Circulating mir-21 and mir-378 are predictive of progression-free survival (PFS) in patients treated with everolimus in metastatic renal cell cancer (mRCC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4617-4617
Author(s):  
James Lin Chen ◽  
Kimryn Rathmell ◽  
David F. McDermott ◽  
Walter Michael Stadler
Keyword(s):  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Clear Cell ◽  
Standard Dose ◽  
Cell Cancer ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Negative Control ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model

4617 Background: The oral mTOR inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and modestly delays RCC progression. We hypothesized that circulating microRNAs, which have been associated with renal cancer and inflammation, may serve as predictive biomarkers to help better define a population more sensitive to treatment. Methods: Plasma from mRCC pts refractory to VEGF inhibition were obtained prior to treatment with standard dose everolimus as part of a clinical trial examining FDG-PET as a potential predictive biomarker. As we were specifically interested in tumor response to drug, only pts who died, remained on trial, or had radiographic progression by RECIST criteria were profiled. Pts who were unable to tolerate drug were excluded. MicroRNAs were extracted and profiled without pre-amplification using Exiqon LNA PCR panels. Crossing point (Cp) values within 5 of the negative control were removed. MicroRNAs must have been present in >90% of samples and varied at least p > 0.10 from mean to be further analyzed. Cox-proportional hazards model and Kaplan-Meier analyses were performed. Results: 28 patients had available plasma and met criteria for profiling. Pt characteristics included: 20 (71%) clear cell histology, median age 57.7 (43 – 76), median number of prior systemic therapies 2 (1 – 3). 103 microRNAs were expressed in at least 90% of all samples. Mir-21 and mir-378 were independently correlated with PFS (FDR: 0.02 and 0.06, respectively). Low circulating plasma mir-21 and mir-378 levels resulted in a median PFS prolongation of 370d vs. 101d (p=0.027) and 368d vs. 106d (p=0.001). Analysis of the clear cell cohort for mir-21 and mir-378 also demonstrated a significant median PFS difference of 350d vs. 173d (p=0.045) and 345d vs. 147d (p=0.004). Conclusions: Elevated levels of circulating mir-21 and mir-378 have been associated with systemic inflammatory states, and in our study are correlated with decreased PFS in mRCC pts undergoing everolimus therapy. Further prospective studies will be required to validate these exploratory results for their potential role as prognostic or predictive biomarkers.

Correlation of survival with tumor histology, age, and prognostic risk group for previously untreated patients with advanced renal cell carcinoma (adv RCC) receiving temsirolimus (TEMSR) or interferon-alpha (IFN)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5033-5033 ◽  
Author(s):  
J. P. Dutcher ◽  
C. Szczylik ◽  
N. Tannir ◽  
P. Benedetto ◽  
P. Ruff ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Clear Cell ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Tumor Histology ◽  
Poor Risk ◽  
Hazards Model

5033 Background: Temsirolimus is a novel mTOR inhibitor and has demonstrated significantly longer overall survival (OS, P=0.0069) and progression-free survival (PFS, P=0.0001) vs IFN for patients (pts) with previously untreated adv RCC with poor-risk features (Hudes et al. ASCO 2006). Planned and post-hoc analyses were performed to assess the influence of tumor histology (clear- cell vs other), age (<65 y vs =65 y), and prognostic-risk groups (intermediate vs poor; Motzer et al. JCO 20:289) on survival in pts treated with TEMSR or IFN. Methods: Pts received IFN 3 million units [MU] subcutaneously 3x weekly, escalating to 18 MU; TEMSR 25-mg intravenous infusion weekly; or TEMSR 15-mg infusion plus IFN 6 MU. Kaplan-Meier analysis and a Cox proportional hazards model were used to analyze OS and PFS for pt subsets. Histologies were reported by investigators. Results: The proportion of pts with different histologies was balanced across the 2 arms (81% clear-cell; 13% indeterminate, 6% non-clear-cell). Of those with additional subtype data, 75% were papillary. For pts with clear-cell tumors, median OS and PFS were longer for TEMSR vs IFN with hazard ratios (HR) of 0.82 and 0.76, respectively ( Table ). For pts with other tumor histologies, median OS and PFS also were longer for TEMSR vs IFN with HR of 0.49 and 0.38, respectively. Among pts <65 y, median OS and PFS were longer for TEMSR than for IFN (OS: TEMSR [n=145] 12.0 mo; IFN [n=142] 6.9 mo; HR=0.62 [95% CI, 0.47, 0.82]; PFS: TEMSR 5.6 mo; IFN 3.1 mo; HR=0.61 [0.47, 0.79]). There was no difference in OS or PFS for pts =65 y treated with TEMSR or IFN but TEMSR had a better side effect profile than IFN. OS and PFS for pts with intermediate- or poor-risk features will be reported. Conclusions: TEMSR benefits pts with clear-cell RCC and other histologies as well as younger and older pts. [Table: see text] No significant financial relationships to disclose.

