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.

Outcomes of patients (pts) with metastatic renal cell carcinoma (mRCC) treated with pazopanib after progression on other targeted therapies (TT): A single-institution experience.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4615-4615
Author(s):  
Marc Ryan Matrana ◽  
Aditya V. Shetty ◽  
Bradley J. Atkinson ◽  
Lianchun Xiao ◽  
Paul G. Corn ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Kinase Inhibitor ◽  
Multivariable Analysis ◽  
Safety Data ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Kaplan Meier ◽  
Cox Proportional Hazards Models ◽  
Treatment Naïve ◽  
Metastatic Sites

4615 Background: Pazopanib is an approved multi-tyrosine kinase inhibitor that prolongs progression-free survival (PFS) compared to placebo in treatment-naive and cytokine-refractory mRCC. Outcomes and safety data on its use after TT are limited. Methods: We retrospectively reviewed pts with mRCC who received salvage pazopanib between 11/09-11/11. Kaplan-Meier method was used to estimate survival outcomes. PFS was calculated from start of pazopanib until progressive disease (PD) or death. Univariable and multivariable Cox proportional hazards models were fitted to evaluate associations of PFS with covariables. Results: 114 consecutive pts met inclusion criteria (median age 62.6 years, 66% males, 83% clear cell). All pts had PD after other TT (median # of prior TT 2, range 1-5; median time on prior TT 23.3 mos). 79% of pts had PD on sunitinib, 39% on sorafenib, 19% on temsirolimus, 59% on everolimus, and 23% on bevacizumab. 25% received prior chemotherapy and 16% received prior cytokines in addition to TT. 87% had prior nephrectomy. 11% had favorable-risk, 68% intermediate-risk, and 21% poor-risk per MSKCC criteria. 85 events (PD or death) occurred. Median OS was 17 mos (95% CI: 10.3-NA). Median PFS was 6.4 mos (95% CI: 4.5-9.5). By multivariable analysis, PFS was associated with male gender (HR=0.433, 95%CI: 0.269-0.696; p=0.0006), # of metastatic sites (HR=1.252; 95%CI: 1.04-1.503; p=0.016), hypertension exacerbation (HR=0.378; CI: 0.175-0.813; p=0.0128) and PS 2+ vs.0-1 (HR=2.067; CI: 1.243-3.437; p=0.0052). 58% discontinued pazopanib due to PD, 12% died of PD on treatment, and 11% discontinued pazopanib due to adverse events (AEs), mostly GI complaints or fatigue. There were no treatment related deaths. Common AEs included: fatigue (44%), diarrhea (29%), nausea/vomiting (15%), anorexia (14%), hypertension exacerbation (11%), hypothyroidism (11%), hand-foot skin reaction (9%), and increase LFTs (4%). 86% of AEs were grade 1/2. Conclusions: In this retrospective study, pazopanib demonstrated efficacy in mRCC following PD with other TT. AEs were mild/moderate and manageable.

Efficacy outcomes of nivolumab + cabozantinib versus pembrolizumab + axitinib in patients with advanced renal cell carcinoma (aRCC): Matching-adjusted indirect comparison (MAIC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4578-4578
Author(s):  
Bradley Alexander McGregor ◽  
Daniel M. Geynisman ◽  
Mauricio Burotto ◽  
Camillo Porta ◽  
Cristina Suarez Rodriguez ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Objective Response ◽  
Indirect Comparison ◽  
Progression Free Survival ◽  
Wald Test ◽  
Patient Characteristics ◽  
Cox Proportional Hazards ◽  
Published Data ◽  
Cox Proportional Hazards Models

