽  
De Novo ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
First Line ◽  
Kaplan Meier ◽  
Platinum Based Chemotherapy ◽  
Metastatic Setting ◽  
Line Setting

e16016 Background: Prior analyses demonstrated worse outcomes with the BP mUC clinical phenotype. UC molecular subtypes that may correlate with the BP phenotype have been defined, however molecular subtyping is not a readily available standard practice. We hypothesized that BP mUC has worse prognosis vs. non-BP (NBP) mUC and evaluated patient (pt) characteristics associated with the mUC subtype, responses and outcomes. Methods: We searched the electronic medical record (EMR) to identify pts with mUC who received systemic therapy in the metastatic setting. Demographic, clinicopathologic, treatment (trt), response, progression-free survival (PFS), overall survival (OS ) from start of first line trt. Imaging was reviewed to identify NBP or BP disease. Logistic regression, Cox proportional-hazards and Kaplan-Meier analyses were performed. Results: 149 mUC pts were identified (64% male, 68% smokers ), median age at 1st line trt was 68 years. 70% had de-novo mets, 46% to lung and 27% to liver. 22% of pts were BP, of these, 36% were de-novo metastatic. In non- de-novo metastatic pts (70% of pts), first progression of disease to bone was associated with development of the BP phenotype (OR = 30.46, 95% CI 6.37 to 145.61; p < 0.0001). BP pts had higher rate of death (HR = 2.28, 95% CI 1.45 to 3.58, p = 0.0004), shorter PFS from 1st line trt, (11.7 vs 14.9 weeks, p = 0.032) as well as shorter OS from 1st line trt (24.6 vs 56.6 weeks, p = 0.002) compared to NBP pts. There was no difference in PFS between BP and NBP groups for pts treated with 1st line platinum-based chemotherapy (11.8 vs 18.3 weeks, p = 0.091) or for BP pts treated with 1st line immunotherapy vs platinum-based chemotherapy (11.71 vs 11.86 weeks, p = 0.135). Conclusions: Early bone metastases are associated with the development of the BP metastatic phenotype. BP pts have worse PFS and OS from 1st line trt compared to NBP pts. PFS remains poor when BP pts are treated with either platinum-based chemotherapy or immunotherapy in the first line setting. Imaging to determine the presence of bone metastases may routinely be pursued and careful attention paid on follow up imaging. Clinical trials and prospective registries focusing on efficacy endpoints for BP mUC are needed.

Sunitinib in patients with pancreatic neuroendocrine tumors (panNETs): Exploratory pharmacogenomic analyses.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 255-255
Author(s):  
Nicola Fazio ◽  
Jean-Francois Martini ◽  
Adina-Emilia Croitoru ◽  
Michael Schenker ◽  
Sherry Li ◽  
...  
Keyword(s):  
Protein Transport ◽  
Proportional Hazards ◽  
Objective Response ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Nucleotide Polymorphisms ◽  
Exact Test ◽  
Kaplan Meier ◽  
Cox Proportional Hazards Models ◽  
Treatment Naïve