Plasma VEGF-A (pVEGF-A) level in efficacy analysis of metastatic colorectal cancer patients (mCRC) treated with mFOLFOX6/XELOX plus bevacizumab (BV) (WJOG7612GTR).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 699-699
Author(s):  
Wataru Okamoto ◽  
Akitaka Makiyama ◽  
Yoshiyuki Yamamoto ◽  
Kohei Shitara ◽  
Tadamichi Denda ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Progression Free Survival ◽  
Predictive Marker ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Enzyme Linked Immunosorbent Assay ◽  
Negative Results

699 Background: Plasma levels of VEGF-A short isoforms (VEGF-A110 and -A121) measured by immunological multiparametric chip technique (IMPACT) were reported to be associated with clinical benefits from bevacizumab (BV) in advanced gastric and pancreatic cancer but not in metastatic colorectal cancer (mCRC). Negative results in mCRC studies might be caused by different sample handling: citrate instead of EDTA and repetition of freeze/thaw. Methods: Blood samples were collected in EDTA before the first-line treatment with BV+mFOLFOX6 or +XELOX for mCRC. Plasma samples were analyzed at Roche Diagnostics Ltd. (Penzberg, Germany) using IMPACT-2 (Roche proprietary multiplex enzyme-linked immunosorbent assay platform). A median value of pVEGF-A was used as a cut-off point to categorize patients (pts) into the low and high pVEGF-A groups. Progression free survival (PFS) and overall survival (OS) between the low and high pVEGF-A groups were compared, using Cox proportional hazards model. We hypothesized that BV-containing treatment extend shorter PFS of pts with high pVEGF-A to that with low pVEGF-A, and estimated a threshold hazard ratio (HR) between them as below 1.15. Results: Among 102 pts enrolled between January 2014 and April 2015, 100 (53 BV+mFOLFOX6 and 47 BV+XELOX) were eligible. Median PFS was 11.4 months [95% CI, 9.5-13.0] and response rate was 64.6 % [range, 53.3-74.9]. pVEGF-A was measured in 97 pts and the median value was 36.8 pg/ml [range, 6.5- 262.2]. The hazard ratios of PFS and OS between the high and low pVEGF-A groups were 1.23 [95%CI, 0.76-1.97, p = 0.40] and 2.47 [95%CI, 1.14-5.36, p = 0.02], respectively. Conclusions: mCRC pts with high pVEGF-A showed shorter PFS than those with low pVEGF-A beyond the predefined threshold (HR 1.15) in BV-containing chemotherapy, suggesting that pVEGF-A could not be a predictive marker for BV efficacy. Clinical trial information: UMIN000012442.