4578 Background: Nivolumab in combination with cabozantinib (N+C) has demonstrated significantly improved progression-free survival (PFS), objective response rate (ORR), and overall survival (OS), compared with sunitinib as a first-line (1L) treatment for aRCC in the phase 3 CheckMate (CM) 9ER trial. As there are no head-to-head trials comparing N+C with pembrolizumab in combination with axitinib (P+A), this study compared the efficacy of N+C with P+A as 1L treatment in aRCC. Methods: An MAIC was conducted using individual patient data on N+C (N = 323) from the CM 9ER trial (median follow-up: 23.5 months) and published data on P+A (N = 432) from the KEYNOTE (KN)-426 trialof P+A (median follow-up: 30.6 months). Individual patients within the CM 9ER trial population were reweighted to match the key patient characteristics published in KN-426 trial, including age, gender, previous nephrectomy, International Metastatic RCC Database Consortium risk score, and sites of metastasis. After weighting, hazards ratios (HR) of PFS, duration of response (DoR), and OS comparing N+C vs. P+A were estimated using weighted Cox proportional hazards models, and ORR was compared using a weighted Wald test. All comparisons were conducted using the corresponding sunitinib arms as an anchor. Results: After weighting, patient characteristics in the CM 9ER trial were comparable to those in the KN-426 trial. In the weighted population, N+C had a median PFS of 19.3 months (95% CI: 15.2, 22.4) compared to a median PFS of 15.7 months (95% CI: 13.7, 20.6) for P+A. Using sunitinib as an anchor arm, N+C was associated with a 30% reduction in risk of progression or death compared to P+A, (HR: 0.70, 95% CI: 0.53, 0.93; P = 0.015; table). In addition, N+C was associated with numerically, although not statistically, higher improvement in ORR vs sunitinib (difference: 8.4%, 95% CI: -1.7%, 18.4%; P = 0.105) and improved DoR (HR: 0.79; 95% CI: 0.47, 1.31; P = 0.359). Similar OS outcomes were observed for N+C and P+A (HR: 0.99; 95% CI: 0.67, 1.44; P = 0.940). Conclusions: After adjusting for cross-trial differences, N+C had a more favorable efficacy profile compared to P+A, including statistically significant PFS benefits, numerically improved ORR and DoR, and similar OS.[Table: see text]

Outcomes of patients (pts) with metastatic renal cell carcinoma (mRCC) treated with pazopanib after progression on other targeted therapies (TT): Updated results.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 367-367
Author(s):  
Marc Ryan Matrana ◽  
Cihan Duran ◽  
Aditya Shetty ◽  
Lianchun Xiao ◽  
Bradley J. Atkinson ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Kinase Inhibitor ◽  
Clear Cell ◽  
Progression Free Survival ◽  
Median Number ◽  
Cox Proportional Hazards ◽  
Clinical Activity ◽  
Pancreatic Metastases ◽  
Cox Proportional Hazards Models ◽  
Treatment Naïve

367 Background: Pazopanib is an multi-tyrosine kinase inhibitor shown to prolong progression-free survival (PFS) compared to placebo in treatment-naive and cytokine-refractory mRCC. Outcomes and safety on its use after TT are limited. Methods: We retrospectively reviewed records of consecutive pts with mRCC who were treated with pazopanib between November 2009-November 2011 after having progressive disease (PD) with other TT. Radiographic response was assessed by a blinded radiologist using RECIST v1.1 criteria. PFS and overall survival (OS) were estimated by the Kaplan-Meier method. Hazard ratios (HR) were estimated by fitting univariable and multivariable Cox proportional hazards models to evaluate the association of PFS with patient co-variates. Results: 112 pts (median age 63 years, 67% male, 83% clear cell) met inclusion criteria. Median number of previous TT was 2 (range 1-5). 85 events (PD or death) occurred. 14 pts (12.5%) had a partial response. Median PFS was 5.7 months (95% CI: 4.3-8.9 months). PFS was significantly associated with male gender (HR=0.55; 95% CI: 0.34-0.87; p=0.011), clear-cell histology (HR=0.42; 95% CI: 0.24-0.74; p=0.0031), number of metastatic sites (HR= 1.26; 95% CI: 1.05-1.52; p=0.0123), pancreatic metastases (HR=0.40; 95% CI: 0.18-0.85;p=0.0185), Karnofsky PS< 80 (HR=2.07; 95% CI: 1.22-3.48; p=0.0062), and elevated LDH (HR=1.63; 95% CI: 1.03-2.573; p=0.035). Median OS was 16.9 months (95% CI: 10.3–21.9). 26% of pts were still receiving pazopanib at the time of analysis. 51% discontinued pazopanib due to PD and 12% died of PD on treatment. 11% discontinued pazopanib due to adverse events (AEs). There were no treatment related deaths. Common AEs included fatigue (43%), increase LFTs (34%), diarrhea (28%), nausea/vomiting (14%), anorexia (14%), hypertension exacerbation (12%), and hypothyroidism (11%). 89% of AEs were grade 1/2. Conclusions: Pazopanib demonstrated meaningful clinical activity in heavily pretreated pts with mRCC following PD with other TT. AEs were mild/moderate and manageable.

Association between rigors and overall survival (OS) in metastatic renal cell carcinoma (mRCC) patients treated with high-dose interleukin-2 (HD IL-2).