255 Background: In a phase IV trial (NCT01525550), median progression-free survival (PFS) was 13.2 mo in sunitinib-treated patients (pts) with well-differentiated panNETs. Objective response rate (ORR) was 24.5% and median overall survival (OS) was 37.8 mo. Exploratory analyses evaluated potential associations between single nucleotide polymorphisms (SNP) in genes involved in angiogenesis, protein transport or inflammatory response and clinical outcomes. Methods: Blood samples were genotyped using TaqMan assays for 12 SNPs previously associated with panNET risk, prognosis or drug effect. Associations between SNP and PFS or OS were assessed by comparing genotypes within treatment-naïve (TN), previously treated (PT) and combined groups, and within a genotype between treatment groups, using Kaplan-Meier analysis and Cox proportional hazards models. Fisher’s exact test was used for association between ORR and genotype. PFS and ORR were investigator-assessed. P values displayed are unadjusted and Bonferroni method was used for multiplicity adjustment. Results: 56 pts were genotyped: 25 TN and 31 PT. There were no significant associations between genotype and PFS or OS but there was a trend toward shorter PFS in pts with VEGFR1 rs9554320 C/A versus C/C (hazard ratio [HR] 1.78; 95% confidence interval [CI] 0.83–3.82; p = 0.117) and VEGFR1 rs9582036 A/C versus A/A (HR 1.88; 95% CI 0.9–3.93; p = 0.102). The genotypes G/G of VEGFA rs2010963 (p = 0.041) , G/G of VEGFA rs833068 (p = 0.041) and A/C of VEGFR1 rs9582036 (p = 0.046) showed a trend toward a higher ORR in the PT versus TN group. Genotype T/T of VEGFR2 rs7692791 (p = 0.103) showed a trend toward to a lower ORR in the TN versus PT group. Higher ORR was associated with IL1B rs16944 G/A versus G/G (46.4% vs 4.5%; p = 0.001) in the combined group. Conclusions: Potential associations between ORR and VEGFA rs2010963 and rs833068, VEGFR1 rs9582036 and VEGFR2 rs7692791 were observed. IL1B rs16944 was significantly associated with ORR, consistent with the role of IL1B in panNET etiology and development. Most correlations were not significant after adjustment for multiplicity. Clinical trial information: NCT01525550.

Association of KRAS and BRAF mutations with progression-free survival (PFS) with second-line FOLFIRI +/- regorafenib in metastatic colorectal cancer (mCRC).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 196-196
Author(s):  
Federico Innocenti ◽  
Sara R. Selitsky ◽  
Joel S. Parker ◽  
James Todd Auman ◽  
Kelli Hammond ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Braf V600e ◽  
Second Line ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Angiogenic Therapy ◽  
Kaplan Meier ◽  
Significant Difference

196 Background: LCCC1029 was a 2:1 randomized phase II trial of 2nd-line FOLFIRI plus either regorafenib or placebo in mCRC. The addition of regorafenib improved PFS (median PFS 6.1 vs 5.3 mo, HR 0.73, 95% CI 0.53-1.01). However, the effect of somatic mutations on regorafenib activity has not been tested. Methods: We performed whole exome sequencing on archival primary tumor tissue and paired normal tissue in 85 patients of LCCC1029. We compared PFS and OS using Kaplan-Meier method and log-rank tests, and hazard ratios (HR) were estimated using Cox proportional hazards method. Results: Among the 85 subjects, 54 (64%) had tumors wild-type (WT) for KRAS and BRAF, 26 (31%) had tumors with KRAS mutations in exons 2-4, and 5 (6%) had tumors with BRAF V600E. The addition of regorafenib to FOLFIRI improved PFS in the KRAS/ BRAF WT subgroup (median PFS 8.0 vs 4.9 mo, HR 0.68, 95% CI 0.48-0.97, log-rank p=0.028), but not in the KRAS mutant subgroup (median PFS 6.8 vs 5.5 mo, HR 0.90, 95% CI 0.61-1.35, log-rank p=0.617) or the BRAF mutant subgroup (log-rank p=0.156). In all of these subgroups, the addition of regorafenib was not associated with significant difference in OS. BRAF V600E was prognostic and associated with significantly worse OS (median OS 8.4 vs 18.0 mo, HR 2.59, 95% CI 1.01-6.66, log-rank p=0.04). Conclusions: The addition of regorafenib to FOLFIRI improves PFS among the subgroup of patients with KRAS and BRAF dual WT CRC, but not among the KRAS mutant subgroup. These results indicate that the addition of anti-angiogenic therapy to second-line chemotherapy backbones may be more effective in KRAS/ BRAF WT tumors in particular. More confirmatory studies are needed to corroborate this finding.

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