ColotypeR gene signature predicts response to cetuximab in colorectal cancer metastases.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 599-599
Author(s):  
Steven Allen Buechler ◽  
Yesim Gokmen-Polar ◽  
Sunil S. Badve
Keyword(s):  
Colorectal Cancer ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Hazard Ratio ◽  
Cox Proportional Hazards Model ◽  
Response To Treatment ◽  
Molecular Characteristics ◽  
Wild Type

599 Background: The consensus molecular subtypes (CMS1-4) partition primary colorectal cancer (CRC) into subgroups with distinct molecular characteristics. We previously reported a 20-genes ColotypeR-CMS signature that accurately defines CMS subtypes for primary CRC tumor samples. The utility of CMS subtyping in defining response to treatment of CRC metastases remains to be established. Here, we report the ability of ColotypeR scores to predict differential response to cetuximab among CMS subtypes in CRC metastases. Methods: The role of ColotypeR-CMS signature scores was assessed in CRC metastasis samples (GSE5851, N = 68, Affymetrix microarray) in predicting response to cetuximab. Progression-free survival (PFS) was the primary endpoint. The predictive significance of ColotypeR-CMS scores relative to KRAS mutation status was also studied using multivariate Cox proportional hazards models. Results: ColotypeR-CMS scores were computed in GSE5851 using the algorithm developed in primary tumor samples. Higher values of ColotypeR-CMS CMS2 score were significantly predictive of longer PFS (p = 5 x 10-5for the score test in Cox proportional hazards model; hazard ratio 0.20 (95%CI 0.09-0.44) in CRC metastases samples (GSE5851, N = 68) treated with cetuximab. PFS was independent of CMS1,3, 4 scores. KRAS wild type tumors had significantly longer PFS (p = 0.01; hazard ratio 0.49 (95%CI 0.28-0.86). In multivariate survival analysis, ColotypeR-CMS CMS2 score added to the significance of KRAS status (p = 0.012) and ColotypeR-CMS CMS2 score was predictive of longer PFS in KRAS wild type tumors (p = 0.009; hazard ratio 0.20 (95%CI 0.06-0.69)). Conclusions: We showed that in CRC metastasis samples, the ColotypeR CMS2 score was highly predictive of sensitivity to cetuximab treatment, while no increase in PFS was observed for higher values of CMS1, 3, 4 scores.

Prognostic factors for overall survival with sunitinib as first-line therapy in patients with metastatic renal cell carcinoma (mRCC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 5042-5042
Author(s):  
S. Patil ◽  
R. A. Figlin ◽  
T. E. Hutson ◽  
M. D. Michaelson ◽  
S. Négrier ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Rank Test ◽  
Type I ◽  
First Line

5042 Background: Sunitinib demonstrated superior progression-free survival (PFS; the primary endpoint) over interferon-alfa (IFN-α) as first-line mRCC therapy (NEJM 2007;356:115). Median overall survival (OS) with sunitinib compared to IFN-α was: 26.4 vs. 21.8 months (HR=0.821; P=0.051 by unstratified log-rank test; Proc ASCO 2008;26, May 20 suppl; abstr 5024). An analysis of prognostic factors for OS was performed on data from this trial. Methods: 750 treatment-naïve mRCC patients were randomized 1:1 to receive sunitinib or IFN-α. By Cox proportional hazards model, selected pretreatment variables were evaluated univariately and in a multivariate model for each treatment arm. Multivariate models for each treatment arm were based on a stepwise algorithm with a type I error of 0.25 for entry and 0.15 for elimination. Further elimination was applied to identify variables significant at P<0.05. Results: In multivariate analysis of sunitinib patients, factors associated with longer OS include: interval from diagnosis to treatment ≥1 yr, ECOG PS of 0, lower corrected calcium, absence of bone metastases, lower lactic dehydrogenase (LDH), and higher hemoglobin (Hgb) ( table ). For the IFN-α treatment arm, male gender, absence of bone or lymph node metastases, lower LDH, higher Hgb, lower corrected calcium, higher neutrophil count, and interval from diagnosis to treatment ≥1 yr were associated with longer OS. Conclusions: For patients in the sunitinib treatment arm, prognostic factors identified were similar to the factors previously identified in the MSKCC risk groups (J Clin Oncol 2002;20:289). Additional prognostic factors were identified for the IFN-α arm. Further studies are warranted to independently validate these findings as well as to identify tumor-specific prognostic factors. [Table: see text] [Table: see text]