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 487-487
Author(s):  
Julia Anne Batten ◽  
Wolfram E. Samlowski ◽  
Kinjal Parikh ◽  
Arun Sendilnathan ◽  
Hilda Crispin ◽  
...  
Keyword(s):  
Overall Survival ◽  
Proportional Hazards ◽  
Objective Response ◽  
Interleukin 2 ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
High Dose ◽  
University Of Utah ◽  
Cox Proportional Hazards Models ◽  
Grade 3

487 Background: HD IL-2 is associated with an objective response rate of 16-20% with durability of response in select mRCC patients. HD IL-2 is also associated with significant toxicity including vascular leak syndrome and inflammatory side effects. Few predictive markers can identify patients likely to respond to HD IL-2. Methods: Patients treated with HD IL-2 at the University of Utah Huntsman Cancer Institute from 2000 to 2012 with clear cell mRCC were evaluated. Grade of toxicities during HD IL-2 treatment were collected based on provider documentation in the electronic health record. Rates of adverse events (AEs) and overall survival stratified grade 3 AEs were evaluated by Kaplan-Meier survival estimates and Cox proportional hazards models. All AEs were graded per common terminology criteria version 4. Grade 3 rigors were defined as severe rigors requiring opioids. Results: A total of 85 patients were included with a median age of 56 years (range 32-76 years) and 79% (n = 67) were male. Patients belonged to the following MSKCC risk categories: 11 (13%) good, 70 (82%) intermediate, and 4 (5%) poor risk. The mean total dose received was 1097 MIU (range: 160 – 3048 MIU). The prevalence of grade 3 AEs is presented in the table. Median survival of patients with ≥grade 3 rigors after HD IL-2 administration was 1501 days vs 533 days for those without (p = 0.0005, HR 2.54). Presence of rigors was also associated with a significant improvement in progression free survival, time to next treatment and response rates. No other AEs predicted response to HD IL-2. Conclusions: Presence of grade 3 rigors predicts improved survival during HD IL-2 therapy. Notably, grade 3 fever was rarely observed because of our institutional protocol of routinely using scheduled antipyretics to diminish fevers. [Table: see text]

A randomized phase II trial of pazopanib (PAZ) versus temsirolimus (TEM) in patients (pts) with advanced clear-cell renal cell carcinoma (aCCRCC) of intermediate and poor-risk (the TemPa trial).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 583-583 ◽  
Author(s):  
Nizar M. Tannir ◽  
Jeremy Aaron Ross ◽  
Catherine E Devine ◽  
Anuradha Chandramohan ◽  
Xuemei Wang ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Intermediate Risk ◽  
Cell Renal Cell Carcinoma ◽  
Exact Test ◽  
Poor Risk ◽  
Kaplan Meier ◽  
Alternative Agent ◽  
Treatment Naïve ◽  
To Receive

583 Background: TEM has level 1 evidence in aRCC with poor-risk disease. No trial compared a VEGFR-TKI with TEM as first-line (1L) therapy in this disease state. Methods: We randomly assigned (1:1) treatment-naïve pts with aCCRCC and > = 3 risk factors (as per Hudes et al., NEJM 2007) to receive PAZ 800 mg po qd or TEM 25 mg iv qw. Pts were offered to receive the alternative agent at disease progression (PD). The primary endpoint was progression-free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR) and safety. A blinded radiologist assessed the radiographic response using RECIST v1.1. A sample size of 90 pts was based on an assumption of improved median PFS from 3.8 mo with TEM to 6.1 mo with PAZ. Pts were stratified by prior nephrectomy (Nx). The Kaplan-Meier method was used for PFS and OS analysis, and the Fisher’s exact test was used for comparison of ORR between PAZ and TEM. Results: The study was closed to new patient enrollment when the results of the CheckMate 214 and CABOSUN studies were presented at ESMO 2017. A total of 69 pts were eligible and evaluable (median age 61, 52 males [75%], 44 [64%] had poor-risk by IMDC criteria). Thirty pts [43%] had prior Nx. Thirty-five pts received PAZ (intermediate-risk 13, poor-risk 22) and 34 pts received TEM (intermediate-risk 12, poor-risk 22). Of the 69 pts, 67 had PD or died. The median PFS was 5.2 mo (95% CI: 3.6 –7.4) for PAZ and 2.6 mo (95% CI: 1.9 –4.2) for TEM (p = 0.16). In 1 pt, no date of death was available. Of the remaining 68 pts, 58 (85.3%) have died. The median OS was 12.0 mo (95% CI: 8.3–20.1) for PAZ and 7.4 mo (95% CI: 5.3–17.4) for TEM (p = 0.61). Sixty-eight pts were evaluable for response: 9/35 pts (26%) who received PAZ and 2/33 pts (6%) who received TEM had partial response (p = 0.046). Adverse events (AEs) were consistent with the known safety profiles of PAZ and TEM. Only 2 pts in each arm discontinued treatment due to AEs. Conclusions: PAZ extended PFS and OS and yielded a significantly higher ORR than TEM as 1L therapy in pts with aCCRCC and intermediate/poor-risk disease. Clinical trial information: NCT01392183.