Association of morphologic response with progression free survival in patients with metastatic colorectal cancer treated with bevacizumab-based chemotherapy: HGCSG0802.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 743-743
Author(s):  
Satoshi Yuki ◽  
Hiroshi Nakatsumi ◽  
Hideyuki Hayashi ◽  
Hiraku Fukushima ◽  
Takashi Kato ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Rank Test ◽  
First Line ◽  
Free Survival ◽  
Contrast Enhanced Ct ◽  
Morphologic Response

743 Background: It was reported that an optimal morphologic response to preoperative chemotherapy was associated with better overall survival (OS) in patients (pts) with colorectal liver metastases (CLM). We investigated association of morphologic response with progression free survival (PFS) in pts with unresectable CLM from HGCSG0802 observational cohort study in pts with mCRC treated with first-line bevacizumab (BV)-based chemotherapy. Methods: The objective of HGCSG0802 was to evaluate PFS, OS, time to treatment failure (TTF), response rate (RR), safety, etc. The key eligibility criteria were evaluable lesions, older than 20 years old, ECOG PS 0-2. Pts with CLM underwent contrast-enhanced CT at the start and every 8-weeks of BV-based chemotherapy. In this analysis, three blinded, independent radiologists evaluated images for morphologic response, based on metastases changing from heterogeneous masses with ill-defined margins into homogeneous hypoattenuating lesions with sharp borders. Association of morphologic response and pts characteristics, RR, and PFS were evaluated. PFS was analyzed with Kaplan-Meier method, log-rank test, and Cox proportional hazards model. Results: Of 108 pts (the full analysis set), 73 pts with CLM were evaluable for morphologic criteria. Eighteen pts (24.7%) had optimal morphologic response (OR), 31 (42.5%) had incomplete (IR), and 24 (32.9%) had no response (NR). The pts characteristics between those with OR, IR and NR were generally balanced. The median TTF was 7.2 months in NR versus 7.2 months in IR versus 6.8 months in OR (HR (OR/NR) = 0.91, HR (OR/IR) = 0.90; p = 0.93). RR was 77.8% in OR versus 64.5% in IR and 58.3% in NR (p = 0.528). The median PFS was 8.3 months in NR versus 8.5 months in IR versus 9.1 months in OR (HR (OR/NR) = 0.72, HR (OR/IR) = 1.04; p = 0.420). Conclusions: In this analysis, morphologic response might not be a prognostic marker in first-line BV-based chemotherapy in pts with CLM.

A multivariate analysis of prognostic factors from assure (E2805): Adjuvant sorafenib or sunitinib for unfavorable renal carcinoma.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 618-618
Author(s):  
Naomi B. Haas ◽  
Judith Manola ◽  
Robert G. Uzzo ◽  
Keith Flaherty ◽  
Michael Pins ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Clear Cell ◽  
Locally Advanced ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Risk Category ◽  
Fuhrman Grade ◽  
Hazards Model ◽  
Postoperative Setting

618 Background: Previous post-surgical prognostic nomograms for clear cell RCC are based upon TNM stage, PS, Fuhrman grade, and sometimes presence of necrosis. 1943 patients (pts) with locally advanced renal cell carcinoma (RCC) participated in the ASSURE trial of one year of sunitinib daily for 4 wks of a 6 wk cycle, sorafenib daily, or placebo, then treated for up to 9 cycles. Of these, 1541 pts had clear cell predominant features. There were no significant differences in DFS (median 5.7 years) between either of the experimental arms and placebo, in the total or clear cell population. We investigated site-reported clinical and surgical factors associated with prolonged DFS. Methods: Patients were staged according to the AJCC 2007 version. Factors considered in addition to those in the final model shown below were age, race/ethnicity, histology, risk category and PS as stratified, and 10 other specific baseline symptoms. A Cox proportional hazards model was built including factors that significantly changed the -2 log likelihood ratio (Collett). Results: Shorter DFS was associated with higher age, stage and Fuhrman grade, male sex, PS > 0, open vs. laparoscopic surgical approach, low hemoglobin and diagnosis based on presence of symptoms. Conclusions: The association of stage, grade, age, and PS with outcome confirms previous analyses in resectable disease. The same factors which predict outcome in metastatic disease now clearly confer relapse risk in the postoperative setting. Clinical trial information: NCT00326898. [Table: see text]