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.

Efficacy and safety of zanubrutinib versus rituximab-based chemoimmunotherapy in Waldenström macroglobulinemia (WM): Matching-adjusted indirect comparisons.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7559-7559
Author(s):  
Jorge J. Castillo ◽  
Keri Yang ◽  
Rongzhe Liu ◽  
Yu Wang ◽  
Aileen Cohen ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Weighted Average ◽  
Hemoglobin Concentration ◽  
Progression Free Survival ◽  
Patient Characteristics ◽  
Cox Proportional Hazards ◽  
International Prognostic Scoring System ◽  
Cox Proportional Hazards Models ◽  
Treatment Naïve ◽  
Indirect Comparisons

7559 Background: Given a lack of WM randomized trials directly comparing zanubrutinib with chemoimmunotherapy, this study aimed to indirectly compare zanubrutinib with bendamustine-rituximab (BR) and with dexamethasone-rituximab-cyclophosphamide (DRC) separately through matching-adjusted indirect comparisons (MAIC). Methods: MAIC were conducted to re-weight the individual data of 102 WM patients (83 relapsed/refractory [R/R] and 19 treatment-naïve [TN]) treated with zanubrutinib in the ASPEN trial (NCT03053440) so that the weighted average baseline characteristics of patients treated with zanubrutinib matched those of 71 R/R patients treated with BR, and 72 TN patients treated with DRC separately. Matching variables for MAIC with BR included age, prior lines of therapy, IgM concentration, International Prognostic Scoring System for WM score, and extramedullary disease (EMD); and for MAIC with DRC included age, platelet count, hemoglobin concentration, and EMD. Kaplan-Meier curves of progression-free survival (PFS) and overall survival (OS) of comparators were digitized to re-create patient-level data. Comparisons of survival and adverse event incidence between treatments were conducted using Cox proportional hazards models and modified Poisson models. Results: Compared to DRC, zanubrutinib was associated with longer PFS (hazard ratio [HR]: 0.39 [95% confidence interval 0.18-0.82] and 0.35 [0.14-0.86] pre- and post-matching, respectively) and longer OS (HR: 0.56 [0.20-1.53] and 0.47 [0.14-1.62] pre- and post-matching, respectively), and insignificantly higher incidences of neutropenia (risk ratio [RR]: 1.63 [0.71-3.77] and 1.47 [0.58-3.74] pre- and post-matching, respectively). Compared to BR, zanubrutinib was associated with longer PFS (HR: 0.32 [0.15-0.69] and 0.37 [0.15-0.91] pre- and post-matching, respectively), longer OS (HR: 0.31 [0.12, 0.80] and 0.29 [0.10-0.85] pre- and post-matching, respectively), lower incidences of neutropenia (RR: 0.45 [0.26-0.78] and 0.50 [0.27-0.91] pre- and post-matching, respectively) and lower incidences of pneumonia (RR: 0.18 [0.02-1.55] and 0.26 [0.03-2.28] pre- and post-matching, respectively). Conclusions: Zanubrutinib demonstrated longer PFS than DRC, and longer PFS and OS than BR in WM, before and after matching adjustment based on patient characteristics. [Table: see text]

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]

Impact of lenvatinib (LEN) dose-intensity and starting dose on survival among patients with advanced hepatocellular carcinoma (HCC): Results from a Canadian multicenter database (HCC CHORD).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16142-e16142
Author(s):  
Carla Pires Amaro ◽  
Michael J Allen ◽  
Jennifer J. Knox ◽  
Erica S. Tsang ◽  
Howard John Lim ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Objective Response ◽  
Dose Intensity ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Advanced Hepatocellular Carcinoma ◽  
First Line ◽  
Cox Proportional Hazards Models ◽  
Starting Dose ◽  
Localized Treatment