Tandem high-dose chemotherapy and autologous hematopoietic stem cell transplantation (SCT) compared to single SCT for relapsed/refractory germ cell tumors (GCT).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 572-572
Author(s):  
Deepak Kilari ◽  
Parameswaran Hari ◽  
Muna Qayed ◽  
Raphael Fraser ◽  
Omar Davila ◽  
...  
Keyword(s):  
Cell Transplantation ◽  
Hematopoietic Cell Transplantation ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Germ Cell Tumors ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
High Dose ◽  
Hematopoietic Stem

572 Background: Single-center observational studies have established the use of single or tandem SCT to salvage relapsed GCT but randomized trials are lacking. We analyzed outcomes and prognostic factors in 2,395 male SCT recipients for relapsed GCT between 1990 and 2015. Methods: Recipients of single or tandem SCT reported to the Center for International Blood and Marrow Transplant Research were identified. Outcomes were compared by SCT year: 1990-94 (N = 288), 1995-99 (N = 351), 2000-04 (N = 376), 2005-09 (N = 509) and 2010-15 (N = 871). A recent subset (n = 267, 2000-2015) with detailed disease- and transplant-related data was further analyzed with a multivariate (MVA) Cox proportional hazards model. Results: Median age at SCT was 31 (11-76) years and 49% received SCT within 12 months of diagnosis consistent with early relapse/primary refractory GCT. 26% had primary extragonadal GCT; 1,167 (49%) had intent to tandem transplant (TT). The median follow up was 51 (3-313) months. Day 100 non-relapse mortality was statistically similar at 8% in 1990-94 (vs. 4% in 2010-15) but 3-year progression-free survival (PFS) improved from 24 (18-31)% in 1990-94 to 47 (43-50)% in 2010-15 (p < 0.0001) and 3-year survival (OS) from 35 (29-40)% to 54 (50-57)% in 2010-15 (p < 0.0001). Compared with single SCT, TT recipients were younger 31 (16-62) vs 34 (13-76), with lower Hematopoietic Cell Transplantation-Comorbidity Index, more likely to undergo SCT after 1 line of chemotherapy (28% vs 9%), and within 1 year of diagnosis (51% vs 38%). TT was preferred over single SCT over time (48% of SCT were TT in 2000-04 vs. 81% in 2010-15). In MVA, non-seminoma histology, residual tumor at SCT, receipt of > 1 line of pre-SCT chemotherapy and single SCT (vs. TT), were associated with worse PFS and OS. Year of SCT was not significant when adjusted for these covariates. Conclusions: In this large longitudinal cohort, improvements in PFS and OS were observed in recent years. SCT earlier in disease course and tandem SCT were associated with superior outcomes. These data involving a large cohort reported from 225 centers confirm specialized centers’ date in a real-world setting.

Alpelisib (ALP) with fulvestrant (FUL) in patients (pts) with PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC): Primary or secondary resistance to prior endocrine therapy (ET) in the SOLAR-1 trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 1038-1038
Author(s):  
Dejan Juric ◽  
Sibylle Loibl ◽  
Fabrice Andre ◽  
J. Ignacio Delgado Mingorance ◽  
Frederic Forget ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Pik3ca Mutation ◽  
Progression Free Survival ◽  
Pi3k Pathway ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Double Blind Study ◽  
Double Blind ◽  
Secondary Resistance

1038 Background: A contributor to ETR, phosphatidylinositol 3-kinase (PI3K) pathway hyperactivation can result from mutations to PIK3CA; ~40% of pts with HR+, HER2– ABC exhibit tumors with this mutation. Use of the oral α-specific PI3K inhibitor ALP + FUL significantly improved progression-free survival (PFS) in pts with a PIK3CA mutation (HR 0.65; 95% CI, 0.50-0.85; P<0.001) in SOLAR-1, which included both ET sensitive (ETS) and ETR pts (Table). ETS pts were later excluded by a protocol amendment. ETR was further defined as primary (1R) or secondary (2R) per ESMO criteria in both 1L and 2L pts. This subgroup analysis evaluated pts with a PIK3CA mutation based on tx line and endocrine status. Methods: SOLAR-1 was a phase 3, randomized, double-blind study of ALP 300 mg QD or PBO Q28d + FUL 500 mg Q28d + C1d15 in men and postmenopausal women with HR+, HER2– ABC whose disease progressed on/after an aromatase inhibitor. PFS was estimated by Kaplan-Meier method and median PFS (mPFS) presented by tx arm. A stratified Cox proportional hazards model estimated HR and 2-sided 95% CI. Results: Of 341 pts in the PIK3CA mutant cohort, 39 (11%) were ETS; 302 (89%) were ETR. mPFS in the ALP vs PBO arms was 22.1 vs 19.1 mo (HR 0.87; 95% CI, 0.35-2.17) for ETS pts and 9.4 vs 4.2 mo (HR 0.64; 95% CI, 0.48-0.84) for ETR pts. For ETR pts, mPFS for 1L (n=138) was 9.0 vs 4.7 mo (HR 0.69; 95% CI, 0.46-1.05) and for 2L (n=161) was 10.9 vs 3.7 mo (HR 0.61; 95% CI, 0.42-0.89). Conclusions: In SOLAR-1, mPFS was improved with ALP + FUL vs PBO + FUL across ETR pts in 1L and 2L. Representation of ETS pts was low in SOLAR-1, which included more ETR pts. Analysis of the PI3K pathway in ETS pts is warranted in future studies. Clinical trial information: NCT02437318. [Table: see text]

Molecular determinants of outcome for metastatic castration-sensitive prostate cancer (mCSPC) with addition of apalutamide (APA) or placebo (PBO) to androgen deprivation therapy (ADT) in TITAN.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5535-5535 ◽  
Author(s):  
Felix Y Feng ◽  
Shibu Thomas ◽  
Clemente Aguilar-Bonavides ◽  
Michael Gormley ◽  
Neeraj Agarwal ◽  
...  
Keyword(s):  
High Risk ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Molecular Subtypes ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
P Value ◽  
Average Risk ◽  
Luminal A