e16142 Background: The REFLECT trial established LEN as a first-line treatment option for HCC. However, decreased LEN exposure is common due to adverse events leading to dose reductions and treatment discontinuations. The aim of this study was to evaluate whether starting dose or dose-intensity of LEN affects survival. To our knowledge, this is the first study to examine dosing of LEN and survival in HCC patients treated outside of Asia. Methods: From July 2018 to December 2019, HCC patients treated with first-line LEN from 10 different Canadian cancer centers were included. Overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and objective response rate (ORR) were retrospectively analyzed and compared across different mean dose-intensities (> 66.7% vs <=66.7%) and starting dose groups (Full vs reduced). Survival outcomes were assessed with Kaplan-Meier curves and Cox proportional hazards models. DCR and ORR were determined radiographically according to the treating physician´s assessment in clinical notes and not RECIST 1.1 or mRECIST. Results: A total of 173 patients were included. Median age was 67 years, 77% were men and 23% East Asian. The most frequent causes of liver disease were hepatitis C (38%) and B (20%). 56% of patients received localized treatment prior to LEN. Of those, 24% had TACE, 6% TARE and 8% had liver transplant. Before starting LEN 31% of patients were ECOG 0 and 57% were ECOG 1. Most patients were Child-Pugh A (81%) and BCLC stage C (73%). Main portal vein invasion was present in 15% of the patients. Median follow-up was 4.5 months. LEN was started at full dose in 54% of patients and 60% had a mean dose intensity greater than 66.7%. ORR, PFS and OS results and their comparison between the different starting dose and dose-intensities are shown in the table. In a multivariate model that adjusted for age, gender, stage, ECOG, Child-Pugh, BCLC, cirrhosis, liver etiology disease (hepatitis B, C and non-viral), presence of tumor thrombus, prior transplant and localized treatment, dose intensity (>66.7 vs <=66.7% [HR 0.70, 95% CI 0.42-1.18; p=0.18]) was not a predictor of survival. Conclusions: In HCC patients starting LEN at a reduced dose does not appear to compromise survival. LEN dose-intensity of > 66.7% was associated with improved survival, but not after controlling for potential confounders.[Table: see text]

Circulating tumor DNA fraction (ctDNA%) to independently predict for clinical outcomes in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5049-5049
Author(s):  
Corinne Maurice-Dror ◽  
Nicolette Fonseca ◽  
Cameron Herberts ◽  
William Fan ◽  
Alexander W. Wyatt ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Proportional Hazards ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Cox Proportional Hazards ◽  
Castration Resistant Prostate Cancer ◽  
Prognostic Information ◽  
Kaplan Meier ◽  
Treatment Naïve ◽  
Ecog Ps

5049 Background: CtDNA% (the tumour-derived proportion of cell-free DNA (cfDNA)) is abundant in >60% of mCRPC pts and associates with adverse clinical prognostic factors. However, prognostic associations have not been comprehensively tested across clinical contexts. We evaluated the utility of ctDNA% as an independent prognostic biomarker in patients with mCRPC prior to first-line (1L) therapy. Methods: 410 treatment-naïve mCRPC pts had blood samples drawn prior to 1L therapy and followed prospectively for outcomes. Plasma cfDNA was subjected to deep targeted sequencing and ctDNA% was calculated using validated methods ( Annala, Cancer Discov, 2018 ). Overall survival (OS), PSA progression free survival (PSA PFS) and PSA declines ≥50% from baseline (PSA50 response rate (RR)) were stratified by ctDNA% and compared using Kaplan-Meier and Cox proportional hazards analysis. Results: Median age was 73 yrs. (range 45-98), the majority of pts had ECOG PS 0-1 (78%) and 9.5% had liver metastases at baseline. The most common 1L therapy employed was androgen receptor pathway inhibitors (90%). Median follow-up was 21 mo. (range 1-75) and median ctDNA% was 4.9% (range: 0-89%). Stratifying patients into high ctDNA (>30%) and Low ctDNA (≤2%) groups showed stronger association with OS and PSA PFS than grouping by median (Table). In a univariate comparison to pts with low ctDNA (≤2%), pts with high ctDNA% (>30%) had significantly shorter median PSA PFS, median OS and a lower PSA50 RR (Table). In a multivariable adjustment for clinical prognostic factors and cfDNA concentration, high ctDNA% remained strongly associated with OS (HR= 3.3, 95%CI: 2.1-5.3, p<0.001) and PSA PFS (HR: 3.7, 95%CI: 2.4-5.9, p<0.001). Although ctDNA% and total cfDNA concentration were correlated (R2=0.55), association with OS was stronger for ctDNA% than cfDNA concentration (stratified at median; HR: 2.9 (2.3-3.7), p<0.001 vs HR: 2.1 (1.7-2.6), p<0.001). Conclusions: In a large cohort of treatment-naïve mCRPC pts, ctDNA% prior to 1L treatment provided strong prognostic information independent of known clinical factors. These data further demonstrate the multipronged clinical utility of ctDNA-based profiling for actionable genomic alterations.[Table: see text]

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