5535 Background: In TITAN, addition of APA to ADT improved radiographic progression-free survival (rPFS) and overall survival (OS) versus PBO plus ADT in patients (pts) with mCSPC. In this post hoc analysis, we performed transcriptome-wide profiling of tumor samples and assessed association of molecular subtypes with rPFS. Methods: The DECIPHER platform (Decipher Biosciences, Inc.) was used to assess gene expression in archival primary prostate tumors from TITAN. Samples were classified into high versus low to average risk of metastases (DECIPHER genomic classifier [GC] > 0.6 and ≤ 0.6, respectively), basal and luminal A/B (PAM50 classifier), and androgen receptor activity (AR-A) signature high and low. Associations between subtypes with rPFS were assessed with Cox proportional hazards model. Results: The biomarker population included 222 pts (APA, 110; PBO, 112). Benefit in rPFS from APA in the biomarker population (HR [95% CI]; p value; 0.49 [0.31-0.78]; 0.002) resembled that in the overall study population (0.49 [0.40-0.61]; < 0.0001). The majority of TITAN pts had GC high scores (n = 166, 75%). GC high risk subtype in the PBO group had poorer prognosis for rPFS than GC low to average risk subtype (median rPFS 18.2 mos for GC high vs not reached [NR] for GC low to average, 0.28 [0.11-0.69]; 0.006), but there was no difference in prognosis between high and low to average GC risk subtypes in the APA group (GC high NR vs GC low to average NR; 0.81 [0.35-1.89]; 0.625). Pts were further stratified based on basal/luminal and AR-A signatures. Basal (n = 112, 50%) and AR-A low (n = 96, 43%) subtypes, known to be nonresponsive to ADT, both showed significant benefit from APA vs PBO (0.30 [0.16-0.57]; < 0.001 and 0.25 [0.12-0.52]; < 0.001, respectively). The majority of AR-A low subtype (74%, 71/96) overlapped with basal subtype. Further conclusions for risk of rPFS in GC low, luminal, and AR-A high subtypes and OS across all subtypes will be assessed as more events occur. Conclusions: In TITAN, addition of APA to ADT improved rPFS for all subtypes of pts with mCSPC. APA overcame the poor prognosis of GC high risk subtype and prolonged rPFS in ADT-resistant AR-A low and basal molecular subtypes, suggesting APA is beneficial especially for the highest risk molecular subtypes. Clinical trial information: NCT02489318 .

Early carcinoembryonic antigen (CEA) dynamics to predict fruquintinib efficacy in FRESCO, a 3+ line metastatic colorectal carcinoma (mCRC) phase III trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16001-e16001
Author(s):  
Yuxian Bai ◽  
Shukui Qin ◽  
Jin Li ◽  
Yanhong Deng ◽  
Lei Yang ◽  
...  
Keyword(s):  
Placebo Group ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Phase Iii ◽  
Rank Test ◽  
P Value ◽  
Radiological Evaluation

e16001 Background: The FRESCO phase 3 trial demonstrated a significant survival benefit with fruquintinib vs. placebo in the third-line or later therapy of mCRC patients. CEA levels are widely used in conjunction with imaging to monitor response to systemic therapy in patients with mCRC. Herein, we undertook post-hoc analyses of FRESCO patient data to investigate the early changes in CEA during treatment, as well as potential relationships with efficacy parameters. Methods: Patients were included if baseline CEA was abnormal according to local lab reference range. Serum CEA levels were measured at baseline and Day 1 of each cycle (except for Cycle 1). Early CEA change was analyzed at first radiological evaluation (C3D1, Week 8), CEA response was defined as ≥ 50% decrease from baseline, and CEA progression was defined as ≥ 100% increase from baseline. Overall survival (OS) and progression-free survival (PFS) were evaluated by Kaplan-Meier method; hazard ratio (HR) was estimated through Cox proportional hazards model; p-value was generated from log rank test. Results: 88.4% (245/277) and 94.9% (130/137) of patients had an abnormal baseline CEA in the fruquintinib group and placebo group, respectively. Median baseline CEA values were similar between treatment groups. After 2 cycles of treatment, the proportion of patients had CEA response was significantly higher in the fruquintinib group than placebo group (30.0% vs. 1.3%, p < 0.001). In the fruquintinib group, patients with early CEA response (n = 63) had longer median OS (12.8 vs. 7.8 months, HR = 0.45, p < 0.001) and median PFS (5.6 vs. 3.7 months, HR = 0.49, p < 0.001) than patients without (n = 147). 66.7% (140/210) of patients in fruquintinib group had stable disease (SD), and fruquintinib in those patients with concomitant CEA response exhibited a significantly greater OS benefit than with CEA progression (14.4 vs. 8.7 months, HR = 0.38, p = 0.004). Conclusions: Fruquintinib increased early CEA response. CEA response at first radiological evaluation after cycle 2 could be considered as a predictor for better OS and PFS. Among patients with SD at first evaluation, those with CEA response seems benefit more from fruquintinib. Clinical trial information: NCT02314819 .

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